CN104402875A - Synthesis method and application N-(2-aminoethyl)-N'-(6-substituted-2-benzothiazolyl)urea and salt compounds thereof - Google Patents
Synthesis method and application N-(2-aminoethyl)-N'-(6-substituted-2-benzothiazolyl)urea and salt compounds thereof Download PDFInfo
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Abstract
The invention belongs to the technical field of antineoplastic drugs, and particularly relates to N-(2-aminoethyl)-N'-(6-substituted-2-benzothiazolyl)urea (Formula I) and salt (Formula II) compounds thereof, and a synthesis method and application thereof. The structural formula of the compounds is disclosed in the specification. The synthesis method of the compounds is easy to implement. The antitumor cell proliferation activity determination indicates that the compounds have an obvious inhibiting action on proliferation of human colon cancer cell HCT116, human mammary cancer cell MCF-7 and human lung cancer cell A549; and the representative compounds have an obvious inhibiting action on growth of tumor cells. The compounds can be used for preparing antineoplastic drug preparations.
Description
Technical field
The invention belongs to antitumor drug technical field, be specifically related to N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) urea and salt compounds, preparation method and use.
Background technology
Cancer is one of malignant disease of serious threat human health.Over nearly 30 years, China's cancer incidence is in the quick rising stage, and cancer morbidity is about 2,00/,100,000 people, and annual pathogenesis of cancer number about 2,600,000, is controlling more than patient 7,000,000 people, dead 1,800,000 people.
The treatment means of current cancer remains traditional operative treatment, radiotherapy and pharmacological agent, but is still based on pharmacological agent to a great extent.Therefore, new antitumor drug is researched and developed significant.
In recent years, along with oncomolecularbiology progress of research, more understanding has been had to tumor pathogenesis, have found the novel targets of many antitumor drug effects, the development of antitumor drug is made to obtain many achievements newly, as topoisomerase enzyme inhibitor, kinases inhibitor, PI3K inhibitor, mTOR inhibitors etc.
In most tumors cell, some kinases present high expression level or excessive activation.For this feature, the kinase whose antitumor drugs of target such as Gefitinib, imatinib, erlotinib, Conmana, Xarelto, Sutent and lapatinibditosylate are developed.But in clinical rear discovery, it is not efficient high in some medicinal application, and some medicine acting on single target spot easily produces resistance.Therefore, research and develop new antitumor drug or act on the antitumor drug of multiple target spot simultaneously significant.
Document J.Med.Chem.2011,54,1789 – 1811 report that compound 2-acetylaminohydroxyphenylarsonic acid 6-[the chloro-3-of 2-(4-fluorophenyl sulfonamido)-5-pyridyl] benzothiazole has the activity of very strong suppression kinases PI3K and mTOR, experimentation on animals proves to have obvious Anticancer effect in vivo, but such toxicity of compound is comparatively large, and oral administration 3mg/kg can cause Mouse Weight obviously to decline, oral administration 15mg/kg once, can cause dead mouse.
Summary of the invention
The object of this invention is to provide N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) urea and salt compounds, preparation method and use, this compounds has anti-tumor activity, can be applicable to the preparation of anti-tumor medicinal preparation, and its synthesis material is easy to get, synthetic method easily realizes.
The present invention is achieved through the following technical solutions:
N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) carbamide compounds, structural formula is as follows:
In formula, NR
1r
2for substituted-amino, R
3for chlorine or methoxyl group, R
4for sulfonamido.
Described substituted-amino is dimethylamino, diethylamino, 4-morpholinyl, 4-methyl isophthalic acid-piperazinyl, 1-Pyrrolidine base.
Described 6-replacement-2-[4-morpholinodithio base is 6-(2-methoxyl group-3-is to fluorobenzene sulfonamido-5-pyridyl)-2-[4-morpholinodithio base, 6-(the chloro-3-of 2-is to fluorobenzene sulfonamido-5-pyridyl)-2-[4-morpholinodithio base, 6-(2-methoxyl group-3-is to chlorobenzenesulfonyl amino-5-pyridyl)-2-[4-morpholinodithio base, 6-(2-methoxyl group-3-tolysulfonyl amino-5-pyridyl)-2-[4-morpholinodithio base, 6-(2-methoxyl group-3-(2, 4-difluorobenzene sulfonamido-5-pyridyl)-2-[4-morpholinodithio base, 6-(2-methoxyl group-3-ring third sulfonamido-5-pyridyl)-2-[4-morpholinodithio base.
