CN103333119A - 1,2-dihydro-6-methyl-4-substituted amino-5-pyrimidinecarboxylic acid compound and its preparation method and use - Google Patents
1,2-dihydro-6-methyl-4-substituted amino-5-pyrimidinecarboxylic acid compound and its preparation method and use Download PDFInfo
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Abstract
The invention relates to a 1,2-dihydro-6-methyl-4-substituted amino-5-pyrimidinecarboxylic acid compound shown in a general formula (I) and its pharmaceutically acceptable salt or pharmaceutically acceptable solvent mixture and also relates to a preparation method thereof, a pharmaceutical composition containing the 1,2-dihydro-6-methyl-4-substituted amino-5-pyrimidinecarboxylic acid compound, and a use of the 1,2-dihydro-6-methyl-4-substituted amino-5-pyrimidinecarboxylic acid compound in preparation of drugs for prevention or treatment on diseases related to cell abnormal proliferation and morphologic change and especially for prevention or treatment on tumor growth and metastasis.
Description
Technical field:
The present invention relates to medical technical field, be specifically related to a class and have 1 of anti-tumor activity, 2-dihydro-6-methyl-4-substituted-amino-5-pyrimidine carboxylic compounds and pharmacy acceptable salt or pharmaceutically acceptable solvate, its preparation method, comprise the pharmaceutical composition of this compound, and these compounds are for the preparation of relevant diseases such as prevention or treatment cellular abnormality propagation, metamorphosis, in particular for the purposes in the medicine for the treatment of or prophylaxis of tumours growth and transfer.
Background technology:
Tumour is a kind of disease of serious threat human health, mainly is owing to unreasonable diet, inherited genetic factors, environmental factors etc. are brought out.The mechanism of action of antitumor drug and the action target spot of medicine are diversified, and often cause the failure for the treatment of because tumour cell easily produces multidrug resistance.Searching effective and safe, the antitumor drug that toxic side effect is little are the targets that tumour medicine R﹠D work person seek assiduously always.
Pyrimidine is the very important 6-membered heterocyclic compound of a class, because of its widely biological activity enjoy people to favor in fields such as medicine, agricultural chemicals, cause showing great attention to of Pharmaceutical Chemist already as SARS drug design and synthetic basic building block.The chemical structure of this class medicine is similar to the necessary metabolic substd pyrimidine base of cell growth and breeding mostly, therefore can compete the binding site of enzyme, and with the pyrimidine in the form interference Nucleotide of pseudo-metabolite and the metabolism of precursor thereof.On the other hand, they also can be combined with nucleic acid, replace corresponding normal oligodeoxynucleotide, thereby disturb the normal biosynthesizing of DNA, stop the fissiparity of tumour cell.The pyrimidines that particularly has anti-tumor activity in recent years in a large number is in the news, and except marketed drug, some new pyrimidine compounds have entered clinical experimental stage.
Pyrimidines has become the important lead compound of finding and developing antitumor drug, is a drug research field that sustains its quality through age.Existing result of study shows, pyrimidine substitution in ring site and substituent diversity change, make the pyrimidines of anti-tumor activity have multifarious action target, as suppressing cell cycle protein dependent kinase, tyrosine protein kinase, carbonic anhydrase, Tetrahydrofolate dehydrogenase and interference tubulin polymerization etc.Therefore, the pyrimidines of composite structure novelty has potential anti-tumor biological and using value, has important theory and realistic meaning.
Nineteen eighty-three scientist in Poland Dlugosz, people such as Machon have reported that in one piece of document following route one is the class 6-[(substituted-phenyl shown in the representative) amino]-1,2-dihydro-4-methyl-2-oxygen-5-pyrimidine carboxylic compound, through preliminary pharmaceutical research test, this compounds has leukemia result for the treatment of preferably, but the synthetic route feedstock production difficulty of reporting, yield is extremely low.(Dlugosz?A，Machon?Z.et?al?Synthesis?and?biological?properties?of?amides?of4-arylamino-2-hydroxy-6-methyl-5-pyrimidinecarboxylic?acids?Acta?Poloniae?Pharmaceutica1983，40：1-6)
Recently, the contriver is according to design philosophys such as bioisostere principle, skeleton transition, fragrant heterocyclic substituted, heteroatoms insertion in the pharmaceutical chemistry, designed one group 1,2-dihydro-6-methyl-4-substituted-amino-5-pyrimidine carboxylic compounds, it is structure shown in the general formula (I), the chemical entities of expectation by synthetic this class novelty influences itself and the combination of receptor binding site, improves bioavailability and biological activity, the untoward reaction of reduction medicine.And based on this imagination, it is the multi-component reaction of the novelty of critical materials with the isocyanic ester that the contriver has invented a class, and synthesized designed 1 easily by this reaction, 2-dihydro-6-methyl-4-substituted-amino-5-pyrimidine carboxylic compounds and derivative thereof (structure shown in the general formula (I)), this reaction scheme has raw material and is easy to get, step is few, the advantage that yield is high.Through preliminary anti tumor activity in vitro test, the compound of this class formation has tumors inhibition activity preferably, wherein the external activity of part of compounds obviously is better than known compound (5 FU 5 fluorouracil and cytosine arabinoside), and this is more for we seek to be that the antineoplastic compound of parent nucleus has been opened up new field with the pyrimidine.
Summary of the invention:
An object of the present invention is to provide 1,2-dihydro-6-methyl-4-substituted-amino-5-pyrimidine carboxylic type of structured compound or its pharmacy acceptable salt or pharmaceutically acceptable solvate, described compound has the structure shown in following general formula (I), and it has good inhibitory effect to kinds of tumor cells.
Simultaneously, also to provide a kind of be the Biginelli-like reaction of three components of raw material with the isocyanic ester to a further object of the present invention.This reaction can be synthesized 1,2-dihydro-6-methyl-4-substituted-amino-5-pyrimidine carboxylic type of structured compound and derivative thereof efficiently.This reaction is reacted by the active carbonyl compound in the isocyanic ester surrogate response (aldehydes or ketones), this also is to utilize isocyanic ester first, urea and derivative thereof, 1,3 dicarbonyl compounds carry out multi-component reaction, react easy, the product yield height, inspiring people to use isocyanic ester is raw material, by the multifarious new compound of component reaction composite structure more the more.
Compound shown in the general formula of the present invention (I), its pharmacy acceptable salt or pharmaceutically acceptable solvate have been brought into play the effect of good inhibition growth of tumour cell.Therefore a further object of the present invention provides the compound shown in the general formula (I) or its pharmacy acceptable salt or pharmaceutically acceptable solvate for the preparation of the application in the medicine of prevention or treatment and relative diseases such as organism inner cell abnormality proliferation, metamorphosis, especially for the preparation for the treatment of or the prophylaxis of tumours growth application with the medicine of transfer.
Another purpose of the present invention provides the compound shown in the general formula (I) or its pharmacy acceptable salt or pharmaceutically acceptable solvate or its mixture as the pharmaceutical composition of active ingredient.
Another purpose of the present invention provides the application of the medicine of relative diseases such as the cellular abnormality propagation of aforementioned pharmaceutical compositions in being used for prevention or treatment and organism, metamorphosis, especially in the application for the preparation of the medicine for the treatment of or prophylaxis of tumours growth and transfer.
Another object of the present invention provides the method for a kind for the treatment of and organism interior cellular abnormality propagation, metamorphosis or the tumor growth disease relevant with transfer, and described method comprises and comprises the compound shown in the general formula (I), its pharmacy acceptable salt or pharmaceutically acceptable solvate or its mixture as the pharmaceutical composition of active ingredient to patient's drug treatment significant quantity
The general structure of pyrimidines of the present invention is shown in following general formula (I):
Wherein:
R
1For replacing arbitrarily or unsubstituted phenyl, heterocyclic radical, benzheterocycle base, low alkyl group or cycloalkyl, low-grade halogenated alkyl, rudimentary 4-nitro alkyl rudimentary cyano group alkyl, low alkyl group-cycloalkyl, cycloalkyl-low alkyl group, low alkyl group-cycloalkyl-low alkyl group;
Preferred R
1Represent following group, replacement or unsubstituted phenyl, heterocyclic radical, benzheterocycle base, low alkyl group;
X is oxygen, sulphur or NR
3Wherein, R
3Phenyl, C1-C4 alkyl, C3-C6 cycloalkyl for hydrogen, replacement arbitrarily;
Preferred X is oxygen, sulphur or NH;
R
2Be hydrogen, replacement or unsubstituted phenyl, replacement or unsubstituted low alkyl group or cycloalkyl, low alkyl group-cycloalkyl, cycloalkyl-low alkyl group, low alkyl group-cycloalkyl-low alkyl group, protection and unprotected glycosyl;
Preferred R
2Expression following groups: hydrogen, replacement or unsubstituted phenyl, low alkyl group or cycloalkyl, low-grade halogenated alkyl, rudimentary 4-nitro alkyl, rudimentary cyano group alkyl, protection and unprotected ribose, protection and unprotected ribodesose, protection and unprotected pectinose, protection and unprotected wood sugar, protection and unprotected glucose;
Wherein, described heterocyclic radical has aromaticity or non-aromaticity, is 5-7 unit heterocycle, and contains 1-3 heteroatoms that is selected among N, O and the S;
The term " rudimentary " relevant with alkyl refers to contain straight chain or the side chain saturated fatty hydrocarbyl group of 1-6 carbon atom herein; The term " rudimentary " relevant with alkenyl or alkynyl group refers to contain the group of 2-6 carbon atom and the one or more pairs of keys or triple bond; Cycloalkyl refers to contain the ring of 3-7 carbon; Aryl refers to list, two or the tricyclic hydrocarbon compound, and wherein at least one ring is aromatic nucleus, and each ring contains 7 carbon atoms at the most.
