CN105777749A - Pyridopyrimidine compound and preparation method and application thereof - Google Patents
Pyridopyrimidine compound and preparation method and application thereof Download PDFInfo
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- CN105777749A CN105777749A CN201610220308.6A CN201610220308A CN105777749A CN 105777749 A CN105777749 A CN 105777749A CN 201610220308 A CN201610220308 A CN 201610220308A CN 105777749 A CN105777749 A CN 105777749A
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- 0 CC(C(C(N1C2CCCC2)=O)=C(C)c2c1nc(Nc(cc1)ncc1N(CC1)CCN1C(*)=O)nc2)=O Chemical compound CC(C(C(N1C2CCCC2)=O)=C(C)c2c1nc(Nc(cc1)ncc1N(CC1)CCN1C(*)=O)nc2)=O 0.000 description 7
- AHJRHEGDXFFMBM-UHFFFAOYSA-N CC(C(C(N1C2CCCC2)=O)=C(C)c2c1nc(Nc(cc1)ncc1N1CCNCC1)nc2)=O Chemical compound CC(C(C(N1C2CCCC2)=O)=C(C)c2c1nc(Nc(cc1)ncc1N1CCNCC1)nc2)=O AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 1
- AILKHAQXUAOOFU-UHFFFAOYSA-N CCCCCC#N Chemical compound CCCCCC#N AILKHAQXUAOOFU-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention relates to a pyridopyrimidine compound with CDK4/6 inhibitory activity shown in the formula, medically acceptable salt or a medically acceptable solvate thereof, a preparation method of the pyridopyrimidine compound, a medicine composition comprising the compound and application of the compound in preparation of medicine for selectively inhibiting CDK4/6, recovering cell cycle control and blocking tumor cell proliferation.
Description
Technical field
The present invention relates to a class such as pyridine compounds and their with CDK4/6 inhibitory activity shown in following formula and pharmaceutically acceptable salt thereof or pharmaceutically acceptable solvate, its preparation method, comprise the pharmaceutical composition of this compound, and these compounds are used for Selective depression CDK4/6 in preparation, recover cell cycle to control, block the purposes in tumor cell proliferation medicine.
Background technology
Cyclin-dependent kinase (cyclin-dependentkinase, CDK) it is a class serine (Ser)/threonine (Thr) kinases, as signal transducers important in cell, with cycle element (cyclin) the CDK-cyclin complex that formed, participate in the growth of cell, propagation, dormancy or enter apoptosis.In the process of cell cycle, expression that cyclins is periodically continued and degraded, and it is respectively incorporated on the CDK by they instant activation, by CDK activity, catalysis difference substrate phosphorylation, it is achieved the propelling of cell cycle difference phase and transformation.
CDK family includes 1-13, cyclin and is divided into A-L, and different CDK couples different cyclin respectively.Wherein, cyclinD family (cyclinD1, D2, D3), start to express in the G1 phase, in conjunction with and activate CDK4 and CDK6, form CDK4/6-CyclinD complex, make to include Retinoblastoma Protein (Retinoblastomaprotein, Rb) at interior a series of substrate phosphorylations.Discharging in connection and by the albumen of its suppression after Rb phosphorylation, mainly transcription factor E2F etc., E2F activates and transcribes some genes necessary to the entrance S phase.CDK-Cyclin is also by CDK kinase inhibition albumen (cyclinkinaseinhibitors, CKIs) negative regulation.CKIs is divided into CIP/KIP family and INK4 family two class.INK4 (inhibitorsofCDK4) family mainly includes p16INK4a, p15INK4b, p18INK4c and p19INK4d, the main activity suppressing CDK4 and CDK6.
The specific activation of CDK4/6 is closely related with the propagation of some tumors, has the abnormal ubiquity of Rb, cyclinD-CDK4/6-INK4-Rb path in the human tumor of about 80%.Show themselves in that (1) p16INK4a gene delection, point mutation, or DNA methylation cause that p16INK4a inactivates；(2) CDK4 gene amplification or point mutation (R24C), lose and p16INK4a binding ability；(3) cyclinD1 overexpression because of gene rearrangement or gene amplification.The change of this path, accelerates G1 phase process so that tumor cell proliferation is accelerated and obtained survival advantage.Therefore, its intervention being become a kind of therapeutic strategy, therefore CDK4/6 becomes one of antineoplastic target spot.
CDK4/6 is in that as the advantage of antitumor target spot: the cell of (1) great majority propagation relies on CDK2 or CDK4/6 propagation, but the inhibitor of CDK4/6 does not show the cytotoxicity of " general-CDK inhibitor ", as bone marrow depression and intestinal react.(2) preclinical laboratory shows, if cell cyclinD level raises or p16INK4a inactivation, the cell sensitivity to medicine can be increased, owing to tumor cell exists above-mentioned phenomenon relative to normal cell, so adds somewhat to the targeting of medicine.