The salt compounds of N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) ureas, structural formula is as follows:
In formula, NR
1r
2for substituted-amino, R
3for chlorine or methoxyl group, R
4for sulfonamido, X is CH or N; HX is hydrochloric acid, methylsulfonic acid.
The synthetic method of N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) carbamide compounds, comprises the steps:
Step 1) 2-amino-6-bromo benzothiazole (X=CH) or 2-amino-5-bromo thiazole also [5,4-b] pyridine (X=N) and carbonyl dimidazoles replace ethamine with 2-again after reacting and react, can intermediate A be obtained;
Step 2) at palladium complex PdCl
2(dppf), under catalysis, 2,3-bis-replaces-5-bromopyridine can obtain intermediate B with the effect of connection pinacol borate;
Step 3) at palladium complex PdCl
2(dppf) under catalysis; intermediate A, intermediate B are mixed in a solvent with an alkali metal salt; stirring and refluxing under nitrogen protection; steam solvent; be separated from reaction mixture and obtain N-replacement ethyl-N-(6-replaces benzo thiazol-2-yl) carbamide compounds, its synthetic route is as follows:
In formula, NR in A
1r
2for substituted-amino, X=CH or N; In intermediate B, R
3for chlorine or methoxyl group, R
4for sulfonamido.
Described intermediate A is N-2-(dimethylamino) ethyl-N '-(the bromo-2-[4-morpholinodithio base of 6-) urea, or N-2-(diethylamino) ethyl-N '-(the bromo-2-[4-morpholinodithio base of 6-) urea, or N-2-(4-morpholinyl) ethyl-N '-(the bromo-2-[4-morpholinodithio base of 6-) urea, or N-2-(4-methyl isophthalic acid-piperazinyl) ethyl-N '-(the bromo-2-[4-morpholinodithio base of 6-) urea, or N-2-(Pyrrolidine-1-base) ethyl-N '-(the bromo-2-[4-morpholinodithio base of 6-) urea, or N-2-(4-morpholinyl) ethyl-N '-(bromo-2-thiazole of 5-also [5, 4-b] pyridyl) urea,
Described intermediate B is that 2-methoxyl group-3-is to fluorobenzene sulfonamido-5-pyridinylboronic acid pinacol ester, or 2-methoxyl group-3-tolysulfonyl amino-5-pyridinylboronic acid pinacol ester or the chloro-3-of 2-are to fluorine sulfonamido-5-pyridinylboronic acid pinacol ester, or 2-methoxyl group-3-is to chlorobenzenesulfonyl amino-5-pyridinylboronic acid pinacol ester, or 2-methoxyl group-3-ring third sulfonamido-5-pyridinylboronic acid pinacol ester, or 2-methoxyl group-3-(2,4 difluorobenzene sulfonamido)-5-pyridinylboronic acid pinacol ester;
Described solvent is the mixture of dioxane or glycol dimethyl ether and water;
Described an alkali metal salt is sodium carbonate, salt of wormwood or sodium-acetate;
Described intermediate A and the mol ratio of intermediate B are 1:1;
Described step 2) in palladium complex be 5% ~ 20% of intermediate A molar weight.
The synthetic method of the salt compounds of N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) ureas, comprises the steps:
N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) carbamide compounds refluxes about 40 minutes with acid in alcohol, can prepare N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) urea salt compounds, reaction formula is as follows:
Wherein, described acid is hydrochloric acid, methylsulfonic acid;
Described alcohol is ethanol, Virahol.
Present invention also offers N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) ureas and salt compounds is preparing the application in anti-tumor medicinal preparation.
N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) ureas and salt compounds thereof add auxiliary material and make tablet, capsule or injection, wherein in every sheet or grain or a preparation containing N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) carbamide compounds or its esters compound 50 ~ 500mg.
Described auxiliary material comprises one or more in additive, stablizer, solubilizing agent, lubricant, disintegrating agent.