Described phenyl, heterocyclic radical or benzheterocycle base not necessarily by 1-3 be selected from C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxyl group, many halos-C1-C4-alkyl, many halogenated-c1-c4-alkoxies, C1-C4-alkoxy-C 1-C4-alkyl, C1-C4-alkoxy-C 1-C4-alkoxy-C 1-C4-alkyl, C3-C8 cycloalkyloxy-C1-C4-alkyl, halogen, nitro, trifluoromethyl, carbamyl, hydroxyl, cyano group, replace;
Described halogen is fluorine, chlorine, bromine or iodine;
Its pharmaceutically acceptable medicinal acid addition salt of the present invention comprises general formula (I) compound, additive salt with following acid formation: sulfuric acid, nitric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, phosphoric acid, formic acid, acetic acid, propionic acid, butyric acid, propanedioic acid, hexanodioic acid, toxilic acid, citric acid, tartrate, lactic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid, Aspartic Acid, how disulfonic acid, oxalic acid, phenylformic acid, succsinic acid, camphorsulfonic acid, L-glutamic acid, aspartic acid, oxysuccinic acid, Whitfield's ointment, xitix, Yi Yansuan, amygdalic acid, pyruvic acid or fumaric acid.
The pharmaceutically acceptable solvate of the compound of general formula of the present invention (I) expression comprises the compound of general formula (I) expression and the solvate of water, ethanol, Virahol, ether or acetone without limitation.
The structure of the pyrimidines of general formula of the present invention (I) is a class by 1 of one of following general formula expression, and 2-dihydro-6-methyl-4-substituted-amino-5-pyrimidine carboxylic compounds and derivative is shown below:
Wherein, R
1, R
2Identical with restriction in the general formula (1).
In part preferred embodiment of the present invention, the compound of described general formula (I) and pharmacy acceptable salt thereof or pharmaceutically acceptable solvate are a kind of compound that is selected from the following compounds:
The two hydrogen of 1,2--1-phenyl-6-methyl-2-oxygen-4-(meta-aminotoluene base)-5-pyrimidine carboxylic (IA1)
The two hydrogen of 1,2--1-ethyl-6-methyl-2-oxygen-4-(meta-aminotoluene base)-5-pyrimidine carboxylic (IA2)
The two hydrogen of 1,2--1-methyl-6-methyl-2-oxygen-4-(meta-aminotoluene base)-5-pyrimidine carboxylic (IA3)
1,2-dihydro-6-methyl-2-oxygen-4-(meta-aminotoluene base)-5-pyrimidine carboxylic (IA4)
The two hydrogen of 1,2--1-isobutyl--6-methyl-2-oxygen-4-(meta-aminotoluene base)-5-pyrimidine carboxylic (IA5)
The two hydrogen of 1,2--1-phenyl-6-methyl-2-oxygen-4-(4-chloroanilino)-5-pyrimidine carboxylic (IB1)
The two hydrogen of 1,2--1-ethyl-6-methyl-2-oxygen-4-(4-chloroanilino)-5-pyrimidine carboxylic (IB2)
The two hydrogen of 1,2--1-methyl-6-methyl-2-oxygen-4-(4-chloroanilino)-5-pyrimidine carboxylic (IB3)
1,2-dihydro-6-methyl-2-oxygen-4-(4-chloroanilino)-5-pyrimidine carboxylic (IB4)
The two hydrogen of 1,2--1-isobutyl--6-methyl-2-oxygen-4-(4-chloroanilino)-5-pyrimidine carboxylic (IB5)
The two hydrogen of 1,2--1-phenyl-6-methyl-2-oxygen-4-(anilino)-5-pyrimidine carboxylic (IC1)
The two hydrogen of 1,2--1-ethyl-6-methyl-2-oxygen-4-(anilino)-5-pyrimidine carboxylic (IC2)
The two hydrogen of 1,2--1-methyl-6-methyl-2-oxygen-4-(anilino)-5-pyrimidine carboxylic (IC3)
1,2-dihydro-6-methyl-2-oxygen-4-(anilino)-5-pyrimidine carboxylic (IC4)
The two hydrogen of 1,2--1-isobutyl--6-methyl-2-oxygen-4-(anilino)-5-pyrimidine carboxylic (IC5)
1,2-dihydro-6-methyl-2-sulphur-4-(meta-aminotoluene base)-5-pyrimidine carboxylic (ID1)
1,2-dihydro-6-methyl-2-sulphur-4-(p-Chlorobenzoic acid amide base)-5-pyrimidine carboxylic (ID2)
1,2-dihydro-6-methyl-2-sulphur-4-(anilino)-5-pyrimidine carboxylic (ID3)
The two hydrogen of 1,2--1-phenyl-6-methyl-2-sulphur-4-(meta-aminotoluene base)-5-pyrimidine carboxylic (ID4)
The two hydrogen of 1,2--1-ethyl-6-methyl-2-sulphur-4-(meta-aminotoluene base)-5-pyrimidine carboxylic (ID5)
The two hydrogen of 1,2--1-phenyl-6-methyl-2-sulphur-4-(p-Chlorobenzoic acid amide base)-5-pyrimidine carboxylic (ID6)
The two hydrogen of 1,2--1-phenyl-6-methyl-2-sulphur-4-(anilino)-5-pyrimidine carboxylic (ID7)
1,2-dihydro-6-methyl-2-imino--4-(meta-aminotoluene base)-5-pyrimidine carboxylic (IE1)
1,2-dihydro-6-methyl-2-imino--4-(p-Chlorobenzoic acid amide base)-5-pyrimidine carboxylic (IE2)
1,2-dihydro-6-methyl-2-imino--4-(anilino)-5-pyrimidine carboxylic (IE3)
Structural formula of compound in the part preferred embodiment of the present invention is as follows:
Pharmaceutical composition of the present invention, wherein contain significant quantity The compounds of this invention, its pharmacy acceptable salt or pharmaceutically acceptable solvate, formulation can be the formulation that tablet, capsule, powder, granule, pill, suppository, oral liquid, suspensoid, injection etc. are pharmaceutically used always.Wherein tablet for oral use and capsule contain traditional vehicle as: weighting material, thinner, lubricant, dispersion agent and tackiness agent can be prepared according to the method for knowing in this area.
The pharmacological agent dosage that contains The compounds of this invention, its pharmaceutically acceptable pharmaceutical salts or pharmaceutically acceptable solvate changes with disease kind, age, body weight difference, dosage range is 0.001-100mg/kg every day, the preferred dose scope is 0.1-50mg/kg every day, can be according to different this dosage ranges that depart from of difference and the formulation of disease degree.
Another object of the present invention provides the preparation method of the compound shown in the above-mentioned general formula (I) or its pharmacy acceptable salt or pharmaceutically acceptable solvate.This also is to utilize isocyanic ester first, urea and derivative thereof, and 1,3 dicarbonyl compound is synthetic to have the cytosine(Cyt) parent nucleus compound, and the preparation method has very strong novelty and very high using value, shown in the following reaction scheme;
Wherein, R
1, R
2Identical with the restriction in the general formula (I) with X;
This method may further comprise the steps;
(1) raw material 1 reacts in the presence of alkali with raw material 2 and generates intermediate 1;
(2) intermediate 1 and raw material 3 reacting generating compound I in the presence of alkali;
Wherein, the alkali of using in the step (1) is triethylamine, morpholine, piperidines, piperazine, methylpiperazine, NaH, pyridine, imidazoles, N-Methylimidazole, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU), 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene (DBN), 4-Dimethylamino pyridine (DMAP) or 1,4-diazabicylo [2.2.2] octane (DABCO) or N, N-diisopropylethylamine (DIPEA); Reaction solvent is 1,2-ethylene dichloride, toluene, benzene, hexanaphthene, methyl tertiary butyl ether, tetracol phenixin, normal hexane or with the optional mixed solvent of forming of these solvents, and is preferred 1,2-ethylene dichloride, toluene, tetrahydrofuran (THF) or acetonitrile; Temperature of reaction is 0 ℃ to 150 ℃, and preferred temperature is 20 ℃ to 70 ℃;
The alkali that uses in the step (2) is triethylamine, pyridine, imidazoles, N-Methylimidazole, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU), 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene (DBN), 4-Dimethylamino pyridine (DMAP) or N, N-diisopropylethylamine (DIPEA); Reaction solvent is 1,2-ethylene dichloride, toluene, benzene, hexanaphthene, methyl tertiary butyl ether, tetracol phenixin, normal hexane or with the optional mixed solvent of forming of these solvents, and is preferred 1,2-ethylene dichloride, toluene, tetrahydrofuran (THF) or acetonitrile; Temperature of reaction is 0 ℃ to 150 ℃, and preferred temperature is 40 ℃ to 100 ℃;
)
Embodiment:
The present invention is further elaborated below in conjunction with specific embodiment.These embodiment only are for purpose of explanation, and do not limit the scope of the invention and essence.
Preparation embodiment
1H-NMR with
13C-NMR is measured by Bruker AVANCE300 type instrument: aniline, p-Chlorobenzoic acid amide, 3-monomethylaniline, solid phosgene, methyl aceto acetate, toluene, 1,2-ethylene dichloride, hexanaphthene, triethylamine, 1,8-diazabicyclo [5.4.0], 11 carbon-7-alkene, 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene, thiocarbamide, Guanidinium hydrochloride, Guanidinium nitrate, urea, phenylurea, ethyl carbamide, the isobutyl-urea is produced by Chinese Medicine reagent company limited.All through distillation again, employed anhydrous solvent all obtains by the standard method drying treatment all solvents before use; Except explanation, it all is to carry out under nitrogen protection and by the thin-layer chromatography chromatogram tracking that institute responds, and all washs and the anhydrous sodium sulfate drying process through saturated sodium-chloride water solution during aftertreatment; The purifying of product all uses silica gel (200-300 order) column chromatography except recrystallization; Wherein column chromatography silica gel (200-300 order) is produced by Haiyang Chemical Plant, Qingdao with GF-254 tlc silica gel plate.