Wherein, the PD0332991 (Palbociclib) of Pfizer company exploitation, structure belongs to Pyridopyrimidine class, Selective depression CDK4 and CDK6.In in February, 2015 FDA approval listing.But, existing clinical research shows that Palbociclib has occurred drug resistance and more side reaction.In order to improve Palbociclib bioavailability in vivo further, we are retaining on the basis of its main body framework at design, adopt different measures that Palbociclib is transformed, it is thus achieved that the derivant that a class is new, it has been found that they have the inhibitory activity of good CDK4 and CDK6.
Summary of the invention
It is an object of the present invention to provide a kind of pyrido-pyrimidines and pharmaceutically acceptable salt thereof or pharmaceutically acceptable solvate.Described compound is a class cyclin-dependent kinase inhibitor, and CDK4 and CDK6 is had good inhibiting effect.
The pyrido-pyrimidines of the present invention, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate are by suppressing and relevant for the CDKs abnormal cell proliferation in mediation organism, the effect of the performance suppression growth of tumour cell such as metamorphosis and hypoerkinesia.
Therefore it is also another object of the present invention to provide the pyrido-pyrimidines according to the present invention, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate are as the purposes of CDK4 and CDK6 inhibitor.
Therefore, it is also another object of the present invention to provide the pyrido-pyrimidines according to the present invention, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate in preparation for preventing or treat the application in the medicine of the disease that the abnormal cell proliferation relevant to CDK4 and CDK6 in organism, metamorphosis and hypoerkinesia are correlated with.
It is yet another object of the invention to provide comprise therapeutically effective amount selected from according to one or more in the pyrido-pyrimidines of the present invention, its pharmaceutically acceptable salt or pharmaceutically acceptable solvate or its mixture as the pharmaceutical composition of active component.Described pharmaceutical composition can also optionally comprise pharmaceutically acceptable carrier, adjuvant or adjuvant.
It is yet another object of the invention to provide aforementioned pharmaceutical compositions application in the disease relevant for preventing or treat the abnormal cell proliferation relevant to CDK4 and CDK6 in organism, metamorphosis and hypoerkinesia.
It is yet another object of the invention to provide a kind of pharmaceutical composition, its comprise therapeutically effective amount selected from according to one or more and one or more CDK4 and CDK6 inhibitor in the pyrido-pyrimidines of the present invention, its pharmaceutically acceptable salt or pharmaceutically acceptable solvate or its mixture as active component.Described pharmaceutical composition can also optionally comprise pharmaceutically acceptable carrier, adjuvant or adjuvant
The method that it is a further object to provide the disease that a kind for the treatment of abnormal cell proliferation relevant to CDK4 and CDK6 in organism, metamorphosis and hypoerkinesia are correlated with, described method includes being selected from according to one or more in the pyrido-pyrimidines of the present invention, its pharmaceutically acceptable salt or pharmaceutically acceptable solvate or its mixture as the pharmaceutical composition of active component to patient's drug treatment effective dose.
Shown in the structure below formula I of pyrido-pyrimidines of the present invention:
Wherein:
R is selected from-C (=O) R1,-C (=O) OR2,-C (=O) CH2NHR3,-(CH2)nC (=O) R4,-(CH2)mXR5, C1-C6 alkyl；
R1Being independently selected from alkyl, haloalkyl, with carboxyl, the alkyl that cyano group replaces；It is preferably selected from independent methyl of taking from, ethyl, propyl group, isopropyl, the tert-butyl group, bromoethyl, bromopropyl, chloroethyl, chloropropyl, formyl, acetate, propionyloxy, cyano group methyl；Finally it is preferably selected from methyl, acetate, cyano group methyl；
R2Each independent take from C1-C8 alkyl, ester group；It is preferred that from C1-C6 alkyl, ester group；Further it preferably is selected from methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, amyl group, methyl acetate base；Finally it preferably is selected from methyl, propyl group, isopropyl, butyl, isobutyl group, amyl group, methyl acetate base；
R3Each independent alkyl of taking from, haloalkyl, with carboxyl, cyano group, ester group, amino, the alkyl that alkoxyl replaces；It is preferred that from alkyl, haloalkyl, with cyano group, ester group, amino, the alkyl of methoxy substitution；Further it preferably is selected from methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, amyl group, aminomethane base, aminoethane base, methoxy methyl alkyl, Ethyl Methyl Ether base, methoxy propyl alkyl；Finally it preferably is selected from methoxy propyl alkyl, aminoethane base；
N takes from 1-5, R4Each independent hydrogen of taking from, alkyl, haloalkyl, with carboxyl, cyano group, ester group, amino, the alkyl that alkoxyl replaces；It is preferred that take from 1-3, R4 from n to be independently selected from hydrogen, alkyl, haloalkyl, with carboxyl, cyano group, ester group, amino, methoxyl group, the alkyl that ethyoxyl replaces；Further it preferably is selected from n to take from 1 and 2, R4 and be independently selected from methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, amyl group, hydroxyl, aminomethane base, aminoethane base, methoxy methyl alkyl, Ethyl Methyl Ether base, methoxy propyl alkyl, formyl, acetate, propionyloxy, cyano group methyl；Finally it preferably is selected from n to take from 1 and 2, R4 and be independently selected from methyl, ethyl, hydroxyl；
M takes from 1-5, R5Each independent taking from hydrogen, alkyl, haloalkyl, with carboxyl, cyano group, ester group, amino, alkoxyl, the alkyl of carbonyl substituted；It is preferred that take from from m, 1-5, R5 are each independent takes from hydrogen, alkyl, and haloalkyl, with carboxyl, cyano group, ester group, amino, methoxyl group, the alkyl of carbonyl substituted；Further preferably being selected from m and take from 1,2 and 5, R5 is each independent takes from hydrogen, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, amyl group, ketone base, ethyl ketone base, acetonyl, butanone base；Finally preferably being selected from m and take from 1,2 and 5, R5 is independently selected from hydrogen, methyl, butanone base；
X takes from O or N；；
Described C1-C6 alkyl is preferable over C1-C4 alkyl, nonrestrictive includes: methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group.