With existing similar Compound Phase ratio, compound provided by the invention has following useful effect:
N-provided by the invention (2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) urea and salt compounds thereof have no bibliographical information.The structure fragment of the present invention's urea instead of J.Med.Chem.2011,54,2-kharophen fragment in compound 2-acetylaminohydroxyphenylarsonic acid 6-[the chloro-3-of 2-(4-fluorophenyl the sulfonamido)-5-pyridyl] benzothiazole that 1789 – 1811 report, obtains N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) urea and salt compounds thereof.In such compound structure, in urea structure fragment, two NH all can form hydrogen bond with acceptor, stronger with the effect of acceptor.
By the introducing benzothiazole structure of morpholinyl, 4-methyl isophthalic acid-amino-substituent such as piperazinyl, diethylamino, the water-soluble of benzothiazoles medicine and pharmacokinetic property can be improved.N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) carbamide compounds is prepared into the water-soluble and stability that mesylate or hydrochloride are conducive to improving compound.
Compound provided by the invention has the activity suppressing the tumor cell proliferations such as human breast cancer cell line Bcap-37, human colon cancer cell HCT116, human lung cancer cell A549, and wherein the activity of part of compounds and positive drug BEZ235 are quite or be better than BEZ235.Such as compound N-2-(diethylamino) ethyl-N '-(6-(2-methoxyl group-3-is to fluorobenzene sulfonamido-5-pyridyl)-2-[4-morpholinodithio base) urea (in table 1 numbering 2 compound) IC to MCF-7, HCT116 and A549
50be respectively 0.20 μm of ol/L, 0.36 μm of ol/L and 0.48 μm ol/L.And under similarity condition, positive drug BEZ235 is to the IC of MCF-7 and HCT116
50be respectively 0.95 μm of ol/L, 0.57 μm of ol/L and 0.54 μm ol/L.
J.Med.Chem.2011,54,1789 – 1811 report that active best compound is to mouse stomach administration 1 time, and 15mg/kg can cause dead mouse.Compound provided by the invention is to mouse stomach administration 1 time, and when dosage is 300mg/kg, mouse is movable normal.
N-provided by the invention (2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) urea and salt compounds thereof, can be used in preparing anti-tumor medicinal preparation, wherein in every sheet or grain or this pharmaceutical preparation containing 10 ~ 500mg.When the active compound provided utilizing the present invention prepares anti-tumor medicinal preparation, this medicine can be made tablet, capsule or injection.These pharmaceutical preparations can be made according to the conventional fabrication process of various preparation.For tablet or capsule, preferred content is 50 ~ 300mg.And can pharmaceutical excipient be contained in the oral preparations that the present invention relates to, comprise additive, stablizer, solubilizing agent, lubricant, disintegrating agent etc., as starch, dextrin, glucose, lactose, Mierocrystalline cellulose, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, pectin, cyclodextrin, twen-80, polyvinyl alcohol, Magnesium Stearate, talcum powder etc.
Embodiment
Below by way of the building-up process of representative compound more of the present invention, the present invention will be further described, and representative compound numbering, structure and MS data (structure of target compound is determined through MS), specifically in table 1.
Some representational compound number of table 1., structure and MS data
Provide the synthetic example of above-claimed cpd below.
Embodiment 1:
The synthesis of N-2-(dimethylamino) ethyl-N '-(6-(2-methoxyl group-3-is to fluorobenzene sulfonamido-5-pyridyl)-2-[4-morpholinodithio base) urea (structural formula is in numbering in table 1 1):
Step 1) preparation of intermediate A 1, N-2-(dimethylamino) ethyl-N '-(the bromo-2-[4-morpholinodithio base of 6-) urea:
Dimethyl formamide 30mL is added in 100mL eggplant-shape bottle, 6-bromo-2-aminobenzothiazole 1.50g and carbonyl dimidazoles 3.20g, stirring at room temperature 10h, add N, N-dimethyl-ethylenediamine 2.0mL, after continuing at stirring at room temperature reaction 3h, removes solvent under reduced pressure, resistates silica gel column chromatography is separated (chloroform: methyl alcohol=30:1) and obtains light yellow solid 1.52g, productive rate 88.2%.