1, the preparation of preparation embodiment 1 compound I A1
The two hydrogen of 1,2--1-phenyl-6-methyl-2-oxygen-4-(meta-aminotoluene base)-5-pyrimidine carboxylic (IA1)
The preparation route is as follows:
1.1 the preparation of a tolyl isocyanic ester
In the there-necked flask that agitator, thermometer and constant pressure funnel are housed, add triphosgene 5.94g (20mmol) and 200mL toluene solvant, after the stirring and dissolving, the triethylamine mixed solution of 2.15g (20mmol) meta-aminotoluene and 0.51g (5mmol) slowly is added dropwise to reaction system equably through constant pressure funnel, 30min dropwises, and ice bath keeps temperature 0-5 ℃ of reaction system in the dropping process.Dropwise the recession deicing and bathe reflux 4-6h.This solution is carried out underpressure distillation (12mmHg), collect 74-76 ℃ of cut, namely get a tolyl isocyanic ester 1.83g, yield 83%.
1.2 carbonyl 3-oxygen-2-[(3-monomethylaniline)] preparation of ethyl butyrate
Methyl aceto acetate 1.30g (10mmol) and sodium hydride 0.24g (10mmol) are dissolved in the 100mL toluene, and behind the stirring 30min, tolyl isocyanic ester 1.33g (10mmol) between slowly adding stirred 3 hours.Reaction solution is poured in the 100mL water, separate organic layer, the saturated common salt water washing, toluene extraction (30mL * 3), merge organic layer, anhydrous sodium sulfate drying revolves desolventizing, column chromatography (sherwood oil: ethyl acetate=4: 1) obtain intermediate 3-oxygen-2-[(3-monomethylaniline) carbonyl] ethyl butyrate 2.50g, yield 95%.
1.3 the preparation of compound I A1
With intermediate 3-oxygen-2-[(3-monomethylaniline) carbonyl] ethyl butyrate 1.32g (5mmol), phenylurea 0.68g (5mmol) is dissolved in the 50mL toluene, drips 0.07g (0.5mmol) DBU, and 80 ℃ were refluxed 2 hours.The TLC monitoring reaction after reaction finishes, after reaction solution concentrated, is poured in the 50mL frozen water, and white solid is filtered, and crude product obtains.With crude product recrystallization (ethanol: water=1: 1) obtain pure product 1.39g, yield 83%.
White solid; Fusing point: 219-221 ℃;
1H-NMR (300MHz, DMSO) δ: 11.78 (1H, s), 10.42 (1H, s), 7.6-6.8 (9H, m), 2.29 (3H, s), 1.93 (3H, s);
13C-NMR (75MHz, DMSO) δ: 162.1,161.5,154.0,150.2,138.8,137.9,136.5,129.5,129.1,128.9,128.6,124.2,119.7,116.4,110.6,21.1,18.7; HRMS (ESI) for (M+Na)
+: calcd358.1168, found358.1179
2, the preparation of preparation embodiment 2 compound I A2
The two hydrogen of 1,2--1-ethyl-6-methyl-2-oxygen-4-(meta-aminotoluene base)-5-pyrimidine carboxylic (IA2)
2.1 the preparation of compound I A2
Use with prepare embodiment 1.1 in identical preparation process, synthesize a tolyl isocyanic ester; Use with preparation embodiment 1.2 in identical preparation process, synthesize 3-oxygen-2-[(3-monomethylaniline) carbonyl] ethyl butyrate; With intermediate 3-oxygen-2-[(3-monomethylaniline) carbonyl] ethyl butyrate 1.32g (5mmol), ethyl carbamide 0.44g (5mmol) is dissolved in the 50mL toluene, drips 0.07g (0.5mmol) DBU, and 80 ℃ were refluxed 3 hours.The TLC monitoring reaction after reaction finishes, after reaction solution concentrated, is poured in the 50mL frozen water, and white solid is filtered, and crude product obtains.With crude product recrystallization (ethanol: water=1: 1) obtain pure product 1.12g, yield 78%.
White solid; Fusing point: 207-210 ℃;
1H-NMR (300MHz, DMSO) δ: 11.59 (1H, s), 10.50 (1H, s), 7.5-6.8 (4H, m), 3.81 (2H, q, J=7.13), 2.37 (3H, s), 2.28 (3H, s), 1.16 (3H, t, J=7.13)
13C-NMR (75MHz, DMSO) δ: 162.5,160.9,150.2,149.5,138.7,138.0,128.5,124.1,119.7,116.4,105.5,35.1,21.1,18.1,16.6; HRMS (ESI) for (M+Na)
+: calcd310.1168, found310.1173
3, the preparation of preparation embodiment 3 compound I A3
The two hydrogen of 1,2--1-methyl-6-methyl-2-oxygen-4-(meta-aminotoluene base)-5-pyrimidine carboxylic (IA3)
3.1 the preparation of compound I A3
Use with prepare embodiment 1.1 in identical preparation process, synthesize a tolyl isocyanic ester; Use with preparation embodiment 1.2 in identical preparation process, synthesize 3-oxygen-2-[(3-monomethylaniline) carbonyl] ethyl butyrate; With intermediate 3-oxygen-2-[(3-monomethylaniline) carbonyl] ethyl butyrate 1.32g (5mmol), methyl urea 0.37g (5mmol) is dissolved in the 50mL toluene, drips 0.07g (0.5mmol) DBU, and 80 ℃ were refluxed 3 hours.The TLC monitoring reaction after reaction finishes, after reaction solution concentrated, is poured in the 50mL frozen water, and white solid is filtered, and crude product obtains.With crude product recrystallization (ethanol: water=1: 2) obtain pure product 1.05g, yield 71%.
White solid; Fusing point: 203-205oC;
1H-NMR (300MHz, DMSO) δ: 11.59 (1H, s), 10.31 (1H, s), 7.5-6.8 (4H, m), 3.34 (3H, s), 2.38 (3H, s), 2.29 (3H, s);
13C-NMR (75MHz, DMSO) δ: 162.4,161.1,155.1,150.6,138.9,137.9,128.5,124.2,119.7,116.4,110.6,30.6,21.1,17.5; HRMS (ESI) for (M+Na)+: calcd296.1011, found296.1018
4, the preparation of preparation embodiment 4 compound I A4
1,2-dihydro-6-methyl-2-oxygen-4-(meta-aminotoluene base)-5-pyrimidine carboxylic (IA4)
4.1 the preparation of compound I A4
Use with prepare embodiment 1.1 in identical preparation process, synthesize a tolyl isocyanic ester; Use with preparation embodiment 1.2 in identical preparation process, synthesize 3-oxygen-2-[(3-monomethylaniline) carbonyl] ethyl butyrate; With intermediate 3-oxygen-2-[(3-monomethylaniline) carbonyl] ethyl butyrate 1.32g (5mmol), urea 0.31g (5mmol) is dissolved in the 50mL toluene, drips 0.07g (0.5mmol) DBU, and 80 ℃ were refluxed 3 hours.The TLC monitoring reaction after reaction finishes, after reaction solution concentrated, is poured in the 50mL frozen water, and white solid is filtered, and crude product obtains.With crude product recrystallization (ethanol: water=1: 4) obtain pure product 0.88g, yield 68%.
White solid; Fusing point: 190-192 ℃;
1H-NMR (300MHz, DMSO) δ: 11.56 (1H, s), 11.43 (1H, s), 10.89 (1H, s), 7.5-6.8 (4H, m), 2.42 (3H, s), 2.28 (3H, s);
13C-NMR (75MHz, DMSO) δ: 164.0,161.9,158.6,149.5,138.7,138.0,128.6,124.0,119.9,116.5,104.7,21.1,18.6; HRMS (ESI) for (M+Na)+: calcd282.0855, found282.0861
5, the preparation of preparation embodiment 5 compound I A5
The two hydrogen of 1,2--1-isobutyl--6-methyl-2-oxygen-4-(meta-aminotoluene base)-5-pyrimidine carboxylic (IA5)
5.1 the preparation of compound I A5
Use with prepare embodiment 1.1 in identical preparation process, synthesize a tolyl isocyanic ester; Use with preparation embodiment 1.2 in identical preparation process, synthesize 3-oxygen-2-[(3-monomethylaniline) carbonyl] ethyl butyrate; With intermediate 3-oxygen-2-[(3-monomethylaniline) carbonyl] ethyl butyrate 1.32g (5mmol), isobutyl-urea 0.59g (5mmol) is dissolved in the 50mL toluene, drips 0.07g (0.5mmol) DBU, and 80 ℃ were refluxed 3 hours.The TLC monitoring reaction after reaction finishes, after reaction solution concentrated, is poured in the 50mL frozen water, and white solid is filtered, and obtains crude product.With crude product recrystallization (ethanol: water=1: 1) obtain pure product 1.23g, yield 78%.
The white powder solid; Fusing point 197-199 ℃;
1H-NMR (300MHz, DMSO) δ: 11.13 (1H, s), 10.34 (1H, s), 7.7-7.3 (4H, m), 3.38 (2H, d, J=6.9Hz), 2.43 (3H, s), 2.29 (3H, s), 2.03 (1H, m), 1.02 (6H, d, J=7.0Hz);
13C-NMR (75MHz, DMSO) δ: 166.7,162.7,158.5,143.7,137.8,137.7,129.0,128.9,118.9,115.2,106.7,30.2,24.4,23.6,21.8,18.6; HRMS (ESI) for (M+Na)
+: calcd316.1161, found316.1169
6, the preparation of preparation embodiment 6 compound I B1
The two hydrogen of 1,2--1-phenyl-6-methyl-2-oxygen-4-(4-chloroanilino)-5-pyrimidine carboxylic (IB1)
6.1 the preparation of rubigan isocyanic ester
In the there-necked flask that agitator, thermometer and constant pressure funnel are housed, add 5.94g (20mmol) triphosgene and 200mL toluene solvant, after the stirring and dissolving, p-Chlorobenzoic acid amide 2.55g (20mmol) slowly is added dropwise to reaction system with triethylamine 0.51g (5mmol) mixed solution equably through constant pressure funnel, 30min dropwises, and ice bath keeps temperature 0-5 ℃ of reaction system in the dropping process.Dropwise the recession deicing and bathe reflux 4-6h.This solution is carried out underpressure distillation (30mmHg), collect 129-133 ℃ of cut, namely get rubigan isocyanic ester 2.49g.Yield 81%.