The pharmaceutically acceptable salt of the compound that described formula I represents includes without limitation: inorganic acid salt, example hydrochloric acid salt, hydrobromate, nitrate, sulfate, sulphite, phosphate etc., metaphosphate and perchlorate；Acylate, such as formates, acetate, propionate, benzoate, maleate, fumarate, hydroxy benzoate, succinate, tartrate, citrate etc.；Alkylsulfonate, such as metilsulfate, ethyl sulfonate etc.；Arylsulphonate, such as benzene sulfonate, tosilate etc..
The pharmaceutically acceptable solvate of the compound that described formula I represents includes the solvate of the formula I compound represented and water, ethanol, isopropanol, ether, acetone, dichloromethane, toluene etc. without limitation.
Preferably, the compound of described formula I is the pyrido-pyrimidines represented by one of below general formula:
Wherein, R1, R2, R3, R4And R5Identical with the restriction in formula I.
In a preferred embodiment of the invention, the compound of described formula I is a kind of compound in following compounds:
Present invention also offers a kind of method preparing the formula I pyrido-pyrimidines represented, wherein, the method comprise the steps in a step or multistep:
Acyl chlorides (the R of compound 1 and different replacements1COCl、R3NHCH2COCl) there is substitution reaction (formula IA or IC), the different chloro-formate (R replaced2OCOCl) there is condensation reaction (formula IB), the different chloro replaced or brominated alkanes ((-CH2)nCOOR4、-(CH2)mXR5) there is nucleophilic substitution (formula 1D, 1E or 1F).
Wherein, R1、R2、R3、R4And R5Identical with the restriction in formula (I).
Described compound 1 and acyl chlorides, chloro-formate or the popular response condition that halogenated alkane generation substitution reaction is this area, generally carry out in the basic conditions, alkali can be cesium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, pyridine, piperidines or triethylamine, it is preferred to potassium carbonate or triethylamine.Generally the two directly reacts in reactant liquor, and reactant liquor is typically chosen the mixed solvent of dichloromethane, ethanol, toluene or several solvent.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is further elaborated.These embodiments are only for illustrative purposes, and do not limit the scope of the invention and essence.
1H-NMR BrukerAV400NMR spectrometer measures, and agents useful for same is all purchased from Chinese Medicine reagent company limited and produces.All solvents are before use all through re-distillation, and the anhydrous solvent used is all obtain by standard method dried；Responded except illustrating and be all heated to reflux carrying out in dichloromethane solvent and TLC tracking；The purification of product all uses silica gel (200-300 order) column chromatography except illustrating；Wherein silica gel (200-300 order) is to be produced by Haiyang Chemical Plant, Qingdao, and thin-layer silicon offset plate is produced by Yantai Jiang You silica gel development corporation, Ltd..
The preparation of preparation embodiment 1 compound 1A-1
Compound 1 (150mg) is dissolved in 10mL dichloromethane, after adding triethylamine (0.1mL), adds cyanoacetyl chloride (100mg).Stirred overnight at room temperature.Filtering, concentrated filtrate, column chromatography (dichloromethane: methanol=30: 1) obtains compound 1A-1 (110mg).1HNMR (DMSO-d6,400MHz) δ: 10.15 (s, 1H), 8.96 (s, 1H), 8.08 (d, 1H), 7.89 (d, 1H), 7.51 (m, 1H), 5.83 (m, 1H), 4.12 (s, 2H), 3.63 (m, 2H), 3.53 (m, 2H), 3.21 (m, 4H), 2.43 (s, 3H), 2.31 (s, 3H), 2.21 (m, 2H), 1.89 (m, 2H), 1.78 (m, 2H), 1.59 (m, 2H)；
