CN103191120B - A kind of pyrimidine derivatives preparation prevent and/or treat and/or adjuvant therapy of tumors medicine in purposes - Google Patents
A kind of pyrimidine derivatives preparation prevent and/or treat and/or adjuvant therapy of tumors medicine in purposes Download PDFInfo
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Abstract
The invention discloses a kind of pyrimidine derivatives preparation prevent and/or treat and/or adjuvant therapy of tumors medicine in purposes.This pyrimidine derivatives comprise there is structural formula (I) pyrimidine compound, its pharmaceutically acceptable salt, solvate, polymorph, tautomer, prodrug, or the compositions containing pyrimidine compound, structural formula (I) is as follows:
pass through in 2,4,6-positions of pyrimidine ring in the present invention, carry out different C-N couplings respectively, introduce different pharmacophore, form the new pyrimidine derivatives with Aurora kinase inhibitory activity, this pyrimidine derivatives can be prepared into and can prevent and/or treat and/or the medicine of auxiliary for treating cancer.
Description
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 adjuvant therapy of tumors medicine in purposes.
Background technology
Aurora A is the serine/threonine kinase that a class has important regulating and controlling effect in cell growth cycle, participates in regulating spindle formation, centrosome maturation, chromosome differentiation and cytokinesis process, has pivotal role to the genomic stability of maintenance.Research finds, the overexpression of Aurora A easily causes cell mitogen abnormal, closely related with the formation of tumor.Aurora A overexpression in many cancerous cell (as pulmonary carcinoma, breast carcinoma, rectal cancer, thyroid carcinoma, cancer of pancreas), suppresses the activity of Aurora A can cause the gathering of tumor cell polyploid, promotes apoptosis, blocks cell proliferation.Be that the research and development that target spot carries out antitumor drug are also more and more subject to people's attention with Aurora A.Aurora A inhibitor belongs to anti-tumor drugs targeting, compared with other non-specific cell cytotoxic drug, will have larger advantage.
According to the difference of aminoacid sequence, mankind's Aurora A is divided into AuroraA, AuroraB and AuroraC tri-kinds of hypotypes.These three kinds of hypotypes have very conservative C-and hold catalytic domain and N-to hold variable region, namely have the ATP-binding site (C-holds catalytic domain) of very high homology, but have larger difference on the amino acid length and sequence of N-end.
Wherein AuroraA is positioned at the centrosome and mitotic spindle two ends that copy, regulates the maturation of centrosome, the assembling of spindle and mitotic start-up course.AuroraA can the regulatory factor Cdc25b of phosphorylation cell periodic protein B 1-Cdk1, regulates the start-up course of cell mitogen after activation Cdc25b.AuroraA is also by participating in adjustment three kinds of centrosome protein, i.e. centrosome protein (centrosomin, CNN), acid coiled-coil protein (trans-formingacidiccoiled-coilprotein is transformed, TACC) and spindle deficiency albumen (spindledefective-2, SPD-2) ensure the maturation of centrosome in a fission process.
After scientist in 1998 confirms that the generation of tumor and the overexpression of Aurora A have substantial connection, academia and pharmaceuticals industry circle are caused using the research boom of Aurora A as antitumor drug action target spot.The application of the deep and computer modeling technique studied along with Aurora A crystal structure, it is found that the Aurora A inhibitor of great majority synthesis belongs to ATP(adenosine triphosphate) competitive inhibitors of kinases, the kinase whose ATP-binding site of competition binding, cut off the direct energy source of kinases, thus suppress it active.
Research finds, the purine ring in ATP structure can be incorporated into the hydrophobic pocket of Aurora A structure, and forms hydrogen bond with the amino acid residue of bonding pad.ATP binding pocket is made up of following region: kinases hinge region, hydrophobic pocket land, phosphate ditch buried district, solvent can and district and ribose moieties.
Aurora A family ATP-binding site has very high homology, and this makes the selectivity of inhibitors of kinases become a very large challenge.The Aurora A inhibitor of many reports still can embody good selectivity, one of them major reason is inhibitor except by except ATP-binding site and kinase interactions, also act on the region near ATP binding pocket, comprise the hydrophobic pocket at kinases rear portion, the difference of all these zone of action amino acid residues determines inhibitors of kinases optionally difference jointly.The basic structure feature of the inhibitors of kinases reported is: the heterocyclic system with a plane is with competition binding kinase whose ATP pocket and simulate adenine and kinase whose interaction; Also " Donor-Acceptor-Donor " binding mode is formed by hydrogen bond action between inhibitor and kinases hinge region; The functional group of inhibitor often can enter kinase phosphorylation salt binding region or selective binding pocket.From structure, the Aurora A inhibitor of synthesis is at present mainly pyrimidine lopps, pyrrolo-pyrazole class, indoles, quinazoline ditosylate salt, benzo nitrogen miazines and other Structure type compound.