Step 2) synthesis of N-2-(dimethylamino) ethyl-N '-(6-(2-methoxyl group-3-is to fluorobenzene sulfonamido-5-pyridyl)-2-[4-morpholinodithio base) urea:
(1) in 100mL round-bottomed flask, 2-methoxyl group-3-is added to fluorobenzene sulfonamido-5-bromopyridine 0.30g, connection pinacol borate 0.27g, potassium acetate 0.24g, PdCl
2(dppf) 45.0m g and anhydrous Isosorbide-5-Nitrae-dioxane 16mL, mixture is stirring and refluxing 3h under nitrogen protection; Cooling, obtains intermediate B;
(2) in intermediate B, N-2-(dimethylamino) ethyl-N '-(the bromo-2-[4-morpholinodithio base of 6-) urea (A1,0.21g) is added, PdCl
2(dppf) 45.0mg; salt of wormwood 0.34g and water 3mL; reaction mixture is stirring and refluxing 4h under nitrogen protection; decompression steams solvent; residue over silica gel pillar layer separation (chloroform: methyl alcohol=30:1) obtains crude product; with ethyl alcohol recrystallization, obtain near-white solid 0.26g, productive rate 50.2%.
Embodiment 2:
The synthesis of N-2-(diethylamino) ethyl-N '-(6-(2-methoxyl group-3-is to fluorobenzene sulfonamido-5-pyridyl)-2-[4-morpholinodithio base) urea (structural formula is in numbering in table 1 2):
Step 1) preparation of intermediate A 2:N-2-(diethylamino) ethyl-N '-(the bromo-2-[4-morpholinodithio base of 6-) urea with the synthesis of A1, replace N, N-dimethyl-ethylenediamine with N, N-diethyl ethylenediamine;
Step 2) synthesis of N-2-(diethylamino) ethyl-N '-(6-(2-methoxyl group-3-is to fluorobenzene sulfonamido-5-pyridyl)-2-[4-morpholinodithio base) urea:
With the synthesis of embodiment 1 numbering 1 compound, replace A1 with A2; Spent glycol dme replaces dioxane, productive rate 46.3%.
Embodiment 3:
The synthesis of N-2-(4-morpholinyl) ethyl-N '-(6-(2-methoxyl group-3-is to fluorobenzene sulfonamido-5-pyridyl)-2-[4-morpholinodithio base) urea (structural formula is in table 1 numbering 3):
Step 1) preparation of intermediate A 3:N-2-(4-morpholinyl) ethyl-N '-(the bromo-2-[4-morpholinodithio base of 6-) urea with the synthesis of A1, replace N, N-dimethyl-ethylenediamine with 2-(4-morpholinyl) ethamine;
Step 2) synthesis of N-2-(4-morpholinyl) ethyl-N '-(6-(2-methoxyl group-3-is to fluorobenzene sulfonamido-5-pyridyl)-2-[4-morpholinodithio base) urea:
With the synthesis of embodiment 1 numbering 1 compound, replace A1 with A3; Spent glycol dme replaces dioxane, productive rate 44.8%.
Embodiment 4:
The synthesis of N-2-(4-methyl isophthalic acid-piperazinyl) ethyl-N '-(6-(2-methoxyl group-3-is to fluorobenzene sulfonamido-5-pyridyl)-2-[4-morpholinodithio base) urea (structural formula is in table 1 numbering 4):
Step 1) preparation of intermediate A 4:N-2-(4-methyl isophthalic acid-piperazinyl) ethyl-N '-(the bromo-2-[4-morpholinodithio base of 6-) urea is with the synthesis of A1, N, N-dimethyl-ethylenediamine is replaced with 2-(4-methyl isophthalic acid-piperazinyl) ethamine;
Step 2) synthesis of N-2-(4-methyl isophthalic acid-piperazinyl) ethyl-N '-(6-(2-methoxyl group-3-is to fluorobenzene sulfonamido-5-pyridyl)-2-[4-morpholinodithio base) urea:
With the synthesis of embodiment 1 numbering 1 compound, replace A1 with A4.Productive rate 55.7%.
Embodiment 5:
The synthesis of N-2-(1-Pyrrolidine base) ethyl-N '-(6-(2-methoxyl group-3-is to fluorobenzene sulfonamido-5-pyridyl)-2-[4-morpholinodithio base) urea (structural formula is in table 1 numbering 5):
Step 1) preparation of intermediate A 5:N-2-(1-Pyrrolidine base) ethyl-N '-(the bromo-2-[4-morpholinodithio base of 6-) urea with the synthesis of A1, replace N, N-dimethyl-ethylenediamine with 2-(1-Pyrrolidine base) ethamine;
Step 2) synthesis of N-2-(4-methyl isophthalic acid-piperazinyl) ethyl-N '-(6-(2-methoxyl group-3-is to fluorobenzene sulfonamido-5-pyridyl)-2-[4-morpholinodithio base) urea:
With the synthesis of embodiment 1 numbering 1 compound, replace A1 with A5, productive rate 40.2%.