The preparation of preparation embodiment 2 compound 1A-2
Except replacing cyanoacetyl chloride with chloroacetic chloride, adopt method synthesis compound 1A-2 (90mg) identical with the synthesis compound 1A-1 of preparation embodiment 1.1HNMR (DMSO-d6,400MHz) δ: 10.21 (s, 1H), 8.97 (s, 1H), 8.08 (d, 1H), 7.88 (d, 1H), 7.55 (d, 1H), 5.83 (t, 1H), 3.60 (m, 4H), 3.18 (m, 4H), 2.43 (s, 3H), 2.32 (s, 3H), 2.26 (m, 2H), 2.06 (s, 3H), 1.91 (m, 2H), 1.78 (m, 2H), 1.60 (m, 2H)；
The preparation of preparation embodiment 3 compound 1A-3
Except replacing cyanoacetyl chloride with succinyl chloride, adopt method synthesis compound 1A-3 (60mg) identical with the synthesis compound 1A-1 of preparation embodiment 1.1HNMR (DMSO-d6,400MHz) δ: 10.2 (s, 1H), 8.94 (s, 1H), 8.14 (m, 1H), 7.96 (m, 1H), 7.67 (m, 1H), 5.86 (m, 1H), 3.65 (m, 4H), 3.21 (m, 4H), 2.97 (d, 4H), 2.46 (s, 3H), 2.37 (s, 3H), 2.25 (m, 2H), 1.94 (m, 2H), 1.82 (m, 2H), 1.60 (m, 2H)；
The preparation of preparation embodiment 4 compound 1B-1
Except replacing cyanoacetyl chloride with methylchloroformate, adopt method synthesis compound 1B-1 (105mg) identical with the synthesis compound 1A-1 of preparation embodiment 1.1HNMR(CDCl3, 400MHz) and δ: 8.92 (t, 1H), 8.21 (d, 1H), 8.13 (d, 1H), 7.35 (dd, 1H), 5.89 (m, 1H), 3.76 (s, 3H), 3.68 (t, 4H), 3.16 (t, 4H), 2.56 (s, 3H), 2.38 (m, 5H), 2.08 (m, 2H), 1.82 (m, 2H), 1.69 (m, 2H)；
The preparation of preparation embodiment 5 compound 1B-2
Except replacing cyanoacetyl chloride with propyl chloroformate., adopt method synthesis compound 1B-2 (100mg) identical with the synthesis compound 1A-1 of preparation embodiment 1.1HNMR(CDCl3, 400MHz) and δ: 8.95 (s, 1H), 8.20 (d, 1H), 8.13 (d, 1H), 7.35 (dd, 1H), 5.89 (m, 1H), 4.09 (t, 2H), 3.68 (t, 4H), 3.16 (t, 4H), 2.55 (s, 3H), 2.37 (m, 5H), 2.07 (m, 2H), 1.89 (m, 2H), 1.70 (m, 4H), 0.96 (t, 3H)；
The preparation of preparation embodiment 6 compound 1B-3
Except replacing cyanoacetyl chloride with isopropyl chlorocarbonate, adopt method synthesis compound 1B-3 (95mg) identical with the synthesis compound 1A-1 of preparation embodiment 1.1HNMR(CDCl3, 400MHz) and δ: 8.96 (s, 1H), 8.20 (d, 1H), 8.14 (d, 1H), 7.35 (dd, 1H), 5.89 (t, 1H), 4.97 (m, 1H), 3.67 (t, 4H), 3.15 (t, 4H), 2.55 (s, 3H), 2.37 (m, 5H), 2.08 (m, 2H), 1.91 (m, 2H), 1.70 (m, 2H), 1.28 (d, 6H)；
The preparation of preparation embodiment 7 compound 1B-4
Except replacing cyanoacetyl chloride with butyl chloroformate, adopt method synthesis compound 1B-4 (90mg) identical with the synthesis compound 1A-1 of preparation embodiment 1.1HNMR(CDCl3, 400MHz) and δ: 8.88 (d, 1H), 8.21 (d, 1H), 8.10 (t, 1H), 7.36 (dd, 1H), 5.90 (m, 1H), 4.15 (t, 2H), 3.69 (t, 4H), 3.16 (t, 4H), 2.57 (s, 3H), 2.40 (m, 5H), 2.08 (m, 2H), 1.90 (q, 2H), 1.74 (m, 2H), 1.66 (m, 2H), 1.42 (m, 2H), 0.97 (t, 3H)；
The preparation of preparation embodiment 8 compound 1B-5
Except replacing cyanoacetyl chloride with isobutyl chlorocarbonate, adopt method synthesis compound 1B-5 (98mg) identical with the synthesis compound 1A-1 of preparation embodiment 1.1HNMR(CDCl3, 400MHz) and δ: 8.86 (s, 1H), 8.22 (d, 1H), 8.09 (d, 1H), 7.36 (dd, 1H), 5.89 (m, 1H), 3.93 (d, 2H), 3.70 (t, 4H), 3.17 (t, 4H), 2.57 (s, 3H), 2.40 (m, 5H), 2.08 (m, 2H), 1.91 (q, 2H), 1.72 (m, 4H), 0.98 (d, 6H)；
The preparation of preparation embodiment 9 compound 1B-6