Pyrimidines is the Aurora A inhibitor reported 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-base)-2-phenylquinazoline-4-amine compound crystal structure.Point out in patent, two atom N on this complex pyrazole ring and kinase whose hinge region form hydrogen bond action, in kinase whose glycine rich region, have π-π to interact between kinases and the phenyl ring of this complex.The achievement in research of Vertex company is that follow-up appropriate design Aurora A inhibitor is laid a good foundation.In patent WO03092607A2, structural formula of compound is as follows:
Vertex company and Merck (Merck) company have developed jointly first Aurora A inhibitor VX-680(and have had another name called MK-0457) (WO2004000833A1).This molecular structure is Y shape, and the pyrimidine ring at center is positioned at kinase whose hydrophobic region, and has hydrophobic interaction between kinase amino acid residue; Arm containing amino-pyrazol stretches into kinase whose hinge area, and nitrogen-atoms and the hinge region amino acid residue of pyrazole ring have hydrogen bond action; Arm containing phenyl stretches in kinase active site pocket, and the cyclopropyl of phenyl end and the kinase whose F275 residue of AuroraA have hydrophobic interaction; Piperazine sidechain then by the active region of enzyme be stretched over enzyme solvent can and district.Research finds, VX-680 has good inhibitory action to AuroraA, B and C, 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 studies, and was mainly used in treating obstinate chronic lymphocytic leukemia and acute lymphatic leukemia.Research finds the QTc of patient can be caused to extend risk by this medicine, and (QTc is the time difference between T ripple and Q ripple that electrocardiogram corrects, QTc prolongation easily causes arrhythmia), in November, 2007, Merck terminated the II clinical trial phase (ExpertOpin.InvestingDrugs.2009 of VX-680,18,379).
Although there is the compound inhibited to Aurora A that some are similar to VX-680 in prior art, but still need that further research has the inhibiting compound of Aurora A more, be suitable for prevent and/or treat and/or the needs of 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 adjuvant therapy of tumors medicine in purposes, a kind of pyrimidine derivatives with new construction is made for 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 adjuvant therapy of tumors medicine in purposes, this pyrimidine derivatives comprise there is structural formula (I) pyrimidine compound, its pharmaceutically acceptable salt, solvate, polymorph, tautomer, prodrug, or the compositions containing pyrimidine compound, structural formula (I) is as follows:
Preferably, in such use, the method that synthesis has the pyrimidine compound of structural formula (I) comprises the following steps: the compd A and 1-methyl piperazine with structural formula (1) are dissolved into 1 according to mol ratio 1:8 ~ 12, in 4-dioxane, 160 ~ 200 DEG C, microwave reaction 30 ~ 60 minutes, reaction gained mixture is spin-dried for solvent, must have the pyrimidine compound of structural formula (I), wherein, in formula (1), X is halogen.
Preferably, in such use, synthesis have be spin-dried for solvent process in the method for the pyrimidine compound of structural formula (I) after comprise step with silica column purification further, be be that the dichloromethane of 100:1 ~ 60:1 and methanol mixed solvent carry out eluting by volume ratio by the step of silica column purification, collect the pyrimidine compound with structural formula (I) of purification.
Preferably, in such use, the method of synthesis compd A is as follows: be dissolved in n-butyl alcohol by the compd B and paranitroanilinum, p-methyl benzenesulfonic acid with structural formula (2) according to mol ratio 1:1 ~ 1.2:0.8 ~ 1, back flow reaction 12 ~ 16h at 130 ~ 150 DEG C, be cooled to room temperature after reaction, add saturated NaHCO
3solution regulates pH to 7 ~ 8, makes to be extracted with ethyl acetate 3 ~ 5 times, organic layer saturated common salt water washing 3 ~ 5 times, then uses anhydrous Na
2sO
4drying, is spin-dried for solvent and namely obtains compd A, and wherein, in formula (2), X is halogen.
Preferably, in such use, comprise further with methanol trituration after being spin-dried for solvent process in the method for synthesis compd A, after sucking filtration, namely obtain compd A.
Preferably, in such use, the method for synthesis compd B is as follows: by 2, and 4,6-tri-halogenated pyrimidine and 3-amino-5-methylpyrazole are dissolved in dehydrated alcohol according to mol ratio 1:1 ~ 2, add triethylamine, 0 DEG C of stirring reaction 8 ~ 16h, after reaction stops, water is added in reaction system, sucking filtration after precipitation white solid, adopts frozen water and ice methanol wash successively, obtains compd B after drying.
Preferably, in such use, it is 2,4,6-trichloropyrimidine that synthesis has 2,4,6-tri-halogenated pyrimidines in the method for the compd B of structural formula (2).
Preferably, in such use, tumor is the tumor because the unconventionality expression of Aurora A causes.
Preferably, in such use, tumor is nasopharyngeal carcinoma, breast carcinoma and neoplastic hematologic disorder.
Simultaneously, present invention also offers the purposes of a kind of pyrimidine derivatives extracorporeal suppression tumor cell growth, pyrimidine derivatives comprise there is structural formula (I) pyrimidine compound, its pharmaceutically acceptable salt, solvate, polymorph, tautomer, prodrug, or the compositions containing pyrimidine compound.
Pass through in 2,4,6-positions of pyrimidine ring in the present invention, carry out different C-N couplings respectively, introduce different pharmacophore, form the new pyrimidine derivatives with Aurora kinase inhibitory activity, this pyrimidine derivatives can be made into and can prevent and/or treat and/or the medicine of adjuvant therapy of tumors.
Except object described above, feature and advantage, the present invention also has other object, feature and advantage.Below with reference to figure, the present invention is further detailed explanation.