6.2 carbonyl 3-oxygen-2-[(4-chloroaniline)] preparation of ethyl butyrate
Methyl aceto acetate 1.30g (10mmol) and sodium hydride 0.24g (10mmol) are dissolved in the 100mL toluene, behind the stirring 30min, slowly add rubigan isocyanic ester 1.54g (10mmol), stirred 3 hours.Reaction solution is poured in the 100mL water, separate organic layer, the saturated common salt water washing, toluene extraction (30mL * 3), merge organic layer, anhydrous sodium sulfate drying revolves desolventizing, column chromatography (sherwood oil: ethyl acetate=4: 1) obtain intermediate 3-oxygen-2-[(4-chloroaniline) carbonyl] ethyl butyrate 2.69g, yield 95%.
6.3 the preparation of compound I B1
With intermediate 3-oxygen-2-[(4-chloroaniline) carbonyl] ethyl butyrate 1.42g (5mmol), phenylurea 0.68g (5mmol) is dissolved in the 50mL toluene, drips 0.07g (0.5mmol) DBU, and 80 ℃ were refluxed 2 hours.The TLC monitoring reaction after reaction finishes, after reaction solution concentrated, is poured in the 50mL frozen water, and white solid is filtered, and crude product obtains.With crude product recrystallization (ethanol: water=1: 1) obtain pure product 1.57g, yield 91%.
White solid; Fusing point: 209-211 ℃;
1H-NMR (300MHz, DMSO) δ: 11.82 (1H, s), 10.63 (1H, s), 7.8-7.3 (9H, m), 1.93 (3H, s);
13C-NMR (75MHz, DMSO) δ: 162.3,161.4,154.2,150.2,137.8,136.4,129.5,129.1,128.9,128.6,127.1,120.8,110.4,18.7; HRMS (ESI) for (M+Na)
+: calcd378.0621, found378.0639
7, the preparation of preparation embodiment 7 compound I B2
The two hydrogen of 1,2--1-ethyl-6-methyl-2-oxygen-4-(4-chloroanilino)-5-pyrimidine carboxylic (IB2)
7.1 the preparation of compound I B2
Use with prepare embodiment 6.1 in identical preparation process, synthesize the rubigan isocyanic ester; Use with preparation embodiment 6.2 in identical preparation process, synthesize 3-oxygen-2-[(4-chloroaniline) carbonyl] ethyl butyrate; With intermediate 3-oxygen-2-[(4-chloroaniline) carbonyl] ethyl butyrate 1.42g (5mmol), ethyl carbamide 0.44g (5mmol) is dissolved in the 50mL toluene, drips 0.07g (0.5mmol) DBU, and 80 ℃ were refluxed 3 hours.The TLC monitoring reaction after reaction finishes, after reaction solution concentrated, is poured in the 50mL frozen water, and white solid is filtered, and crude product obtains.With crude product recrystallization (ethanol: water=1: 1) obtain pure product 1.29g, yield 84%.
White solid; Fusing point: 221-223 ℃;
1H-NMR (300MHz, DMSO) δ: 11.13 (1H, s), 10.34 (1H, s), 7.7-7.3 (4H, m), 3.87 (2H, q, J=6.9Hz), 2.43 (3H, s), 1.22 (3H, t, J=6.9Hz);
13C-NMR (75MHz, DMSO) δ: 166.7,162.7,158.5,143.7,137.8,137.7,129.0,128.9,118.9,115.2,106.7,30.2,24.4,21.8; HRMS (ESI) for (M+Na)
+: calcd330.0621, found330.0627
8, the preparation of preparation embodiment 8 compound I B3
The two hydrogen of 1,2--1-methyl-6-methyl-2-oxygen-4-(4-chloroanilino)-5-pyrimidine carboxylic (IB3)
8.1 the preparation of compound I B3
Use with prepare embodiment 6.1 in identical preparation process, synthesize the rubigan isocyanic ester; Use with preparation embodiment 6.2 in identical preparation process, synthesize 3-oxygen-2-[(4-chloroaniline) carbonyl] ethyl butyrate; With intermediate 3-oxygen-2-[(4-chloroaniline) carbonyl] ethyl butyrate 1.42g (5mmol), methyl urea 0.37g (5mmol) is dissolved in the 50mL toluene, drips 0.07g (0.5mmol) DBU, and 80 ℃ were refluxed 3 hours.The TLC monitoring reaction after reaction finishes, after reaction solution concentrated, is poured in the 50mL frozen water, and white solid is filtered, and crude product obtains.With crude product recrystallization (ethanol: water=1: 2) obtain pure product 1.10g, yield 75%.
White solid; Fusing point: 206-209 ℃;
1H-NMR (300MHz, DMSO) δ: 11.09 (1H, s), 9.63 (1H, s), 7.5-7.3 (4H, m), 3.09 (3H, s), 2.37 (3H, s)
13C-NMR (75MHz, DMSO) δ: 167.6,164.5,154.0,148.3,137.1,136.8,130.1,123.0,116.0,110.3,29.5,16.3.HRMS (ESI) for (M+Na)
+: calcd316.0465, found316.0469
9, the preparation of preparation embodiment 9 compound I B4
1,2-dihydro-6-methyl-2-oxygen-4-(4-chloroanilino)-5-pyrimidine carboxylic (IB4)
9.1 the preparation of compound I B4
Use with prepare embodiment 6.1 in identical preparation process, synthesize the rubigan isocyanic ester; Use with preparation embodiment 6.2 in identical preparation process, synthesize 3-oxygen-2-[(4-chloroaniline) carbonyl] ethyl butyrate; With intermediate 3-oxygen-2-[(4-chloroaniline) carbonyl] ethyl butyrate 1.42g (5mmol), urea 0.31g (5mmol) is dissolved in the 50mL toluene, drips 0.07g (0.5mmol) DBU, and 80 ℃ were refluxed 3 hours.The TLC monitoring reaction after reaction finishes, after reaction solution concentrated, is poured in the 50mL frozen water, and white solid is filtered, and crude product obtains.With crude product recrystallization (ethanol: water=1: 4) obtain pure product 0.94g, yield 67%.
White solid; Fusing point: 195-197 ℃;
1H-NMR (300MHz, DMSO) δ: 11.55 (2H, s), 11.02 (1H, s), 7.7-7.3 (4H, m), 2.40 (3H, s);
13C-NMR (75MHz, DMSO) δ: 162.4,161.1,155.0,150.6,138.9,137.9,128.5,124.2,119.7,110.6,17.5; HRMS (ESI) for (M+Na)
+: calcd302.0308, found302.0314
10, the preparation of preparation embodiment 10 compound I B5
The two hydrogen of 1,2--1-isobutyl--6-methyl-2-oxygen-4-(4-chloroanilino)-5-pyrimidine carboxylic (IB5)
10.1 the preparation of compound I B5
Use with prepare embodiment 6.1 in identical preparation process, synthesize the rubigan isocyanic ester; Use with preparation embodiment 6.2 in identical preparation process, synthesize 3-oxygen-2-[(4-chloroaniline) carbonyl] ethyl butyrate; With intermediate 3-oxygen-2-[(4-chloroaniline) carbonyl] ethyl butyrate 1.42g (5mmol), isobutyl-urea 0.59g (5mmol) is dissolved in the 50mL toluene, drips 0.07g (0.5mmol) DBU, and 80 ℃ were refluxed 3 hours.The TLC monitoring reaction after reaction finishes, after reaction solution concentrated, is poured in the 50mL frozen water, and white solid is filtered, and crude product obtains.With crude product recrystallization (ethanol: water=1: 1) obtain pure product 1.40g, yield 84%.
The white powder solid; Fusing point 193-195 ℃;
1H-NMR (300MHz, DMSO) δ: 11.83 (1H, s), 10.23 (1H, s), 7.7-7.3 (4H, m), 3.26 (2H, d, J=7.5Hz), 2.41 (3H, s), 2.18 (3H, s), 1.98 (1H, m), 0.92 (6H, d, J=6.9Hz);
13C-NMR (75MHz, DMSO) δ: 166.5,162.6,158.3,144.1,138.4,137.7,129.1,129.0,119.0,115.1,106.4,30.1,24.5,23.3,21.4,19.1; HRMS (ESI) for (M+Na)
+: calcd358.0934, found358.0969
11, the preparation of preparation embodiment 11 compound I C1
The two hydrogen of 1,2--1-phenyl-6-methyl-2-oxygen-4-(anilino)-5-pyrimidine carboxylic (IC1)
11.1 the preparation of phenyl isocyanate
In the there-necked flask that agitator, thermometer and constant pressure funnel are housed, add 5.94g (20mmol) triphosgene and 200mL toluene solvant, after the stirring and dissolving, aniline 1.86g (20mmol) slowly is added dropwise to reaction system with triethylamine 0.50g (5mmol) mixed solution equably through constant pressure funnel, 30min dropwises, and ice bath keeps temperature 0-5 ℃ of reaction system in the dropping process.Dropwise the recession deicing and bathe reflux 4-6h.This solution is carried out fractionation, collect 159-168 ℃ of cut, namely get benzene isocyanic ester 1.91g, yield 81%.
11.2 carbonyl 3-oxygen-2-[(aniline)] preparation of ethyl butyrate
Methyl aceto acetate 1.30g (10mmol) and sodium hydride 0.24g (10mmol) are dissolved in the 100mL toluene, behind the stirring 30min, slowly add phenyl isocyanate 1.19g (10mmol), stirred 3 hours.Reaction solution is poured in the 100mL water, separate organic layer, the saturated common salt water washing, toluene extraction (30mL * 3), merge organic layer, anhydrous sodium sulfate drying revolves desolventizing, column chromatography (sherwood oil: ethyl acetate=4: 1) obtain intermediate 3-oxygen-2-[(aniline) carbonyl] ethyl butyrate 2.31g, yield 93%.