Except replacing cyanoacetyl chloride with amyl chlorocarbonate, adopt method synthesis compound 1B-6 (80mg) identical with the synthesis compound 1A-1 of preparation embodiment 1.1HNMR(CDCl3, 400MHz) and δ: 8.89 (t, 1H), 8.21 (d, 1H), 8.11 (t, 1H), δ 7.36 (dd, 1H), 5.89 (m, 1H), 4.13 (t, 2H), 3.69 (t, 4H), 3.16 (t, 4H), 2.56 (s, 3H), 2.38 (m, 5H), 2.08 (q, 2H), 1.75 (t, 2H), 1.71 (q, 2H), 1.67 (m, 4H), 1.37 (m, 2H), 0.94 (m, 3H)；
The preparation of preparation embodiment 10 compound 1B-7
Except replacing cyanoacetyl chloride with chloro-carbonic acid acetyl-o-methyl ester, adopt method synthesis compound 1B-7 (60mg) identical with the synthesis compound 1A-1 of preparation embodiment 1.1HNMR(CDCl3, 400MHz) and δ: 8.92 (s, 1H), 8.22 (d, 1H), 8.12 (d, 1H), 7.36 (dd, 1H), 5.89 (m, 1H), 5.84 (s, 2H), 3.72 (t, 4H), 3.18 (d, 4H), 2.56 (t, 3H), 2.38 (m, 5H), 2.15 (d, 3H), 2.09 (m, 2H), 1.90 (m, 2H), 1.73 (m, 2H)；
The preparation of preparation embodiment 11 compound 1C-1
Except replacing cyanoacetyl chloride with substituted-amino chloroacetic chloride, adopt method synthesis compound 1C-1 (90mg) identical with the synthesis compound 1A-1 of preparation embodiment 1.1HNMR (DMSO-d6,400MHz) δ: 10.13 (s, 1H), 8.96 (s, 1H), 8.10 (d, 1H), 7.89 (m, 1H), 7.52 (m, 1H), 5.83 (m, 1H), 3.65 (m, 4H), 3.22 (m, 2H), 3.09 (m, 4H), 2.69 (m, 4H), 2.47 (m, 3H), 2.33 (m, 3H), 2.25 (m, 2H), 1.89 (m, 2H), 1.78 (m, 2H), 1.59 (m, 2H).
The preparation of preparation embodiment 12 compound 1C-2
Except replacing cyanoacetyl chloride with N-methoxy-propyl glycyl chloro, adopt method synthesis compound 1C-2 (98mg) identical with the synthesis compound 1A-1 of preparation embodiment 1.1HNMR (DMSO-d6,400MHz) δ: 10.15 (s, 1H), 8.96 (s, 1H), 8.09 (d, 1H), 7.88 (d, 1H), 7.50 (m, 1H), 5.82 (m, 1H), 3.65 (m, 4H), 3.46 (m, 2H), 3.15 (s, 3H), 3.14 (m, 4H), 2.59 (m, 4H), 2.42 (s, 3H), 2.25 (s, 3H), 2.22 (m, 2H), 1.91 (m, 2H), 1.76 (m, 2H), 1.59 (m, 4H)；
The preparation of preparation embodiment 13 compound 1D-1
Except replacing cyanoacetyl chloride, reaction temperature to be increased to outside reflux temperature with bromoacetate, adopt method synthesis compound 1D-1 (70mg) identical with the synthesis compound 1A-1 of preparation embodiment 1.1HNMR(CDCl3, 400MHz) and δ: 8.87 (s, 1H), 8.16 (d, 1H), 8.09 (d, 1H), 7.34 (dd, 1H), 5.88 (m, 1H), 4.22 (q, 2H), 3.27 (m, 7H), 2.79 (t, 4H), 2.38 (m, 5H), 2.05 (m, 2H), 1.88 (m, 2H), 1.68 (m, 2H), 1.28 (m, 5H)；
The preparation of preparation embodiment 14 compound 1D-2
Except replacing bromoacetate with chloroacetamide, adopt method synthesis compound 1D-2 (110mg) identical with the synthesis compound 1D-1 of preparation embodiment 13.MSm/z:505.2 [M+H]+.
The preparation of preparation embodiment 15 compound 1D-3
Except replacing bromoacetate with methyl bromide c, adopt method synthesis compound 1D-3 (90mg) identical with the synthesis compound 1D-1 of preparation embodiment 13.1HNMR(CDCl3, 400MHz) and δ: 8.82 (s, 1H), 8.18 (d, 1H), 8.01 (d, 1H), 7.32 (dd, 1H), 5.88 (m, 1H), 4.17 (m, 2H), 3.20 (m, 4H), 2.81 (m, 2H), 2.79 (m, 4H), 2.37 (m, 5H), 2.04 (m, 5H), 1.88 (m, 2H), 1.68 (m, 2H), 1.28 (m, 5H)；
The preparation of preparation embodiment 16 compound 1D-4
Except replacing bromoacetate with bromo-propionic acid, adopt method synthesis compound 1D-4 (78mg) identical with the synthesis compound 1D-1 of preparation embodiment 13.1HNMR (DMSO-d6,400MHz) δ: 11.3 (s, 1H), 9.05 (s, 1H), 8.15 (m, 1H), 8.04 (m, 1H), 7.95 (m, 1H), 5.84 (m, 1H), 5.39 (t, 2H), 3.61 (m, 4H), 3.19 (m, 4H), 2.95 (m, 2H), 2.43 (s, 3H), 2.35 (s, 3H), 2.22 (m, 2H), 1.94 (m, 2H), 1.80 (m, 2H), 1.59 (m, 2H).