Accompanying drawing explanation
Accompanying drawing form this description a part, for understanding the present invention further, accompanying drawing shows the preferred embodiments of the present invention, and be used for principle of the present invention is described together with description.In figure:
Fig. 1 shows the proton nmr spectra spectrogram of the pyrimidine compound according to the present invention with structural formula (I);
Fig. 2 shows the carbon-13 nmr spectra spectrogram of the pyrimidine compound according to the present invention with structural formula (I);
What Fig. 3 a showed variable concentrations has the pyrimidine compound (AKI603) of structural formula (I) to AuroraA kinase inhibition assay result figure in breast cancer cell SUM149 according to the present invention;
What Fig. 3 b showed variable concentrations has the pyrimidine compound (AKI603) of structural formula (I) to AuroraA kinase inhibition assay result figure in breast cancer cell BT549 according to the present invention;
What Fig. 4 a showed variable concentrations has the pyrimidine compound (AKI603) of structural formula (I) to the drug dose effect figure of leukaemia HL-60 according to the present invention;
What Fig. 4 b showed variable concentrations has the pyrimidine compound (AKI603) of structural formula (I) to the drug dose effect figure of breast cancer cell BT549 according to the present invention;
What Fig. 4 c showed variable concentrations has the pyrimidine compound (AKI603) of structural formula (I) to the drug dose effect figure of breast cancer cell MCF-7 according to the present invention;
What Fig. 4 d showed variable concentrations has the pyrimidine compound (AKI603) of structural formula (I) to the drug dose effect figure of the MCF-7 Breast Cancer Cell (MCF-7-Epi) of epirubicin drug resistance according to the present invention;
What Fig. 4 e showed variable concentrations has the pyrimidine compound (AKI603) of structural formula (I) to the drug dose effect figure of breast cancer cell MDA-MB-231 according to the present invention;
What Fig. 4 f showed variable concentrations has the pyrimidine compound (AKI603) of structural formula (I) to the drug dose effect figure of breast cancer cell MDA-MB-453 according to the present invention;
What Fig. 4 g showed variable concentrations has the pyrimidine compound (AKI603) of structural formula (I) to the drug dose effect figure of breast cancer cell MDA-MB-468 according to the present invention;
What Fig. 4 h showed variable concentrations has the pyrimidine compound (AKI603) of structural formula (I) to the drug dose effect figure of breast cancer cell Sk-br-3 according to the present invention;
What Fig. 4 i showed variable concentrations has the pyrimidine compound (AKI603) of structural formula (I) to the drug dose effect figure of breast cancer cell SUM149 according to the present invention;
What Fig. 5 a showed variable concentrations has the pyrimidine compound (AKI603) of structural formula (I) to the Cycle Arrest result figure of leukaemia HL-60 according to the present invention;
What Fig. 5 b showed variable concentrations has the pyrimidine compound (AKI603) of structural formula (I) to the Cycle Arrest result figure of breast cancer cell SUM149 according to the present invention;
What Fig. 5 c showed variable concentrations has the pyrimidine compound (AKI603) of structural formula (I) to the Cycle Arrest result figure of breast cancer cell BT549 according to the present invention;
Fig. 6 shows the result figure that the pyrimidine compound (AKI603) having structural formula (I) according to the present invention suppresses breast cancer cell BT549 and SUM149 Clone formation;
Fig. 7 a shows the cells survival rate comparison diagram of breast cancer cell MCF-7 and breast cancer cell MCF-7-Epi under epirubicin effect;
Fig. 7 b shows the disparity map that breast cancer cell MCF-7 and breast cancer cell MCF-7-Epi expresses through flow cytomery CD24-CD44+;
In breast cancer cell MCF-7-Epi after Fig. 7 c shows pyrimidine compound (AKI603) process having structural formula (I) through the present invention, CD24-CD44+ expresses the result figure of change; And
Fig. 7 d show the present invention there is the pyrimidine compound process of structural formula (I) after breast cancer cell MCF-7-Epi in CD24-CD44+ express change cartogram.
Detailed description of the invention
Below in conjunction with the accompanying drawing in the embodiment of the present invention, technical scheme in embodiments of the invention is described in detail, but following embodiment and accompanying drawing are only understand the present invention, and the present invention can not be limited, 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 adjuvant therapy of tumors medicine in purposes, this pyrimidine derivatives comprise there is structural formula (I) pyrimidine compound, its pharmaceutically acceptable salt, solvate, polymorph, tautomer, prodrug, or the compositions containing described pyrimidine compound, described structural formula (I) is as follows:
The pyrimidine compound that the present invention has structural formula (I) is N
4-(5-methyl isophthalic acid H-pyrazole-3-yl)-6-(4-methylpiperazine-1-yl)-N
2-(4-nitrobenzophenone) pyrimidine-2,4-diamidogen, its chemical formula is C
19h
23n
9o
2relative molecular weight is 409.2g/mol, this compound is by 2 of pyrimidine ring, 4,6-position, carries out different C-N couplings respectively, introduces different pharmacophore, form the new pyrimidine derivatives with Aurora kinase inhibitory 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 above-mentioned method with the pyrimidine compound of structural formula (I) of synthesis to comprise the following steps: the compd A and 1-methyl piperazine with structural formula (1) are dissolved into 1 according to mol ratio 1:8 ~ 12, in 4-dioxane, 160 ~ 200 DEG C, microwave reaction 30 ~ 60 minutes, reaction gained mixture is spin-dried for solvent, has the pyrimidine compound of structural formula (I) described in obtaining, wherein, in formula (1), X is halogen.