11.3 the preparation of compound I C1
With intermediate 3-oxygen-2-[(aniline) carbonyl] ethyl butyrate 1.25g (5mmol), phenylurea 0.68g (5mmol) is dissolved in the 50mL toluene, drips 0.07g (0.5mmol) DBU, and 80 ℃ were refluxed 2 hours.The TLC monitoring reaction after reaction finishes, after reaction solution concentrated, is poured in the 50mL frozen water, and white solid is filtered, and crude product obtains.(ethanol: water=1: 1) recrystallization obtains pure product 1.24g, yield 77% with crude product.
The white powder solid; Fusing point 215-217 ℃;
1H-NMR (300MHz, DMSO) δ: 11.47 (1H, s), 10.80 (1H, s), 7.89-7.20 (10H, m), 2.30 (3H, s);
13C-NMR (75MHz, DMSO) δ: 162.4,161.7,154.6,150.3,137.9,135.1,130.5,129.1,128.3,127.4,120.2,109.8,19.2; HRMS (ESI) for (M+Na)
+: calcd344.1011, found344.1027
12, the preparation of preparation embodiment 12 compound I C2
The two hydrogen of 1,2--1-ethyl-6-methyl-2-oxygen-4-(anilino)-5-pyrimidine carboxylic (IC2)
12.1 the preparation of compound I C2
Use with prepare embodiment 11.1 in identical preparation process, synthesize phenyl isocyanate; Use with preparation embodiment 11.2 in identical preparation process, synthesize 3-oxygen-2-[(aniline) carbonyl] ethyl butyrate; With intermediate 3-oxygen-2-[(aniline) carbonyl] ethyl butyrate 1.25g (5mmol), ethyl carbamide 0.44g (5mmol) is dissolved in the 50mL toluene, drips 0.07g (0.5mmol) DBU, and 80 ℃ were refluxed 3 hours.The TLC monitoring reaction after reaction finishes, after reaction solution concentrated, is poured in the 50mL frozen water, and white solid is filtered, and crude product obtains.With crude product recrystallization (ethanol: water=1: 1) obtain pure product 1.17g, yield 86%.
The white powder solid; Fusing point 222-224 ℃;
1H-NMR (300MHz, DMSO) δ: 11.03 (1H, s), 10.14 (1H, s), 7.81-7.28 (5H, m), 3.79 (2H, q, J=7.5Hz), 2.47 (3H, s), 1.42 (3H, t, J=7.5Hz);
13C-NMR (75MHz, DMSO) δ: 166.7,162.7,158.5,143.7,137.8,137.7,129.0,128.9,118.9,115.2,106.7,29.6,23.3,20.5; HRMS (ESI) for (M+Na)
+: calcd296.1011, found296.1027
13, the preparation of preparation embodiment 13 compound I C3
The two hydrogen of 1,2--1-methyl-6-methyl-2-oxygen 4-(anilino)-5-pyrimidine carboxylic (IC3)
13.1 the preparation of compound I C3
Use with prepare embodiment 11.1 in identical preparation process, synthesize phenyl isocyanate; Use with preparation embodiment 11.2 in identical preparation process, synthesize 3-oxygen-2-[(aniline) carbonyl] ethyl butyrate; With intermediate 3-oxygen-2-[(aniline) carbonyl] ethyl butyrate 5mmol, methyl urea 0.37g (5mmol) is dissolved in the 50mL toluene, drips 0.07g (0.5mmol) DBU, and 80 ℃ were refluxed 3 hours.The TLC monitoring reaction, after reaction finished, after reaction solution concentrated, it was pregnant to pour the 50mL frozen water into, and white solid is filtered, and crude product obtains.With crude product recrystallization (ethanol: water=1: 2) obtain pure product 0.99g, yield 77%.
The white powder solid; Fusing point 202-204 ℃;
1H-NMR (300MHz, DMSO) δ: 11.49 (1H, s), 9.68 (1H, s), 7.51-7.20 (5H, m), 3.19 (3H, s), 2.41 (3H, s);
13C-NMR (75MHz, DMSO) δ: 168.7,162.3,153.9,148.3,136.8,135.3,134.1,121.0,118.1,109.3,29.7,16.3.HRMS (ESI) for (M+Na)
+: calcd282.0855, found282.0863
14, the preparation of preparation embodiment 14 compound I C4
1,2-dihydro-6-methyl-2-oxygen 4-(anilino)-5-pyrimidine carboxylic (IC4)
14.1 the preparation of compound I C4
Use with prepare embodiment 11.1 in identical preparation process, synthesize phenyl isocyanate; Use with preparation embodiment 11.2 in identical preparation process, synthesize 3-oxygen-2-[(aniline) carbonyl] ethyl butyrate; With intermediate 3-oxygen-2-[(aniline) carbonyl] ethyl butyrate 1.25g (5mmol), urea 0.31g (5mmol) is dissolved in the 50mL toluene, drips 0.07g (0.5mmol) DBU, and 80 ℃ were refluxed 3 hours.The TLC monitoring reaction after reaction finishes, after reaction solution concentrated, is poured in the 50mL frozen water, and white solid is filtered, and crude product obtains.With crude product recrystallization (ethanol: water=1: 4) obtain pure product 0.73g, yield 59%.
White solid; Fusing point: 206-208 ℃;
1H-NMR (300MHz, DMSO) δ: 11.15 (1H, s), 9.9 (2H, s), 8.1-7.0 (5H, m), 2.21 (3H, s);
13C-NMR (75MHz, DMSO) δ: 166.7,158.5,155.1,154.6,137.8,137.7,129.0,128.9,122.5,118.8,106.7,24.4; HRMS (ESI) for (M+Na)
+: calcd268.0698, found268.0706
15, the preparation of preparation embodiment 15 compound I C5
The two hydrogen of 1,2--1-isobutyl--6-methyl-2-oxygen-4-(anilino)-5-pyrimidine carboxylic (IC5)
15.1 the preparation of compound I C5
Use with prepare embodiment 11.1 in identical preparation process, synthesize phenyl isocyanate; Use with preparation embodiment 11.2 in identical preparation process, synthesize 3-oxygen-2-[(aniline) carbonyl] ethyl butyrate; With intermediate 3-oxygen-2-[(aniline) carbonyl] ethyl butyrate 1.25g (5mmol), isobutyl-urea 0.59g (5mmol) is dissolved in the 50mL toluene, drips 0.07g (0.5mmol) DBU, and 80 ℃ were refluxed 3 hours.The TLC monitoring reaction after reaction finishes, after reaction solution concentrated, is poured in the 50mL frozen water, and white solid is filtered, and crude product obtains.With crude product recrystallization (ethanol: water=1: 1) obtain pure product 1.22g, yield 81%.
The white powder solid; Fusing point 201-203 ℃; 1H-NMR (300MHz, DMSO) δ: 11.64 (1H, s), 10.38 (1H, s), 7.80-7.03 (5H, m), 3.56 (2H, d, J=7.2Hz), 2.43 (3H, s), 2.09 (3H, s), 1.96 (1H, m), 0.91 (6H, d, J=7.0Hz); 13C-NMR (75MHz, DMSO) δ: 167.1,161.8,159.0,145.8,138.7,136.3,128.7,128.0,120.1,115.8,106.7,31.2,23.8,22.7,21.1,19.6; HRMS (ESI) for (M+Na)
+: calcd324.1324, found324.1339
16, the preparation of preparation embodiment 16 compound I D1
1,2-dihydro-6-methyl-2-sulphur-4-(meta-aminotoluene base)-5-pyrimidine carboxylic (ID1)
16.1 the preparation of compound I D1
Use with prepare embodiment 1.1 in identical preparation process, synthesize a tolyl isocyanic ester; Use with preparation embodiment 1.2 in identical preparation process, synthesize 3-oxygen-2-[(3-monomethylaniline) carbonyl] ethyl butyrate; With intermediate 3-oxygen-2-[(3-monomethylaniline) carbonyl] ethyl butyrate 1.32g (5mmol), thiocarbamide 0.38g (5mmol) is dissolved in the 50mL toluene, drips 0.07g (0.5mmol) DBU, N
2Protection, 70 ℃ were refluxed 2 hours.The TLC monitoring reaction after reaction finishes, after reaction solution concentrated, is poured in the 50mL frozen water, and white solid is filtered, and obtains crude product.With crude product recrystallization (ethanol: water=1: 4) obtain pure product 1.01g, yield 73%.
White solid; Fusing point: 164-166 ℃;
1H-NMR (300MHz, DMSO) δ: 11.58 (1H, s), 11.47 (1H, s), 10.89 (1H, s), 7.5-6.8 (4H, m), 2.41 (3H, s), 2.28 (3H, s);
13C-NMR (75MHz, DMSO) δ: 164.0,161.9,158.6,149.5,138.7,138.0,128.6,124.0,119.9,116.6,107.5,23.1,15.9; HRMS (ESI) for (M+Na)
+: calcd275.3262, found275.3278
17, the preparation of preparation embodiment 17 compound I D2
1,2-dihydro-6-methyl-2-sulphur-4-(p-Chlorobenzoic acid amide base)-5-pyrimidine carboxylic (ID2)
17.1 the preparation of compound I D2
Use with prepare embodiment 6.1 in identical preparation process, synthesize the rubigan isocyanic ester; Use with preparation embodiment 6.2 in identical preparation process, synthesize 3-oxygen-2-[(4-chloroaniline) carbonyl] ethyl butyrate; With intermediate 3-oxygen-2-[(4-chloroaniline) carbonyl] ethyl butyrate 1.42g (5mmol), thiocarbamide 0.38g (5mmol) is dissolved in the 50mL toluene, drips 0.07g (0.5mmol) DBU, N
2Protection, 70 ℃ were refluxed 2 hours.The TLC monitoring reaction after reaction finishes, after reaction solution concentrated, is poured in the 50mL frozen water, and white solid is filtered, and crude product obtains.With crude product recrystallization (ethanol: water=1: 4) obtain pure product 0.98g, yield 66%.