The preparation of preparation embodiment 17 compound 1E-1
Except replacing bromoacetate with 2-methoxyl group bromoethane, adopt method synthesis compound 1E-1 (105mg) identical with the synthesis compound 1D-1 of preparation embodiment 13.1HNMR (DMSO-d6,400MHz) δ: 10.08 (s, 1H), 8.96 (s, 1H), 8.05 (d, 1H), 7.85 (d, 1H), 7.46 (m, 1H), 5.83 (m, 1H), 3.48 (m, 2H), 3.26 (s, 3H), 3.16 (m, 4H), 2.59 (m, 4H), 2.57 (m, 2H), 2.32 (s, 3H), 2.27 (s, 3H), 2.22 (m, 2H), 1.89 (m, 2H), 1.79 (m, 2H), 1.61 (m, 2H)；
The preparation of preparation embodiment 18 compound 1E-2
Except replacing bromoacetate with bromoethanol, adopt method synthesis compound 1E-2 (97mg) identical with the synthesis compound 1D-1 of preparation embodiment 13.1HNMR (DMSO-d6,400MHz) δ: 10.09 (s, 1H), 8.96 (s, 1H), 8.06 (d, 1H), 7.85 (d, 1H), 7.47 (m, 1H), 5.83 (m, 1H), 4.55 (s, 1H), 3.57 (m, 2H), 3.20 (m, 4H), 2.66 (m, 4H), 2.57 (m, 2H), 2.43 (s, 3H), 2.33 (s, 3H), 2.27 (m, 2H), 1.88 (m, 2H), 1.76 (m, 2H), 1.59 (m, 2H)；
The preparation of preparation embodiment 19 compound 1E-3
Except replacing bromoacetate with butanoic acid chloromethyl ester, adopt method synthesis compound 1E-3 (80mg) identical with the synthesis compound 1D-1 of preparation embodiment 13.1HNMR(CDCl3, 400MHz) and δ: 8.92 (s, 1H), 8.25 (d, 1H), 8.12 (d, 1H), 7.36 (dd, 1H), 5.89 (m, 1H), 3.83 (t, 2H), 3.69 (t, 2H), 3.18 (m, 4H), 2.56 (s, 3H), 2.38 (m, 7H), 2.08 (m, 2H), 1.89 (m, 4H), 1.72 (m, 4H), 1.01 (t, 3H)；
The preparation of preparation embodiment 20 compound 1E-4
Except replacing bromoacetate with N-methoxy ethyl bromine ethamine, adopt method synthesis compound 1E-4 (60mg) identical with the synthesis compound 1D-1 of preparation embodiment 13.MSm/z:549.1 [M+H]+.
The preparation of preparation embodiment 21 compound 1E-5
Except replacing bromoacetate with N-bromoethyl ethylenediamine, adopt method synthesis compound 1E-5 (50mg) identical with the synthesis compound 1D-1 of preparation embodiment 13.MSm/z:534.2 [M+H]+.
The preparation of preparation embodiment 22 compound 1F
Except replacing bromoacetate with iodomethane, adopt method synthesis compound 1F-1 (130mg) identical with the synthesis compound 1D-1 of preparation embodiment 13.1HNMR (DMSO-d6,400MHz) δ: 10.09 (s, 1H), 8.96 (s, 1H), 8.06 (d, 1H), 7.87 (d, 1H), 7.48 (d, 1H), 5.83 (t, 1H), 3.60 (m, 4H), 3.18 (m, 4H), 2.78 (s, 3H), 2.43 (s, 3H), 2.29 (s, 3H), 2.25 (m, 2H), 1.91 (m, 2H), 1.78 (m, 2H), 1.60 (m, 2H)；
The preparation of preparation embodiment 23 compound 1F-2
Except replacing bromoacetate with bromoethane, adopt method synthesis compound 1F-2 (120mg) identical with the synthesis compound 1D-1 of preparation embodiment 13.1HNMR (DMSO-d6,400MHz) δ: 10.09 (s, 1H), 8.96 (s, 1H), 8.06 (d, 1H), 7.87 (d, 1H), 7.48 (d, 1H), 5.83 (t, 1H), 3.60 (m, 4H), 3.18 (m, 4H), 2.76 (m, 2H), 2.43 (s, 3H), 2.29 (s, 3H), 2.25 (m, 2H), 1.91 (m, 2H), 1.78 (m, 2H), 1.60 (m, 2H), 1.13 (m, 3H)；
EXPERIMENTAL EXAMPLE cyclin-dependent kinase CDK4 and CDK6 inhibitory activity are analyzed:
Test example one: molecular level cyclin-dependent kinase CDK4 activity Inhibition test
Synthesized compound FRET (fluorescence resonance energy transfer) (FRET) method measures the inhibitory activity to CDK4/ cyclin D1, and compares with positive control drug.CDK4/ cyclin D1 obtains by directly buying test kit.
CDK4/ cyclin D1 kinase dilution liquid uses after being diluted to suitable concn.Containing CDK4/ cyclin D1, peptidesunstrate, HEPES (pH7.5), BRIJ-35, MgCl in kinase reaction mixture2And EDTA.CDK4phospho-peptidesubstrate is used as 100% phosphorylation comparison, is not added with ATP and is used as 0% phosphorylation comparison.After reacting 1 hour under room temperature, add the DevelopmentReagentA of appropriateness dilution to system.Room temperature continues reaction 1 hour, adds StopReagent and terminates reaction.Excitation wavelength 400nm, detection wavelength is 445nm (coumarin) and the fluorescence intensity of 520nm (fluorescein) simultaneously.Test-compound suppression ratio is calculated by formula.