Embodiment 6:
The synthesis of N-2-(4-morpholinyl) ethyl-N '-(6-(2-methoxyl group-3-(2,4 difluorobenzene sulfonamido)-5-pyridyl)-2-[4-morpholinodithio base) urea (structural formula is in table 1 numbering 6):
With the synthesis of embodiment 1 compound 1, replace A1 with A3; Replace 2-methoxyl group-3-to fluorobenzene sulfonamido-5-bromopyridine with 2-methoxyl group-3-(2,4 difluorobenzene sulfonamido)-5-bromopyridine, productive rate 43.2%.
Embodiment 7:
The synthesis of N-2-(4-morpholinyl) ethyl-N '-(6-(the chloro-3-of 2-is to fluorobenzene sulfonamido-5-pyridyl)-2-[4-morpholinodithio base) urea (structural formula is in table 1 numbering 7):
With the synthesis of embodiment 1 compound 1, replace A1 with A3; Replace 2-methoxyl group-3-to fluorobenzene sulfonamido-5-bromopyridine with the chloro-3-of 2-to fluorobenzene sulfonamido-5-bromopyridine, productive rate 50.4%.
Embodiment 8:
The synthesis of N-2-(4-morpholinyl) ethyl-N '-(6-(2-methoxyl group-3-is to chlorobenzenesulfonyl amino-5-pyridyl)-2-[4-morpholinodithio base) urea (structural formula is in table 1 numbering 8):
With the synthesis of embodiment 1 compound 1, replace A1 with A3; Replace 2-methoxyl group-3-to fluorobenzene sulfonamido-5-bromopyridine with 2-methoxyl group-3-to chlorobenzenesulfonyl amino-5-bromopyridine.Productive rate 49.1%.
Embodiment 9:
The synthesis of N-2-(4-morpholinyl) ethyl-N '-(6-(2-methoxyl group-3-is to Methyl benzenesulfonyl amino-5-pyridyl)-2-[4-morpholinodithio base) urea (structural formula is in table 1 numbering 9):
With the synthesis of embodiment 1 compound 1, replace A1 with A3; Replace 2-methoxyl group-3-to fluorobenzene sulfonamido-5-bromopyridine with the chloro-3-of 2-to Methyl benzenesulfonyl amino-5-bromopyridine, replace salt of wormwood with sodium carbonate.Productive rate 42.1%.
Embodiment 10:
The synthesis of N-2-(4-morpholinyl) ethyl-N '-(5-(2-methoxyl group-3-is to fluorobenzene sulfonamido-5-pyridyl)-2-thiazole also [5,4-b] pyridyl) urea (structural formula is in table 1 numbering 10):
Step 1) intermediate A 6:N-2-(4-morpholinyl) ethyl-N '-(bromo-2-thiazole of 5-also [5,4-b] pyridyl) preparation of urea is with the synthesis of A1, N, N-dimethyl-ethylenediamine is replaced with 2-(4-morpholinyl) ethamine; With 2-amino-5-bromo thiazole also [5,4-b] pyridine replacement 2-amino-6-bromo benzothiazole.
Step 2) with the synthesis of embodiment 1 numbering 1 compound, replace A1 with A6.Productive rate 43.6%.
Embodiment 11:
The synthesis of N-2-(4-morpholinyl) ethyl-N '-(5-(the chloro-3-of 2-is to fluorobenzene sulfonamido-5-pyridyl)-2-thiazole also [5,4-b] pyridyl) urea (structural formula is in table 1 numbering 11):
With the synthesis of embodiment 10 numbering 10 compound, replace 2-methoxyl group-3-to fluorobenzene sulfonamido-5-bromopyridine with the chloro-3-of 2-to fluorobenzene sulfonamido-5-bromopyridine.Productive rate 49.4%.
Embodiment 12:
The synthesis of N-2-(4-morpholinyl) ethyl-N '-(6-(2-chloro-3-ring third sulfonamido-5-pyridyl)-2-[4-morpholinodithio base) urea (structural formula is in table 1 numbering 12):
With the synthesis of embodiment 1 numbering 1 compound, replace A1 with A3, replace 2-methoxyl group-3-to fluorobenzene sulfonamido-5-bromopyridine with 2-chloro-3-ring third sulfonamido-5-bromopyridine.Productive rate 62.7%.