Preferably, synthesize above-mentioned have be spin-dried for solvent process in the method for the pyrimidine compound of structural formula (I) after comprise step with silica column purification further, be be that the dichloromethane of 100:1 ~ 60:1 and methanol mixed solvent carry out eluting by volume ratio by the step of silica column purification, collect the pyrimidine compound described in purification with structural formula (I).Add the step with silica column purification in the method, the increase of this step is conducive to the purity with the pyrimidine compound of structural formula (I) synthesized by raising, is conducive to later stage pharmaceutical applications.
In one embodiment of the invention, the method described in synthesis with the compd A in structural formula (1) comprises and is dissolved in n-butyl alcohol by the compd B and paranitroanilinum, p-methyl benzenesulfonic acid with structural formula (2) according to mol ratio 1:1 ~ 1.2:0.8 ~ 1, back flow reaction 12 ~ 16h at 130 ~ 150 DEG C, be cooled to room temperature after reaction, add saturated NaHCO
3solution regulates pH to 7 ~ 8, makes to be extracted with ethyl acetate 3 ~ 5 times, organic layer saturated common salt water washing 3 ~ 5 times, then uses anhydrous Na
2sO
4drying, is spin-dried for solvent and namely obtains the compd A with structural formula (1), and wherein, in formula (2), X is halogen.
Preferably, synthesis have be spin-dried for solvent process in the method for the compd A of structural formula (1) after comprise with methanol trituration further, there is described in namely obtaining after sucking filtration the compd A of structural formula (1).Add the step of methanol trituration in the method, the increase of this step is conducive to obtaining the higher compd A of purity, and then the by-product being conducive to reducing when follow-up synthesis has a pyrimidine compound of structural formula (I), and then improve the purity with the pyrimidine compound of structural formula (I), be conducive to later stage pharmaceutical applications.
In one embodiment of the invention, the method described in synthesis with the compd B of structural formula (2) comprises 2,4,6-tri-halogenated pyrimidine and 3-amino-5-methylpyrazole are dissolved in dehydrated alcohol according to mol ratio 1:1 ~ 2, add triethylamine, 0 DEG C of stirring reaction 8 ~ 16h, reaction adds water after stopping in reaction system, sucking filtration after precipitation white solid, adopt frozen water and ice methanol wash successively, after drying, obtain the compd B with structural formula (2).Wherein, 2,4,6-tri-halogenated pyrimidine is preferably 2,4,6-trichloropyrimidine.
In one embodiment of the present invention, tumor is the tumor excessively caused because of Aurora A.Be preferably nasopharyngeal carcinoma, breast carcinoma and neoplastic hematologic disorder.
Simultaneously, in one embodiment of the invention, provide the purposes of a kind of pyrimidine derivatives extracorporeal suppression tumor cell growth, this pyrimidine derivatives comprise there is structure above (I) pyrimidine compound, its pharmaceutically acceptable salt, solvate, polymorph, tautomer, prodrug, or the compositions containing described pyrimidine compound.
Exemplary of the present invention will be described in detail below.But these embodiments only for the purpose of illustration, are not intended to limit the scope of the invention.
As used herein, if for providing concrete restriction, term of the present invention has following implication.
" halogen " comprises fluorine, chlorine, bromine and iodine.
" treatment effective dose " refers to when giving the mammal needing such treatment, is enough to the amount of the general formula compound of effectively treatment.Treatment effective dose changes depending on the given activity of healing potion used, age of patient, physiological situation, the existence of Other diseases state and nutriture.In addition, the other medicines treatment that patient may just accept will affect the determination of the treatment effective dose of the healing potion that will give.
Compound of the present invention also comprises all isotopic atoms, no matter is at intermediate or last compound.Isotopic atom comprises and has identical atomic number, but different quality number.Such as, the isotope of hydrogen comprises tritium and deuterium.
Compound of the present invention also comprises pharmaceutically acceptable salt.Pharmaceutically acceptable salt refers to the form the basic group conversion salify in parent compound.Pharmaceutically acceptable salt include but not limited to, the inorganic or organic acid salt of basic group such as amine (ammonia) base.Pharmaceutically acceptable salt of the present invention can be synthesized by parent compound, and the acid of the basic group namely in parent compound and 1-4 equivalent is reacted in a solvent system.Suitable salt is set forth in Remington ' sPharmaceuticalSciences, 17thed., MackPublishingCompany, Easton, Pa., and 1985, p.1418 and JournalofPharmaceuticalScience, and 66, in 2 (1977).
Pharmaceutically acceptable acid-addition salts can be prepared by inorganic and organic acid.Hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc. are comprised by the mineral acid of derived acids addition salts.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. are comprised by the organic acid of derived acids addition salts.The mineral acid of derived acids addition salts and organic acid are especially 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 incompatible with active component, its application in therapeutic combination is expected.The active component supplemented also can be incorporated in compositions.
Said composition is preferably formulated into unit dosage forms.Term " unit dosage forms " refers to the physical discrete unit being suitable for use as and giving human experimenter and other mammiferous single doses, and per unit contains the predetermined amount and relevant suitable pharmaceutical excipient (as tablet, capsule, ampoule) that calculate to produce the effective active substance of required treatment.The compound of general formula (I) is effective and usually gives active drug amount in dosage range widely.Preferably, for oral administration, each dosage unit comprises general formula (I) compound of 10mg to 2g, is more preferably 10 to 700mg, and for parenteral, is preferably general formula (I) compound of 10 to 700mg, more preferably from about 50 to 200mg.But, should understand, the amount of actual general formula (I) compound given is determined by doctor according to relevant situation, comprise the disease that will treat, the route of administration selected, the pragmatize compound given and its relative activity, age of each patient, body weight and reaction, the seriousness etc. of patients symptomatic.