Test example two: molecular level cyclin-dependent kinase CDK6 activity Inhibition test
Synthesized compound FRET (fluorescence resonance energy transfer) (FRET) method measures the inhibitory activity to CDK6/ Cyclin D2, and compares with positive control drug.CDK4/ cyclin D1 obtains by directly buying test kit.
CDK6/ Cyclin D2 kinase dilution liquid uses after being diluted to suitable concn.Containing CDK6/ Cyclin D2, peptidesunstrate, HEPES (pH7.5), BRIJ-35, MgCl in kinase reaction mixture2And EDTA.CDK6phospho-peptidesubstrate is used as 100% phosphorylation comparison, is not added with ATP and is used as 0% phosphorylation comparison.After reacting 1 hour under room temperature, add the DevelopmentReagentA of appropriateness dilution to system.Room temperature continues reaction 1 hour, adds StopReagent and terminates reaction.Excitation wavelength 400nm, detection wavelength is 445nm (coumarin) and the fluorescence intensity of 520nm (fluorescein) simultaneously.Test-compound suppression ratio is calculated by formula.
Test example three: the anti tumor activity in vitro test of cellular level
The inhibitory action to tumor cell lines such as breast carcinoma cell strain MDA-231, breast cancer cell line mcf-7s is measured with mtt assay.
Mtt assay utilizes the bluish violet crystal that the dehydrogenase that in living cells mitochondrion, existence is relevant to NADP can make ectogenic MTT be reduced into slightly solubility, and is deposited in cell, and dead cell is without this function.Again with the purple crystal thing in dimethyl sulfoxide (DMSO) dissolved cell, measure its OD its amount of viable cell of value indirect reaction at 570nm wavelength place with enzyme-linked immunosorbent assay instrument.
Compound DMSO is dissolved, dilution, tumor cell MCF-7 (human breast cancer cell), MDA-231 (human breast cancer cell) plant into 4000/200 μ L/ holes on 96 orifice plates, adding the sample (suspension cell can directly add after succeeding) sieved after cultivating 24 hours, cell is at 37 DEG C, 5%CO2After continuing cultivation under condition 48 hours, add MTT and continue to cultivate 4 hours, dissolving crystallized with DMSO, detect under microplate reader.
Following table is external CDK4 and CDK6 kinase activity and the tumor cell in vitro inhibitory activity test result of compound:
By the result in upper table it can be seen that CDK4 and CDK6 is all had stronger inhibitory action by all compounds under 10 micro-molar concentrations, especially compound 1B-6,1C-1,1D-2,1D-4,1E-2 and 1-F2 inhibitory activity higher than positive control drug.Further cell in vitro inhibitory activity experimental result is consistent with enzyme level inhibitory activity experimental result.
By to the structure of modification gained compound of Palbociclib retaining highly active while, part of compounds such as 1C-1, IC-2 isoreactivity relatively positive control has increased significantly, and lays a good foundation for research further.
Claims (10)
1. the pyrido-pyrimidines shown in below formula I and pharmaceutically acceptable salt thereof or pharmaceutically acceptable solvate:
Wherein:
R is selected from-C (=O) R1,-C (=O) OR2,-C (=O) CH2NHR3,-(CH2)nC (=O) R4,-(CH2)mXR5, C1-C6 alkyl；
R1Being independently selected from alkyl, haloalkyl, with carboxyl, the alkyl that cyano group replaces；
R2Each independent take from C1-C8 alkyl, ester group；
R3Each independent alkyl of taking from, haloalkyl, with carboxyl, cyano group, ester group, amino, the alkyl that alkoxyl replaces；
N takes from 1-5, R4Each independent hydrogen of taking from, alkyl, haloalkyl, with carboxyl, cyano group, ester group, amino, the alkyl that alkoxyl replaces；
M takes from 1-5, R5Each independent taking from hydrogen, alkyl, haloalkyl, with carboxyl, cyano group, ester group, amino, alkoxyl, the alkyl of carbonyl substituted；
X takes from O or N.
2. pyrido-pyrimidines as claimed in claim 1 and pharmaceutically acceptable salt thereof or pharmaceutically acceptable solvate, wherein,
R is selected from-C (=O) R1,-C (=O) OR2,-C (=O) CH2NHR3,-(CH2)nC (=O) R4,-(CH2)mXR5, C1-C6 alkyl；
R1Being independently selected from alkyl, haloalkyl, with carboxyl, the alkyl that cyano group replaces；
R2It is independently selected from C1-C6 alkyl, ester group；
R3Each independent taking from alkyl, haloalkyl, with cyano group, ester group, amino, the alkyl of methoxy substitution；
N takes from 1-5, R4Being independently selected from hydrogen, alkyl, haloalkyl, with carboxyl, cyano group, ester group, amino, methoxyl group, the alkyl that ethyoxyl replaces；
M takes from 1-5, R5Each independent taking from hydrogen, alkyl, haloalkyl, with carboxyl, cyano group, ester group, amino, methoxyl group, the alkyl of carbonyl substituted；
X takes from O or N.