Pale solid; Fusing point: 166-168 ℃;
1H-NMR (300MHz, DMSO) δ: 12.90 (1H, s), 12.65 (1H, s), 10.79 (1H, s), 7.7-7.3 (4H, m), 2.37 (3H, s);
13C-NMR (75MHz, DMSO) δ: 166.5,159.3,154.2,150.7,142.9,138.3,129.3,123.1,121.1,117.7,106.7,24.5; HRMS (ESI) for (M+Na)
+: calcd318.0080, found318.0086
18, the preparation of preparation embodiment 18 compound I D3
1,2-dihydro-6-methyl-2-sulphur 4-(anilino)-5-pyrimidine carboxylic (ID3)
18.1 the preparation of compound I D3
Use with prepare embodiment 11.1 in identical preparation process, synthesize phenyl isocyanate; Use with preparation embodiment 11.2 in identical preparation process, synthesize 3-oxygen-2-[(aniline) carbonyl] ethyl butyrate; With intermediate 3-oxygen-2-[(aniline) carbon back] ethyl butyrate 5mmol, thiocarbamide 0.38g (5mmol) is dissolved in the 50mL toluene, drips 0.07g (0.5mmol) DBU, N
2Protection, 70 ℃ were refluxed 2 hours.The TLC monitoring reaction after reaction finishes, after reaction solution concentrated, is poured in the 50mL frozen water, and white solid is filtered, and crude product obtains.With crude product recrystallization (ethanol: water=1: 4) obtain pure product 0.95g, yield 73%.
The white powder solid; Fusing point 156-158 ℃;
1H-NMR (300MHz, DMSO) δ: 11.15 (1H, s), 9.90 (2H, s), 8.12-7.01 (5H, m), 2.21 (3H, s);
13C-NMR (75MHz, DMSO) δ: 166.7,158.5,155.1,154.6,137.8,137.7,129.0,128.9,122.5,118.8,106.7,24.4; HRMS (ESI) for (M+Na)
+: calcd268.0698, found268.0706
19, the preparation of preparation embodiment 19 compound I D4
The two hydrogen of 1,2--1-phenyl-6-methyl-2-sulphur 4-(meta-aminotoluene base)-5-pyrimidine carboxylic (ID4)
19.1 the preparation of compound I D4
Use with prepare embodiment 1.1 in identical preparation process, synthesize a tolyl isocyanic ester; Use with preparation embodiment 1.2 in identical preparation process, synthesize 3-oxygen-2-[(3-monomethylaniline) carbonyl] ethyl butyrate; With intermediate 3-oxygen-2-[(3-monomethylaniline) carbonyl] ethyl butyrate 1.32g (5mmol), phenylthiourea 0.76g (5mmol) is dissolved in the 50mL toluene, drips 0.07g (0.5mmol) DBU, N
2Protection, 75 ℃ were refluxed 2 hours.The TLC monitoring reaction after reaction finishes, after reaction solution concentrated, is poured in the 50mL frozen water, and white solid is filtered, and obtains crude product.With crude product recrystallization (ethanol: water=1: 4) obtain pure product 1.49g, yield 85%.
The white powder solid; Fusing point 219-221oC;
1H-NMR (300MHz, DMSO) δ: 11.78 (1H, s), 10.42 (1H, s), 7.6-6.8 (9H, m), 2.29 (3H, s), 1.93 (3H, s);
13C-NMR (75MHz, DMSO) δ: 162.1,161.5,154.0,150.2,138.8,137.9,136.5,129.5,129.1,128.9,128.6,124.2,119.7,116.4,110.6,21.1,18.7; HRMS (ESI) for (M+Na)+: calcd358.1168, found358.1179
20, the preparation of preparation embodiment 20 compound I D5
The two hydrogen of 1,2--1-ethyl-6-methyl-2-sulphur-4-(meta-aminotoluene base)-5-pyrimidine carboxylic (ID5)
20.1 the preparation of compound I D5
Use with prepare embodiment 1.1 in identical preparation process, synthesize a tolyl isocyanic ester; Use with preparation embodiment 1.2 in identical preparation process, synthesize 3-oxygen-2-[(3-monomethylaniline) carbonyl] ethyl butyrate; With intermediate 3-oxygen-2-[(3-monomethylaniline) carbonyl] ethyl butyrate 1.32g (5mmol), ethyl thiourea 0.52g (5mmol) is dissolved in the 50mL toluene, drips 0.07g (0.5mmol) DBU, N
2Protection, 75 ℃ were refluxed 2 hours.The TLC monitoring reaction after reaction finishes, after reaction solution concentrated, is poured in the 50mL frozen water, and white solid is filtered, and obtains crude product.With crude product recrystallization (ethanol: water=1: 2) obtain pure product 1.18g, yield 78%.
The white powder solid; Fusing point 187-189 ℃;
1H-NMR (300MHz, DMSO) δ: 11.29 (1H, s), 9.85 (1H, s), 7.5-6.8 (4H, m), 3.81 (2H, q, J=7.70), 2.47 (3H, s), 2.38 (3H, s), 1.46 (3H, t, J=7.70);
13C-NMR (75MHz, DMSO) δ: 162.5,160.9,150.2,149.2,139.4,137.4,129.6,125.2,120.6,117.3,106.4,36.0,22.2,19.0,17.5; HRMS (ESI) for (M+Na)
+: calcd326.0939, found326.0947;
21, the preparation of preparation embodiment 21 compound I D6
The two hydrogen of 1,2--1-phenyl-6-methyl-2-sulphur-4-(p-Chlorobenzoic acid amide base)-5-pyrimidine carboxylic (ID6)
21.1 the preparation of compound I D6
Use with prepare embodiment 6.1 in identical preparation process, synthesize the rubigan isocyanic ester; Use with preparation embodiment 6.2 in identical preparation process, synthesize 3-oxygen-2-[(4-chloroaniline) carbonyl] ethyl butyrate; With intermediate 3-oxygen-2-[(4-chloroaniline) carbonyl] ethyl butyrate 1.42g (5mmol), phenylthiourea 0.76g (5mmol) is dissolved in the 50mL toluene, drips 0.07g (0.5mmol) DBU, N
2Protection, 70 ℃ were refluxed 2 hours.The TLC monitoring reaction after reaction finishes, after reaction solution concentrated, is poured in the 50mL frozen water, and white solid is filtered, and crude product obtains.With crude product recrystallization (ethanol: water=1: 1) obtain pure product 1.60g, yield 86%.
The white powder solid; Fusing point 219-221 ℃;
1H-NMR (300MHz, DMSO) δ: 11.61 (1H, s), 10.48 (1H, s), 7.80-7.21 (9H, m), 2.11 (3H, s);
13C-NMR (75MHz, DMSO) δ: 161.7,160.1,153.2,151.2,138.8,136.9,129.4,128.9,128.3,127.0,120.8,109.6,19.7; HRMS (ESI) for (M+Na)
+: calcd394.0393, found394.0401
22, the preparation of preparation embodiment 22 compound I D7
The two hydrogen of 1,2--1-phenyl-6-methyl-2-sulphur-4-(anilino)-5-pyrimidine carboxylic (ID7)
22.1 the preparation of compound I D7
Use with prepare embodiment 11.1 in identical preparation process, synthesize phenyl isocyanate; Use with preparation embodiment 11.2 in identical preparation process, synthesize 3-oxygen-2-[(aniline) carbonyl] ethyl butyrate; With intermediate 3-oxygen-2-[(aniline) carbonyl] ethyl butyrate 1.25g (5mmol), phenylthiourea 0.76g (5mmol) is dissolved in the 50mL toluene, drips 0.07g (0.5mmol) DBU, N
2Protection, 80 ℃ were refluxed 2 hours.The TLC monitoring reaction after reaction finishes, after reaction solution concentrated, is poured in the 50mL frozen water, and white solid is filtered, and crude product obtains.With crude product recrystallization (ethanol: water=1: 1) obtain pure product 1.19g, yield 71%.
The white powder solid; Fusing point 203-205 ℃; 1H-NMR (300MHz, DMSO) δ: 11.78 (1H, s), 10.42 (1H, s), 7.70-6.81 (10H, m), 2.29 (3H, s);
13C-NMR (75MHz, DMSO) δ: 162.7,161.4,154.1,150.4,138.3,137.2,136.1,129.7,128.4,124.2,119.7,116.4,110.6,23.1; HRMS (ESI) for (M+Na)
+: calcd360.0783, found360.0776
23, preparation embodiment 23 compound I E1 preparation
1,2-dihydro-6-methyl-2-imino-4-(meta-aminotoluene base)-5-pyrimidine carboxylic (IE1)
23.1 the preparation of compound I E1
Use with prepare embodiment 1.1 in identical preparation process, synthesize a tolyl isocyanic ester; Use with preparation embodiment 1.2 in identical preparation process, synthesize 3-oxygen-2-[(3-monomethylaniline) carbonyl] ethyl butyrate; Guanidinium hydrochloride 0.48g (5mmol) and triethylamine 0.41g (4mmol) are added in the 50mL toluene, liquid to be mixed is clarified fully, add intermediate 3-oxygen-2-[(3-monomethylaniline) carbonyl] ethyl butyrate 1.32g (5mmol), drip 0.07g (0.5mmol) DBU simultaneously, N
2Protection, 75 ℃ were refluxed 2 hours.The TLC monitoring reaction after reaction finishes, after reaction solution concentrated, is poured in the 50mL frozen water, with pale brown look solid filtering, obtains crude product.With crude product recrystallization (acetone: water=1: 1) obtain pure product 0.50g, yield 39%.