In order to prepare solid composite as tablet, main active component carried out mixing to form solid preformulation composition with drug excipient (or carrier), it comprises the homogeneous mixture of compound of the present invention.In time claiming these preformulation composition to be uniform, it refers to that active component is dispersed in whole compositions, so that compositions easily can be subdivided into identical effective unit dosage forms as tablet, pill and capsule.
Tablet of the present invention or pill applied or otherwise can be had to provide a kind of the dosage form extending effect beneficial by compound, or protection tablet or pill are from the effect of acid condition in stomach.Such as, tablet or pill can comprise interior dosage and external dose composition, and 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 composition is complete in allowing enters duodenum or be delayed by release.Various material may be used for such enteric layer or coating, and above-mentioned material comprises many polymer acids and polymer acid and such material as the mixture of Lac, hexadecanol and cellulose acetate.
Solution in pharmaceutically acceptable aqueous solvent or organic solvent or its mixture and suspension is included in for the compositions of inhalation or insufflation, and powder.Liquid or solid compositions can comprise suitable pharmaceutical excipient as described above.Preferably, these compositionss are given to obtain local or systemic effect by oral or nasal respiratory route.The compositions in the acceptable solvent of preferred pharmacy can be atomized by using noble gas.Directly can suck atomized soln from atomising device, or atomising device can be connected to face shield account shape thing or intermittent positive pressure breathing machine.Can by the device sending dosage form in a suitable manner, preferred oral or nose approach, give solution, suspensoid or powder composite.
Compound of the present invention and pharmaceutically acceptable salt also comprise the form of solvate or hydrate.In general, the form of solvate or hydrate is equal to form that is non-solvated or non-hydrated, and contains within the scope of the invention.Likely there is polycrystal or unbodied form in some compound in the present invention.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 compound.Prodrug is a pharmacological agents (medicine), is derived by parent drug.Once enter in body, prodrug is just become parent drug by metabolic transformation.Prodrug is prepared by replacing one or more functional groups of parent drug, and its substituted radical will be degraded and discharge parent compound in vivo.Preparation and the use of prodrug can at T.HiguchiandV.Stella, " Pro-drugsasNovelDeliverySystems; " Vol.14oftheA.C.S.SymposiumSeries, and BioreversibleCarriersinDrugDesign, ed.EdwardB.Roche, AmericanPharmaceuticalAssociationandPergamonPress, finds in 1987.
The present invention also provides the pharmaceutical composition comprising general formula (I) compound or the acceptable salt of its pharmacy or its prodrug and the pharmaceutically acceptable carrier of at least one.Pharmaceutical composition of the present invention can be oral, and injection is injected, and spraying sucks, skin external, rectum use, nasal cavity use, vagina use, abdominal cavity use, or use by implanting the approach such as reservoir or transdermal patch.
Beneficial effect of the present invention is proved further below with reference to specific embodiment.
Embodiment 1
Synthesis compd B:
Take 2,4,6-trichloropyrimidine (1.83g, 10mmol), 3-amino-5-methylpyrazole (0.97g, 10mmol) is dissolved in 100mL dehydrated alcohol, adds 1.4mL triethylamine, stirring reaction 12h at 0 DEG C.After stopped reaction, in reaction solution, add 150mL water, separate out a large amount of white solids immediately, sucking filtration, and use 50mL frozen water and 20mL ice methanol wash successively, obtain white solid B(1.82g after drying, 75%).
Product analysis: the nuclear magnetic data of the white solid B obtained is
1hNMR (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);
13cNMR (100MHz, DMSO-d
6) δ: 161.1,159.7,158.4,147.1,139.0,102.6,95.2,10.4ppm.White solid B obtained as can be seen here has structure in structural formula (2).
Synthesis compd A:
Weigh Compound B(244mg, 1.0mmol), paranitroanilinum (166mg, 1.2mmol), a hydration p-methyl benzenesulfonic acid (152mg, 0.8mmol), is dissolved in 10mL n-butyl alcohol, back flow reaction 12h at 140 DEG C.The saturated NaHCO of 2.5mL is added after being cooled to room temperature
3solution, is neutralized to pH=7-8, uses dichloromethane extraction (20mL × 3), organic over anhydrous Na
2sO
4after drying, be spin-dried for solvent, with methanol trituration, sucking filtration obtains yellow solid A(130mg, and 36.8%).
Product analysis: the nuclear magnetic data of the yellow solid A obtained is
1hNMR (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).Yellow solid A obtained as can be seen here has structure in structural formula (2).
Synthesis has the pyrimidine compound of structural formula (I):
Weigh Compound A(100mg, 0.29mmol), 1-methyl piperazine (0.32mL, 2.9mmol) is dissolved in the Isosorbide-5-Nitrae-dioxane of 2mL, and at 180 DEG C, microwave reaction 45 minutes, is spin-dried for solvent, uses silica column purification (CH
2cl
2: MeOH=100:1-60:1), obtain yellow solid (57mg, 48%).