3. pyrido-pyrimidines as claimed in claim 1 and pharmaceutically acceptable salt thereof or pharmaceutically acceptable solvate, wherein,
R is selected from-C (=O) R1,-C (=O) OR2,-C (=O) CH2NHR3,-(CH2)nC (=O) R4,-(CH2)mXR5, C1-C6 alkyl；
R1Each independent take from methyl, ethyl, propyl group, isopropyl, the tert-butyl group, bromoethyl, bromopropyl, chloroethyl, chloropropyl, formyl, acetate, propionyloxy, cyano group methyl；
R2It is independently selected from methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, amyl group, acetyl Oxymethylene；
R3Each take from methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, amyl group, aminomethane base, aminoethane base, methoxy methyl alkyl, Ethyl Methyl Ether base, methoxy propyl alkyl；
N takes from 1-5, R4It is independently selected from methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, amyl group, hydroxyl, aminomethane base, aminoethane base, methoxy methyl alkyl, Ethyl Methyl Ether base, methoxy propyl alkyl, formyl, acetate, propionyloxy, cyano group methyl；
M takes from 1-5, R5Each independent take from hydrogen, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, amyl group, ketone base, ethyl ketone base, acetonyl, bytyry；
X takes from O or N.
4. pyrido-pyrimidines as claimed in claim 1 and pharmaceutically acceptable salt thereof or pharmaceutically acceptable solvate, wherein,
R is selected from-C (=O) R1,-C (=O) OR2,-C (=O) CH2NHR3,-(CH2)nC (=O) R4,-(CH2)mXR5, C1-C6 alkyl；
R1It is independently selected from methyl, propionyloxy, cyano group methyl；
R2It is independently selected from methyl, propyl group, isopropyl, butyl, isobutyl group, amyl group, acetyl Oxymethylene；
R3It is independently selected from methoxy propyl alkyl, aminoethane base；
N takes from 1-5, R4It is independently selected from hydrogen, methyl, ethyl；
M takes from 1-5, R5It is independently selected from hydrogen, methyl, bytyry；
X takes from O or N.
5. pyrido-pyrimidines as claimed in claim 1 and pharmaceutically acceptable salt thereof or pharmaceutically acceptable solvate, wherein, the compound of described formula I is the pyrido-pyrimidines represented by one of below general formula:
Wherein, R1, R2, R3, R4 and R5 is identical with the restriction in formula I.
6. pyrido-pyrimidines as claimed in claim 1 and pharmaceutically acceptable salt thereof or pharmaceutically acceptable solvate, wherein, the compound of described formula I is a kind of compound in following compounds:
7. pyrido-pyrimidines according to any one of claim 1-6 and pharmaceutically acceptable salt thereof or its pharmaceutically acceptable solvate are as the purposes of CDK4 and CDK6 inhibitor.
8. pyrido-pyrimidines according to any one of claim 1-6, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate in preparation for preventing or treat the application in the medicine of the disease that the abnormal cell proliferation relevant to CDK4 and CDK6 in organism, metamorphosis and hypoerkinesia are correlated with.
9. a pharmaceutical composition, it comprises therapeutically effective selected from the pyrido-pyrimidines according to any one of claim 1-6, one or more in its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate or its mixture are as the pharmaceutical composition of active component, and optional pharmaceutically acceptable carrier, adjuvant or adjuvant.
10. a pharmaceutical composition, it comprises one or more and one or more CDK4 and CDK6 inhibitor in the pyrido-pyrimidines according to any one of claim 1-6, its pharmaceutically acceptable salt or pharmaceutically acceptable solvate or its mixture of therapeutically effective amount as active component.With optional pharmaceutically acceptable carrier, adjuvant or adjuvant.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014183520A1 (en) * | 2013-05-17 | 2014-11-20 | 上海恒瑞医药有限公司 | Thiophene miazines derivate, preparation method therefor, and medical application thereof |
| CN104447739A (en) * | 2014-11-07 | 2015-03-25 | 郑州泰基鸿诺药物科技有限公司 | Deuterated palbociclib derivative, and preparation method and application thereof |
| WO2016015597A1 (en) * | 2014-07-26 | 2016-02-04 | Sunshine Lake Pharma Co., Ltd. | Compounds as cdk small-molecule inhibitors and uses thereof |
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| WO2014183520A1 (en) * | 2013-05-17 | 2014-11-20 | 上海恒瑞医药有限公司 | Thiophene miazines derivate, preparation method therefor, and medical application thereof |
| WO2016015597A1 (en) * | 2014-07-26 | 2016-02-04 | Sunshine Lake Pharma Co., Ltd. | Compounds as cdk small-molecule inhibitors and uses thereof |
| CN104447739A (en) * | 2014-11-07 | 2015-03-25 | 郑州泰基鸿诺药物科技有限公司 | Deuterated palbociclib derivative, and preparation method and application thereof |
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