Embodiment 13:
The synthesis of N-2-(4-morpholinyl) ethyl-N '-(6-(2-methoxyl group-3-ring third sulfonamido-5-pyridyl)-2-[4-morpholinodithio base) urea (structural formula is in table 1 numbering 13):
With the synthesis of embodiment 1 numbering 1 compound, replace A1 with A3, replace 2-methoxyl group-3-to fluorobenzene sulfonamido-5-bromopyridine with 2-methoxyl group-3-ring third sulfonamido-5-bromopyridine.Productive rate 50.7%.
Embodiment 14:
The synthesis of N-2-(4-morpholinyl) ethyl-N '-(6-(2-methoxyl group-3-is to fluorobenzene sulfonamido-5-pyridyl)-2-[4-morpholinodithio base) urea dihydrochloride (structural formula is in table 1 numbering 14):
Numbering 3 compound (0.3g) is dissolved in Virahol (10mL), adds concentrated hydrochloric acid (0.1mL), and mixture stirs 30 minutes in 50 DEG C, cooling, and leave standstill, suction filtration, dries, and obtains solid 0.29g.Yield 86.3%.
Embodiment 15:
The synthesis of N-2-(diethylamino) ethyl-N '-(6-(2-methoxyl group-3-is to fluorobenzene sulfonamido-5-pyridyl)-2-[4-morpholinodithio base) urea dimethanesulfonate (structural formula is in table 1 numbering 15):
With the synthesis of compound 14, replace numbering 3 compound with numbering 2 compound; Replace Virahol with ethanol, replace concentrated hydrochloric acid with methylsulfonic acid.Yield 85.0%.
The checking of anti tumor activity in vitro:
In order to verify the anti-tumor activity of N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) urea that the present invention synthesizes and salt compounds thereof, be positive control medicine with BEZ235, adopt external mtt assay to determine the growth-inhibiting effect of compound 1-15 to human breast cancer cell line Bcap-37, human colon cancer cell HCT116 and human lung cancer cell A549.
Verification method: tumour cell U87 is cultivated containing in the RPMI1640 substratum of 10% calf serum, includes mould and have 100UmL
-1, Streptomycin sulphate 100 μ gmL
-1, in 37 DEG C, 5%CO
2secondary Culture in incubator.Get the tumour cell that 0.3% trysinization is adherent, containing the RPMI1640 nutrient solution preparation cell suspension of 10% calf serum, concentration is 6 × 10
3individual cells/ml.In 96 well culture plates, 200 μ L (about containing 1000 tumour cells) are inoculated in every hole, cultivate 24h for 37 DEG C.Administration group adds different concns medicine, every medicine setting 10
-5, 10
-6, 10
-7, 10
-8molL
-14 concentration gradients, often group establishes 3 parallel holes.Control group adds isopyknic solvent with medicine, is placed in 37 DEG C, 5%CO
2discard nutrient solution after cultivating 72h in incubator, every hole adds the MTT solution of 20 μ L 5mg/mL, and after hatching 4h, abandoning supernatant, every hole adds DMSO 150 μ L, measures optical density value (OD) after gentle agitation by microplate reader under 570nm.
Result calculates:
With the tumour cell of solvent control process for control group, ask the inhibiting rate of drug on tumor cell according to the following formula:
And adopt improvement karber's method to obtain half-inhibition concentration (IC further
50).
Measurement result shows, and compound 1-15 is to the IC of MCF-7
50value is 0.20-2.02 μm of ol/L; To the IC of HCT116
50for 0.26-1.68 μm of ol/L; To the IC of A549
50for 0.20-5.16 μm of ol/L.And under similarity condition, positive drug BEZ235 is to the IC of MCF-7, HCT116 and A549
50be respectively 0.95 μm of ol/L, 0.57 μm of ol/L and 0.54 μm ol/L.
The checking of anti-tumor in vivo activity:
Active in order to verify the anti-tumor in vivo that the invention provides compound, we adopt mouse S180 Transplanted tumor model, gastric infusion, and the anti-tumor in vivo having investigated compound 4 is active.