Pale brown look solid; Fusing point: 178-181 ℃;
1H-NMR (300MHz, DMSO) δ: 11.47 (2H, s), 10.91 (1H, s), 9.97 (1H, s), 7.53-6.80 (4H, m), 2.28 (3H, s), 2.07 (3H, s);
13C-NMR (75MHz, DMSO) δ: 165.8,162.7,159.4,149.3,136.3,135.0,128.0,118.1,117.6,115.0,110.4,26.7,20.8; HRMS (ESI) for (M+Na)
+: calcd281.1014, found281.1021
24, the preparation of preparation embodiment 24 compound I E2
1,2-dihydro-6-methyl-2-imino--4-(p-Chlorobenzoic acid amide base)-5-pyrimidine carboxylic (IE2)
24.1 the preparation of compound I E2
Use with prepare embodiment 6.1 in identical preparation process, synthesize the rubigan isocyanic ester; Use with preparation embodiment 6.2 in identical preparation process, synthesize 3-oxygen-2-[(4-chloroaniline) carbonyl] ethyl butyrate; Guanidinium hydrochloride 0.48g (5mmol) and triethylamine 0.41g (4mmol) are added in the 50mL toluene, and liquid to be mixed is clarified fully, adds intermediate 3-oxygen-2-[(4-chloroaniline) carbonyl] ethyl butyrate 1.42g (5mmol), drip 0.07g (0.5mmol) DBU simultaneously, N
2Protection, 75 ℃ were refluxed 2 hours.The TLC monitoring reaction after reaction finishes, after reaction solution concentrated, is poured in the 50mL frozen water, with pale brown look solid filtering, obtains crude product.With crude product through recrystallization (acetone: water=1: 1) obtain pure product 0.61g, yield 44%.
Pale brown look solid; Fusing point: 171-173 ℃;
1H-NMR (300MHz, DMSO) δ: 11.51 (2H, m), 10.91 (1H, s), 9.49 (1H, m), 7.50-7.17 (4H, m), 2.33 (3H, s);
13C-NMR (75MHz, DMSO) δ: 166.7,162.7,153.5,143.7,137.9,137.8,129.0,118.8,115.2,106.7,21.8; HRMS (ESI) for (M+Na)
+: calcd301.0468, found301.0476
25, the preparation of preparation embodiment 25 compound I E3
1,2-dihydro-6-methyl-2-imino--4-(anilino)-5-pyrimidine carboxylic (IE3)
25.1 the preparation of compound I E3
Use with prepare embodiment 11.1 in identical preparation process, synthesize phenyl isocyanate; Use with preparation embodiment 11.2 in identical preparation process, synthesize 3-oxygen-2-[(aniline) carbonyl] ethyl butyrate; Guanidinium hydrochloride 0.48g (5mmol) and triethylamine 0.41g (4mmol) are added in the 50mL toluene, and liquid to be mixed is clarified fully, adds intermediate 3-oxygen-2-[(aniline) carbonyl] ethyl butyrate 1.25g (5mmol), drip 0.07g (0.5mmol) DBU simultaneously, N
2Protection, 75 ℃ were refluxed 3 hours.The TLC monitoring reaction after reaction finishes, after reaction solution concentrated, is poured in the 50mL frozen water, with pale brown look solid filtering, obtains crude product.With crude product with recrystallization (acetone: water=1: 1) obtain pure product 0.57g, yield 47%.
Pale brown look solid; Fusing point: 176-178oC;
1H-NMR (300MHz, DMSO) δ: 11.31 (1H, s), 10.63 (1H, s), 9.90 (1H, s), 8.11-7.03 (5H, m), 2.21 (3H, s);
13C-NMR (75MHz, DMSO) δ: 166.7,158.5,154.5,144.4,137.1,136.7,129.0,128.9,122.5,119.2,106.4,25.4; HRMS (ESI) for (M+Na)
+: calcd267.0858, found267.0846
26, EXPERIMENTAL EXAMPLE: the anti-tumor activity test of The compounds of this invention
Compound of the present invention has been carried out the tumor cell proliferation inhibition test, and test method adopts conventional mtt assay (as Lv Qiujun chief editor " developmental pharmacology research method ", 2007:242-243)
Cell strain is selected human liver cancer cell (HepG2) for use, cervical cancer cell (Hela), and esophageal cancer cell (Eca109), non-small cell lung cancer cell (A549),
Human lung carcinoma cell (A549), human colon cancer cell (HT-29), human liver cancer cell (SMMC-7721), people's glioma cell (U251), people's adenocarcinoma of stomach cell (SGC-7901), human breast cancer cell (MCF-7).Nutrient solution is that DMEM+15%NBS+ is two anti-.
The preparation of sample liquid: after DMSO (Merck) dissolving, the solution of the 100 μ mol/L that adding PBS (-) is made into or uniform suspension are used PBS (-) dilution of DMSO then, and ultimate density is respectively 0.1,1,10,20,40,60,80,100 μ mol/L.
Antitumor drug cytosine arabinoside (Ara-C), the 5 FU 5 fluorouracil (5-FU) of listing are made into reference substance solution with same condition.
Cell cultures: adherent growth tumour cell cell cultures places 37 ℃, 5%CO in the RPMI-1640 that contains 10% deactivation new-born calf serum and penicillin, Streptomycin sulphate (each 1,000,000 U/L)
2, cultivate in the CO2gas incubator of saturated humidity.The cell attachment growth was gone down to posterity 1 time in per 2～3 days, at first poured out nutrient solution when going down to posterity, and PBS washes 2 times, after the trysinization, added fresh nutrient solution piping and druming evenly, adjusted cell to proper concn and moved in the new culturing bottle, added nutrient solution to an amount of.The vegetative period cell of taking the logarithm is used for experiment.
Mtt assay detects cytoactive and IC
50Mensuration;
Experimental principle: desaturase can be reduced into the MTT of yellow water-fast bluish voilet product first Za (MTT formazan) in the viable cell plastosome, and is deposited in the cell, and the amount of generation is directly proportional with the viable cell number, and dead cell does not have this function.DMSO can dissolve the bluish voilet crystallisate, and shade is directly proportional with contained amount, and therefore the absorbance value of measuring with microplate reader can reflect cell survival rate.
Experimental technique: the cell in vegetative period of taking the logarithm, digestion, counting are inoculated in 96 well culture plates every hole 100 μ l with the density of 2 * 104/mL.Cultivate after 24 hours, with 0.1,1,10,20,40,60,80,100 μ mol/L concentration are handled cell with testing compound.Each concentration of experimental group is established 5 multiple holes, compares with the nutrient solution that contains 0.4%DMSO.Behind the drug effect 48 hours, remove supernatant, every hole adds 100 μ l MTT (2-(4,5-dimethyl-2-thiazolyl)-3,5-phenylbenzene-2H-tetrazolium hydrobromate) (1mg/mL), continue to cultivate 4 hours, abandon supernatant, every hole adds 100 μ l DMSO, the vibration mixing, measure absorbance at the 570nm place with microplate reader, adopt IC
50Software for calculation (China Medicine University) is obtained half-inhibition concentration (IC
50).
Test-results sees table for details, wherein, sample refer to prepare among the corresponding embodiment 1,2-dihydro-6-methyl-4-substituted-amino-5-pyrimidine carboxylic compounds, the concrete numbering of resulting compound among the corresponding preparation of the sample number into spectrum embodiment.
Table 1 compound is to the half-inhibition concentration IC of different tumour cells
50(unit: μ mol/L)
Above experimental result shows, compound of the present invention has good antineoplastic activity, the anti tumor activity in vitro of compound I A1, IB1, IB2, IB5, IC5, ID1, ID4, ID6, IE3 obviously is better than cytosine arabinoside and 5 FU 5 fluorouracil, the anti-tumor activity of all the other compounds in the part cell strain is better than positive control drug cytosine arabinoside and 5 FU 5 fluorouracil, simultaneously N
1The antitumor activity of compound of substd is better than that obviously substituent compound is not arranged (IA1, IB4, IC4).Therefore the present invention 1,2-dihydro-6-methyl-4-substituted-amino-5-pyrimidine carboxylic compounds and pharmacy acceptable salt thereof or pharmaceutically acceptable solvate or its mixture can be for the preparation of antitumor drugs as the pharmaceutical composition of active ingredient.
Claims (8)
1. the present invention relates to 1,2-dihydro-6-methyl-4-substituted-amino-5-pyrimidine carboxylic type of structured compound or its pharmacy acceptable salt or hydrate or its mixture are as the pharmaceutical composition of active ingredient, and described structural general formula is as shown in the formula shown in (I):
Wherein:
R
1For replacing arbitrarily or unsubstituted phenyl, heterocyclic radical, benzheterocycle base, low alkyl group or cycloalkyl, low-grade halogenated alkyl, rudimentary 4-nitro alkyl rudimentary cyano group alkyl, low alkyl group-cycloalkyl, cycloalkyl-low alkyl group, low alkyl group-cycloalkyl-low alkyl group;
X is oxygen, sulphur or NR
3Wherein, R
3Phenyl, C1-C4 alkyl, C3-C6 cycloalkyl for hydrogen, replacement arbitrarily;
R
2Be hydrogen, replacement or unsubstituted phenyl, replacement or unsubstituted low alkyl group or cycloalkyl, low alkyl group-cycloalkyl, cycloalkyl-low alkyl group, low alkyl group-cycloalkyl-low alkyl group, protection and unprotected glycosyl;
Wherein, described heterocyclic radical has aromaticity or non-aromaticity, is 5-7 unit heterocycle, and contains 1-3 heteroatoms that is selected among N, O and the S;
The term " rudimentary " relevant with alkyl refers to contain straight chain or the side chain saturated fatty hydrocarbyl group of 1-6 carbon atom in the literary composition; The term " rudimentary " relevant with alkenyl or alkynyl group refers to contain the group of 2-6 carbon atom and the one or more pairs of keys or triple bond; Cycloalkyl refers to contain the ring of 3-7 carbon; Aryl refers to list, two or the tricyclic hydrocarbon compound, and wherein at least one ring is aromatic nucleus, and each ring contains 7 carbon atoms at the most.