Product analysis: the nuclear magnetic data of the yellow solid obtained is
1hNMR (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).
13cNMR (100MHz, DMSO-d
6) 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, the 10.7ppm. yellow solid high resolution mass spectrum data obtained are HRMS (ESI-TOF): m/zcalcdforC
19h
23n
9o
2, [M+H]
+: 410.2047, found:410.2050.As can be seen here obtain the pyrimidine compound with structure formula I.
Embodiment 2
Synthesis compd B:
Take 2,4,6-trichloropyrimidine (1.83g, 10mmol), 3-amino-5-methylpyrazole (1.94g, 20mmol) is dissolved in 100mL dehydrated alcohol, adds 1.4mL triethylamine, stirring reaction 16h at 0 DEG C.After stopped reaction, in reaction solution, add 150mL water, separate out a large amount of white solids immediately, sucking filtration, and use 50mL frozen water and 20mL ice methanol wash successively, obtain white solid B(1.82g after drying, 70%).
Synthesis compd A:
Weigh Compound B(244mg, 1.0mmol), paranitroanilinum (138mg, 1mmol), a hydration p-methyl benzenesulfonic acid (190mg, 1mmol), is dissolved in 10mL n-butyl alcohol, back flow reaction 10h at 150 DEG C.The saturated NaHCO of 2.5mL is added after being cooled to room temperature
3solution, is neutralized to pH=7-8, uses dichloromethane extraction (20mL × 3), organic over anhydrous Na
2sO
4after drying, be spin-dried for solvent, with methanol trituration, sucking filtration obtains yellow solid A(117mg, and 33%).
Synthesis has the pyrimidine compound of structural formula (I)
Weigh Compound A(100mg, 0.29mmol), 1-methyl piperazine (0.348mL, 3.48mmol) is dissolved in the Isosorbide-5-Nitrae-dioxane of 2mL, and at 160 DEG C, microwave reaction 60 minutes, is spin-dried for solvent, uses silica column purification (CH
2cl
2: MeOH=100:1-60:1), obtain yellow solid (53mg, 45%).This yellow solid detects the pyrimidine compound analyzed as having structural formula (I) through nuclear-magnetism.
Can both obtain by method in embodiment 1 and embodiment 2 pyrimidine compound that the application has structural formula (I), wherein adopt the productive rate with the pyrimidine compound of structural formula (I) that in embodiment 1, method obtains higher.
One, the pyrimidine compound (AKI603) with structural formula (I) that embodiment 1 is synthesized is tested the kinase whose inhibit activities of Aurora-A in 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 culture fluid.The pyrimidine compound solution with structural formula (I) of variable concentrations is adopted to process breast cancer cell, 48 h before harvest cell lysates, Westernblot method is adopted to detect the expression (T288) of phosphorylation Aurora-A in cell lysate, using GAPDH as internal reference, result as shown in Figure 3 a and Figure 3 b shows.
Experimental result: in breast cancer cell SUM149 and BT549, has the reduction Aurora-A kinase activity (T288 site) of the pyrimidine compound energy dose dependent of structural formula (I), shows the targeting specific of this inhibitor.
Fig. 3 a is for having the pyrimidine compound of structural formula (I) to the inhibitory action figure of phosphorylation Aurora-A in breast cancer cell SUM149.The kinase whose activity of AuroraA in breast cancer cell SUM149 can be suppressed by the known pyrimidine compound with structural formula (I) of Fig. 3 a.
If Fig. 3 b is for having the pyrimidine compound of structural formula (I) to the inhibitory action figure of Aurora-A in breast cancer cell BT549.The kinase whose activity of AuroraA in breast cancer cell BT549 can be suppressed by the known pyrimidine compound with structural formula (I) of Fig. 3 b.
Two, the pyrimidine compound (AKI603) with structural formula (I) of embodiment 1 synthesis is to the growth experiment of inhibition tumor cell in cell.
Experiment object: leukaemia HL-60, the MCF-7(MCF-7-Epi of breast cancer cell BT549, MCF-7 and 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 in 96 orifice plates respectively, the each tumor cell 24 of the pyrimidine compound process with structural formula (I) adopting the embodiment 1 of variable concentrations to synthesize respectively or add MTT after 48 hours, 37 ° of C cultivate 4 hours, OD value is detected with 490nm, result is as shown in Fig. 4 a to 4i, in each figure, abscissa is the concentration of compound, and vertical coordinate is cell relative survival rate.