Verification method: Kunming mouse, male, body weight 18-22g.Take out the ascites of the 8th day after mouse peritoneal inoculation S180, with physiological saline with 1:1.5 dilution proportion, make S180 cell suspension.With syringe at every mouse right armpit subcutaneous vaccination 0.1mL.Inoculate next day, mouse be divided into 3 groups at random, often organize 8, be respectively:
1) blank group (NMP/PEG400/H
2o)
2) compound 4 low dose group (3mg/kg)
3) compound 4 high dose group (10mg/kg)
Compound 4 is used NMP/PEG400/H
2o (volume ratio is 1:6:3) dissolves.Inoculate latter second day and start by above-mentioned dosage regimen gastric infusion, once-a-day, successive administration 10 days.Administration was designated as d1 the same day, and administration volume is 20mL/kg body weight.Record Mouse Weight daily.Drug withdrawal next day (d11), by sacrifice, separates knurl block, weighs after rejecting its hetero-organization.
Result: compound 4, when dosage is 3mg/kg and 10mg/kg, is respectively 45.8% and 80.2% to the growth inhibition ratio of S180 transplanted tumor in Mice Body.
Conclusion: it is active that compound 4 provided by the invention has obvious anti-tumor in vivo.
Acute toxicity test:
Compound NMP, PEG400 and water dissolution, with different dosage, to the disposable gastric infusion of Kunming mouse, observe 7 days, determine the minimum dose causing dead mouse.Result shows: 2-acetylaminohydroxyphenylarsonic acid 6-[the chloro-3-of 2-(to fluorophenyl sulfonamido)-5-pyridyl] benzothiazole (literature compound) administration 15mg/kg causes dead mouse, the LD recorded
50for 25mg/kg; And the compound administration 300mg/kg of numbering 2 in the present invention, mouse is movable normal; The compound administration 200mg/kg of numbering 4 in the present invention, mouse is movable normal.Test-results shows that toxicity of compound provided by the invention is very little.
The testing method that the present invention does not describe in detail is testing method conventional in this area or existing method, does not describe one by one at this.
More than exemplify is only illustrate of the present invention; do not form the restriction to protection scope of the present invention; although by preferred embodiment to invention has been detailed description; but those of ordinary skill in the art is to be understood that; can modify to the present invention under not departing from the scope of the present invention, be out of shape or equivalent replacement, all belong to protection scope of the present invention.
Claims (10)
1.N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) carbamide compounds, is characterized in that: structural formula is as follows:
In formula, NR
1r
2for substituted-amino, R
3for chlorine or methoxyl group, R
4for sulfonamido.
2. N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) carbamide compounds as claimed in claim 1, is characterized in that: described substituted-amino is dimethylamino, diethylamino, 4-morpholinyl, 4-methyl isophthalic acid-piperazinyl, 1-Pyrrolidine base.
3. N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) urea as claimed in claim 1, it is characterized in that: described 6-replacement-2-[4-morpholinodithio base is 6-(2-methoxyl group-3-is to fluorobenzene sulfonamido-5-pyridyl)-2-[4-morpholinodithio base, 6-(the chloro-3-of 2-is to fluorobenzene sulfonamido-5-pyridyl)-2-[4-morpholinodithio base, 6-(2-methoxyl group-3-is to chlorobenzenesulfonyl amino-5-pyridyl)-2-[4-morpholinodithio base, 6-(2-methoxyl group-3-tolysulfonyl amino-5-pyridyl)-2-[4-morpholinodithio base, 6-(2-methoxyl group-3-(2, 4-difluorobenzene sulfonamido-5-pyridyl)-2-[4-morpholinodithio base, 6-(2-methoxyl group-3-ring third sulfonamido-5-pyridyl)-2-[4-morpholinodithio base.
4. the salt compounds of N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) ureas as claimed in claim 1, it is characterized in that, structural formula is as follows:
In formula, NR
1r
2for substituted-amino, R
3for chlorine or methoxyl group, R
4for sulfonamido, X is CH or N; HX is hydrochloric acid, methylsulfonic acid.