Described phenyl, heterocyclic radical or benzheterocycle base not necessarily are selected from C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxyl group, many halos-C1-C4-alkyl, many halogenated-c1-c4-alkoxies, C1-C4-alkoxy-C 1-C4-alkyl, C1-C4-alkoxy-C 1-C4-alkoxy-C 1-C4-alkyl, C3-C8 cycloalkyloxy-C1-C4-alkyl, halogen, nitro, trifluoromethyl, carbamyl, hydroxyl, cyano group by 1-3 and replace;
Described halogen is fluorine, chlorine, bromine or iodine.
2. according to claim 11,2-dihydro-6-methyl-4-substituted-amino-5-pyrimidine carboxylic type of structured compound or its pharmacy acceptable salt or hydrate or its mixture is characterized in that as the pharmaceutical composition of active ingredient:
R
1The expression following groups, replacement or unsubstituted phenyl, heterocyclic radical, benzheterocycle base, low alkyl group;
X is oxygen, sulphur or NH;
R
2Expression following groups: hydrogen, replacement or unsubstituted phenyl, low alkyl group or cycloalkyl, low-grade halogenated alkyl, rudimentary 4-nitro alkyl, rudimentary cyano group alkyl, protection and unprotected ribose, protection and unprotected ribodesose, protection and unprotected pectinose, protection and unprotected wood sugar, protection and unprotected glucose;
Described substituted phenyl comprises without limitation: 2,3 or the 4-p-methoxy-phenyl, 2,3 or the 4-ethoxyl phenenyl, 2,3 or the 4-aminomethyl phenyl, 2,3 or the 4-ethylphenyl, 2,3 or the 4-chloro-phenyl-, 2,3 or the 4-bromophenyl, 2,3 or the 4-fluorophenyl, 2,3 or the 4-nitrophenyl, 2,3 or the 4-trifluoromethyl, 2,3 or the 4-cyano-phenyl, 2,3 or 2, the 4-dichlorophenyl, 2,3 or 2,4-Dimethoxyphenyl, 2,3 or 2,4-dinitrophenyl, 2,3 or 2,4-3,5-dimethylphenyl, 2,3 or 2,4-diethyl phenyl, 2,3 or 2,4-, two trifluoromethyls, 2,4,6-trimethylphenyl, 2,4,6-triethyl phenyl, 2,4, the 6-trimethoxyphenyl, 2,4,6-trichlorophenyl
Described heterocyclic radical and substituted heterocyclic radical comprise without limitation: furans-2 or 3-base, 2,3 or 4-methyl furan-2-base, 2,3 or 4-fluorine furans-2-base, 2,3 or 4-chlorine furans-2-base, 2,3 or 4-bromine furans-2-base, 2,4 or 5-methyl furan-3 base, 2,4 or 5-fluorine furans-3 base, 2,4 or 5-chlorine furans-3 base, 2,4 or 5-bromine furans-3 base, thiophene-2 or 3 bases, 2,3 or 4-thiotolene-2-base, 2,3 or 4-fluorine thiophene-2-base, 2,3 or 4-chlorothiophene-2-base, 2,3 or 4-bromothiophene-2-base, 2,4 or 5-thiotolene-3 base, 2,4 or 5-fluorine thiophene-3 base, 2,4 or 5-chlorothiophene-3 base, 2,4 or 5-bromothiophene-3 base, 1H-pyrroles-2 or 3 base and pyridines-2,3 or the 4-base;
Described benzheterocycle base and substituted benzheterocycle base comprise without limitation: benzo [c] [1,2,5] oxadiazole quinoline-4 or 5-bases, 1H-indoles-2,3,4,5,6 or the 7-base, 1,3-dihydro-benzo [d] imidazoles-2-ketone or 5-base, 1H-draw diindyl-ketone-4,5,6 or 7-base and 1 skatole-2-ketone-4,5,6 or the 7-base.
3. according to claim 11,2-dihydro-6-methyl-4-substituted-amino-5-pyrimidine carboxylic type of structured compound or its pharmacy acceptable salt or pharmaceutically acceptable solvate or its mixture are as the pharmaceutical composition of active ingredient, it is characterized in that: the structure of the pyrimidines of wherein said general formula (I) is a class by 1 of one of following general formula expression, 2-dihydro-6-methyl-4-substituted-amino-5-pyrimidine carboxylic compounds and derivative:
Wherein, R
1, R
2Identical with the restriction in claim 1 formula of (1).
4. according to claim 11,2-dihydro-6-methyl-4-substituted-amino-5-pyrimidine carboxylic type of structured compound or its pharmacy acceptable salt comprise general formula (I) compound, additive salt with following acid formation: sulfuric acid, nitric acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, phosphoric acid, formic acid, acetic acid, propionic acid, butyric acid, propanedioic acid, hexanodioic acid, toxilic acid, citric acid, tartrate, lactic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid, Aspartic Acid, how disulfonic acid, oxalic acid, phenylformic acid, succsinic acid, camphorsulfonic acid, L-glutamic acid, aspartic acid, oxysuccinic acid, Whitfield's ointment, xitix, Yi Yansuan, amygdalic acid, pyruvic acid or fumaric acid.
Pharmaceutically acceptable solvate comprises the compound of general formula (I) expression and the solvate of water, ethanol, Virahol, ether or acetone without limitation.
5. according to claim 1-4 described arbitrary 1,2-dihydro-6-methyl-4-substituted-amino-5-pyrimidine carboxylic type of structured compound or its pharmacy acceptable salt or pharmaceutically acceptable solvate or its mixture are as the pharmaceutical composition of active ingredient, it is characterized in that: the pharmaceutical composition of described general formula (I), wherein contain the significant quantity The compounds of this invention, its pharmacy acceptable salt or pharmaceutically acceptable solvate, formulation can be tablets, capsule, powder, granule, pill, suppository, oral liquid, suspensoid, the formulation that injection etc. are pharmaceutically used always.Wherein tablet for oral use and capsule contain traditional vehicle as: weighting material, thinner, lubricant, dispersion agent and tackiness agent can be prepared according to the method for knowing in this area.
The pharmacological agent dosage that contains The compounds of this invention, its pharmaceutically acceptable pharmaceutical salts or pharmaceutically acceptable solvate changes with disease kind, age, body weight difference, dosage range is 0.001-100mg/kg every day, the preferred dose scope is 0.1-50mg/kg every day, can be according to different this dosage ranges that depart from of difference and the formulation of disease degree.
6. according to claim 1-5, prepare arbitrary described 1,2-dihydro-6-methyl-4-substituted-amino-5-pyrimidine carboxylic type of structured compound or its pharmacy acceptable salt or pharmaceutically acceptable solvate or its mixture are as the method for the pharmaceutical composition of active ingredient, described method is utilized isocyanic ester, urea and derivative thereof or thiocarbamide and derivative thereof or guanidine and derivative thereof, 1,3 dicarbonyl compound is synthetic to have the cytosine(Cyt) parent nucleus compound, shown in the following reaction scheme;
Wherein, R
1, R
2Identical with the restriction in the general formula (I) with X;
This method may further comprise the steps;
(1) raw material 1 reacts in the presence of alkali with raw material 2 and generates intermediate 1;
(2) intermediate 1 and raw material 3 reacting generating compound I in the presence of alkali;
Wherein, the alkali of using in the step (1) is triethylamine, morpholine, piperidines, piperazine, methylpiperazine, NaH, pyridine, imidazoles, N-Methylimidazole, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU), 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene (DBN), 4-Dimethylamino pyridine (DMAP) or 1,4-diazabicylo [2.2.2] octane (DABCO) or N, N-diisopropylethylamine (DIPEA); Reaction solvent is 1,2-ethylene dichloride, toluene, benzene, hexanaphthene, methyl tertiary butyl ether, tetracol phenixin, normal hexane or with the optional mixed solvent of forming of these solvents, and is preferred 1,2-ethylene dichloride, toluene, tetrahydrofuran (THF) or acetonitrile; Temperature of reaction is 0 ℃ to 150 ℃, and preferred temperature is 20 ℃ to 70 ℃;
The alkali that uses in the step (2) is triethylamine, pyridine, imidazoles, N-Methylimidazole, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU), 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene (DBN), 4-Dimethylamino pyridine (DMAP) or N, N-diisopropylethylamine (DIPEA); Reaction solvent is 1,2-ethylene dichloride, toluene, benzene, hexanaphthene, methyl tertiary butyl ether, tetracol phenixin, normal hexane or with the optional mixed solvent of forming of these solvents, and is preferred 1,2-ethylene dichloride, toluene, tetrahydrofuran (THF) or acetonitrile; Temperature of reaction is 0 ℃ to 150 ℃, and preferred temperature is 40 ℃ to 100 ℃.
7. according to claim 1-6 described arbitrary 1,2-dihydro-6-methyl-4-substituted-amino-5-pyrimidine carboxylic class and pharmacy acceptable salt thereof or pharmaceutically acceptable solvent mixture or its mixture as the pharmaceutical composition of active ingredient for the preparation of the application in the medicine of relative diseases such as prevention or treatment and organism inner cell abnormality proliferation, metamorphosis, especially for the preparation for the treatment of or the prophylaxis of tumours growth application with the medicine that shifts.
8. application according to claim 7, provide the method for a kind for the treatment of and organism interior cellular abnormality propagation, metamorphosis or the tumor growth disease relevant with transfer, described method comprises and comprises the compound shown in the general formula (I), its pharmacy acceptable salt or pharmaceutically acceptable solvate or its mixture as the pharmaceutical composition of active ingredient to patient's drug treatment significant quantity.
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Application publication date: 20131002 |