Experimental result:
As shown in fig. 4 a, the pyrimidine compound (concentration is 0 μM, 0.1 μM, 0.2 μM, 0.5 μM, 1 μM, 2 μMs, 5 μMs, 10 μMs, 20 μMs) with structural formula (I) has dosage and time dependent inhibitory action to the growth of HL-60 cell;
As shown in Figure 4 b, the pyrimidine compound (concentration is 0 μM, 0.049 μM, 0.097 μM, 0.195 μM, 0.39 μM, 0.78 μM, 1.56 μMs, 3.13 μMs, 6.25 μMs, 12.5 μMs, 25 μMs, 50 μMs) with structural formula (I) has the inhibitory action of dose dependent to the growth of BT549 cell;
As illustrated in fig. 4 c, the pyrimidine compound (concentration is 0 μM, 0.049 μM, 0.097 μM, 0.195 μM, 0.39 μM, 0.78 μM, 1.56 μMs, 3.13 μMs, 6.25 μMs, 12.5 μMs, 25 μMs, 50 μMs) with structural formula (I) has the inhibitory action of dose dependent to the growth of MCF-7 cell;
As shown in figure 4d, the pyrimidine compound (concentration is 0 μM, 0.049 μM, 0.097 μM, 0.195 μM, 0.39 μM, 0.78 μM, 1.56 μMs, 3.13 μMs, 6.25 μMs, 12.5 μMs, 25 μMs, 50 μMs) with structural formula (I) has the inhibitory action of dose dependent to the growth of MCF-7-Epi cell;
As shown in fig 4e, the pyrimidine compound (concentration is 0 μM, 0.049 μM, 0.097 μM, 0.195 μM, 0.39 μM, 0.78 μM, 1.56 μMs, 3.13 μMs, 6.25 μMs, 12.5 μMs, 25 μMs, 50 μMs) with structural formula (I) has the inhibitory action of dose dependent to the growth of MDA-MB-231 cell;
As shown in fig. 4f, the pyrimidine compound (concentration is 0 μM, 0.049 μM, 0.097 μM, 0.195 μM, 0.39 μM, 0.78 μM, 1.56 μMs, 3.13 μMs, 6.25 μMs, 12.5 μMs, 25 μMs, 50 μMs) with structural formula (I) has the inhibitory action of dose dependent to the growth of MDA-MB-453 cell;
As shown in figure 4g, the pyrimidine compound (concentration is 0 μM, 0.049 μM, 0.097 μM, 0.195 μM, 0.39 μM, 0.78 μM, 1.56 μMs, 3.13 μMs, 6.25 μMs, 12.5 μMs, 25 μMs, 50 μMs) with structural formula (I) has the inhibitory action of dose dependent to the growth of MDA-MB-468 cell;
As shown in figure 4h, the pyrimidine compound (concentration is 0 μM, 0.049 μM, 0.097 μM, 0.195 μM, 0.39 μM, 0.78 μM, 1.56 μMs, 3.13 μMs, 6.25 μMs, 12.5 μMs, 25 μMs, 50 μMs) with structural formula (I) has the inhibitory action of dose dependent to the growth of Sk-br-3 cell;
As shown in figure 4i, the pyrimidine compound (concentration is 0 μM, 0.049 μM, 0.097 μM, 0.195 μM, 0.39 μM, 0.78 μM, 1.56 μMs, 3.13 μMs, 6.25 μMs, 12.5 μMs, 25 μMs, 50 μMs) with structural formula (I) has the inhibitory action of dose dependent to the growth of SUM149 cell.
Three, pyrimidine compound (AKI603) the cell cycle retardation with structural formula (I) that embodiment 1 is synthesized is tested.
Experiment object: leukaemia HL-60, breast cancer cell BT549 and SUM149.
Test method: getting concentration is respectively that the pyrimidine compound with structural formula (I) of 0,0.1,0.5 and 5 μM is to leukaemia HL-60 process, 24 h before harvest cells, or concentration is that the pyrimidine compound with structural formula (I) of 0,0.3125,0.625,1.25,2.5 and 5 μM is to breast cancer cell BT549 and SUM149 process, 48 h before harvest cells, dye with 50 μ g/mlPI after 70% ethanol is fixing, adopt flow cytometer to carry out cell cycle and apoptosis (sub-G1) detection, testing result is as shown in Fig. 5 a, 5b, 5c.
Experimental result:
As shown in Fig. 5 a, 5b, 5c, in leukaemia HL-60 and breast cancer cell SUM149, BT549, the synthesized pyrimidine compound with structural formula (I) all can obviously cause G2/M cell cycle arrest in shown concentration range, and there is polyploid phenomenon, show that the pyrimidine compound with structural formula (I) has an impact by suppressing Aurora-A and then cell cycle.
As shown in Fig. 5 a, 5b, 5c, in leukaemia HL-60 and breast cancer cell SUM149, BT549, the synthesized pyrimidine compound with structural formula (I) can promote apoptosis in shown concentration range, shows as the increase of Sub-G1 peak ratio.This compound all can cause obvious apoptosis phenomenon when concentration 5 μMs in above-mentioned cell.
Four, the pyrimidine compound (AKI603) with structural formula (I) of embodiment 1 synthesis is to the experiment of the Clone formation of inhibition tumor cell in cell.
Experiment object: breast cancer cell BT549 and SUM149.
Test method: each breast cancer cell BT549 and SUM149 is incubated at 6 orifice plates with the density in 103/ hole, the each tumor cell of pyrimidine compound process with structural formula (I) that the embodiment 1 being 0 μM, 0.625 μM, 1.25 μMs with concentration respectively after cell attachment is synthesized, observe the number of clone after 6 days by 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 with the dose-dependent inhibition tumor cell of pyrimidine compound energy of structure formula I of variable concentrations, result shows that this compound has the effect of Tumor suppression growth further.
The change of the flow cytomery CD24-CD44+ expression of the cell after the pyrimidine compound (AKI603) with structural formula (I) that five, embodiment 1 is synthesized processes.
Experiment object: breast cancer cell MCF-7 and MCF-7-Epi.