5. the synthetic method of N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) carbamide compounds as claimed in claim 1, is characterized in that, comprise the steps:
Step 1) 2-amino-6-bromo benzothiazole (X=CH) or 2-amino-5-bromo thiazole also [5,4-b] pyridine (X=N) and carbonyl dimidazoles replace ethamine with 2-again after reacting and react, can intermediate A be obtained;
Step 2) at palladium complex PdCl
2(dppf), under catalysis, 2,3-bis-replaces-5-bromopyridine can obtain intermediate B with the effect of connection pinacol borate;
Step 3) at palladium complex PdCl
2(dppf) under catalysis; intermediate A, intermediate B are mixed in a solvent with an alkali metal salt; stirring and refluxing under nitrogen protection; steam solvent; be separated from reaction mixture and obtain N-replacement ethyl-N-(6-replaces benzo thiazol-2-yl) carbamide compounds, its synthetic route is as follows:
In formula, NR in A
1r
2for substituted-amino, X=CH or N; In intermediate B, R
3for chlorine or methoxyl group, R
4for sulfonamido.
6. the synthetic method of N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) carbamide compounds as claimed in claim 5, it is characterized in that, described intermediate A is N-2-(dimethylamino) ethyl-N '-(the bromo-2-[4-morpholinodithio base of 6-) urea, or N-2-(diethylamino) ethyl-N '-(the bromo-2-[4-morpholinodithio base of 6-) urea, or N-2-(4-morpholinyl) ethyl-N '-(the bromo-2-[4-morpholinodithio base of 6-) urea, or N-2-(4-methyl isophthalic acid-piperazinyl) ethyl-N '-(the bromo-2-[4-morpholinodithio base of 6-) urea, or N-2-(Pyrrolidine-1-base) ethyl-N '-(the bromo-2-[4-morpholinodithio base of 6-) urea, or N-2-(4-morpholinyl) ethyl-N '-(bromo-2-thiazole of 5-also [5, 4-b] pyridyl) urea,
Described intermediate B is that 2-methoxyl group-3-is to fluorobenzene sulfonamido-5-pyridinylboronic acid pinacol ester, or 2-methoxyl group-3-tolysulfonyl amino-5-pyridinylboronic acid pinacol ester or the chloro-3-of 2-are to fluorine sulfonamido-5-pyridinylboronic acid pinacol ester, or 2-methoxyl group-3-is to chlorobenzenesulfonyl amino-5-pyridinylboronic acid pinacol ester, or 2-methoxyl group-3-ring third sulfonamido-5-pyridinylboronic acid pinacol ester, or 2-methoxyl group-3-(2,4 difluorobenzene sulfonamido)-5-pyridinylboronic acid pinacol ester;
Described solvent is the mixture of dioxane or glycol dimethyl ether and water;
Described an alkali metal salt is sodium carbonate, salt of wormwood or sodium-acetate;
Described intermediate A and the mol ratio of intermediate B are 1:1;
Described step 2) in palladium complex be 5% ~ 20% of intermediate A molar weight.
7. the synthetic method of the salt compounds of N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) urea as claimed in claim 4, is characterized in that, comprise the steps:
N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) carbamide compounds refluxes about 40 minutes with acid in alcohol, can prepare N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) urea salt compounds, reaction formula is as follows:
Wherein, described acid is hydrochloric acid, methylsulfonic acid;
Described alcohol is ethanol, Virahol.
8.N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) ureas and salt compounds thereof are preparing the application in anti-tumor medicinal preparation.
9. N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) ureas as claimed in claim 8 and salt compounds thereof are preparing the application in anti-tumor medicinal preparation; it is characterized in that: N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) urea and salt compounds thereof add auxiliary material and make tablet, capsule or injection, wherein in every sheet or grain or a preparation containing N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) carbamide compounds or its esters compound 50 ~ 500mg.
10. N-(2-amino-ethyl)-N '-(6-replacement-2-[4-morpholinodithio base) ureas as claimed in claim 9 and salt compounds thereof are preparing the application in anti-tumor medicinal preparation, it is characterized in that: described auxiliary material comprises one or more in additive, stablizer, solubilizing agent, lubricant, disintegrating agent.
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| CN105175411A (en) * | 2015-05-06 | 2015-12-23 | 西安交通大学 | Synthesis method and application of urea compound and salt compound thereof |
| CN117069676A (en) * | 2023-08-11 | 2023-11-17 | 北京中医药大学 | 6-methoxybenzothiazole compound and preparation method and application thereof |
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| CN117069676A (en) * | 2023-08-11 | 2023-11-17 | 北京中医药大学 | 6-methoxybenzothiazole compound and preparation method and application thereof |
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