Test method:
With the epirubicin that concentration is 0 μM, 0.049 μM, 0.097 μM, 0.195 μM, 0.39 μM, 0.78 μM, 1.56 μMs, 3.13 μMs, 6.25 μMs, 12.5 μMs, 25 μMs, 50 μMs, each breast cancer cell is processed, MTT is added after 48 hours, 37 ° of C cultivate 4 hours, detect OD value with 490nm, test result as shown in Figure 7a;
Collect each breast cancer cell, with CD24 and CD44 antibody staining, adopt the change that the CD24-CD44+ of flow cytomery expresses, test result as shown in Figure 7b;
Employing concentration is the pyrimidine compound process breast cancer cell MCF-7-EPi with structural formula (I) that the embodiment 1 of 0.625 μM is synthesized, 0 day, 6 days and 9 days collecting cells respectively, with CD24 and CD44 antibody staining, adopt the change that the CD24-CD44+ of flow cytomery expresses, test result as shown in Figure 7 c; The CD24-CD44+ of this breast cancer cell MCF-7-Epi after the pyrimidine compound process that the present invention has structural formula (I) expresses the statistical result of change as shown in figure 7d, in 7d, L1 is contrast statistics line, and L2 is for having the pyrimidine compound statistics line of structural formula (I).
Experimental result: as shown in 7a, breast cancer cell MCF-7-Epi shows as obvious epirubicin drug resistance, and as shown in Figure 7b, CD24-CD44+ breast carcinoma stem cell ratio obviously rises.As Fig. 7 c and 7d adopt there is the pyrimidine compound effect of structural formula (I) after, the ratio of breast carcinoma stem cell is observed respectively 0 day, 6 days and 9 days, found that the pyrimidine compound with structural formula (I) obviously suppresses the ratio of CD24-CD44+ breast carcinoma stem cell, illustrate that this compound can target killing tumor cell, also can target killing tumor stem cell, than traditional chemotherapeutics, there is superiority.
These are only the preferred embodiments of the present invention, be not limited to the present invention, for a person skilled in the art, the present invention can have various modifications and variations.Within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (10)
1. pyrimidine derivatives preparation prevent and/or treat and/or adjuvant therapy of tumors medicine in a purposes, it is characterized in that, described pyrimidine derivatives for having the pyrimidine compound of structural formula (I) or its pharmaceutically acceptable salt,
Described structural formula (I) is as follows:
2. purposes according to claim 1, is characterized in that, the method described in synthesis with the pyrimidine compound of structural formula (I) comprises the following steps:
The compd A and 1-methyl piperazine with structural formula (1) are dissolved into 1 according to mol ratio 1:8 ~ 12, in 4-dioxane, 160 ~ 200 DEG C, microwave reaction 30 ~ 60 minutes, reaction gained mixture is spin-dried for solvent, there is described in obtaining the pyrimidine compound of structural formula (I)
Wherein, in formula (1), X is halogen.
3. purposes according to claim 2, it is characterized in that, there is described in synthesis the step comprising further after being spin-dried for solvent process in the method for the pyrimidine compound of structural formula (I) and use silica column purification, be be that the dichloromethane of 100:1 ~ 60:1 and methanol mixed solvent carry out eluting by volume ratio by the step of silica column purification, collect the pyrimidine compound described in purification with structural formula (I).
4. purposes according to claim 2, is characterized in that, the method for synthesizing described compd A is as follows:
To have compd B and the paranitroanilinum of structural formula (2), p-methyl benzenesulfonic acid is dissolved in n-butyl alcohol according to mol ratio 1:1 ~ 1.2:0.8 ~ 1, and at 130 ~ 150 DEG C, back flow reaction 12 ~ 16h, is cooled to room temperature after reaction, adds saturated NaHCO
3solution regulates pH to 7 ~ 8, makes to be extracted with ethyl acetate 3 ~ 5 times, organic layer saturated common salt water washing 3 ~ 5 times, then uses anhydrous Na
2sO
4drying, is spin-dried for solvent and namely obtains compd A,
Wherein, in formula (2), X is halogen.
5. purposes according to claim 4, is characterized in that, synthesizes after being spin-dried for solvent process in the method for described compd A and comprises further with methanol trituration, namely obtain described compd A after sucking filtration.
6. purposes according to claim 4, is characterized in that, the method for synthesizing described compd B is as follows:
By 2,4,6-tri-halogenated pyrimidine and 3-amino-5-methylpyrazole are dissolved in dehydrated alcohol according to mol ratio 1:1 ~ 2, add triethylamine, 0 DEG C of stirring reaction 8 ~ 16h, after reaction stops, water is added in reaction system, sucking filtration after precipitation white solid, adopts frozen water and ice methanol wash successively, obtains described compd B after drying.
7. purposes according to claim 6, is characterized in that, described in the method described in synthesis with the compd B of structural formula (2), 2,4,6-tri-halogenated pyrimidines are 2,4,6-trichloropyrimidine.
8. the purposes described in any one of claim 1 to 7, is characterized in that, described tumor is the tumor because the unconventionality expression of Aurora A causes.
9. purposes according to claim 8, is characterized in that, described tumor is nasopharyngeal carcinoma, breast carcinoma and neoplastic hematologic disorder.
10. a purposes for pyrimidine derivatives extracorporeal suppression tumor cell growth, is characterized in that, described pyrimidine derivatives for having the pyrimidine compound of structural formula (I) or its pharmaceutically acceptable salt,
Described structural formula (I) is as follows:
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