CN102746241A - 2, 3, 5-trisubstituted benzamide compound, and preparation method and application thereof - Google Patents
2, 3, 5-trisubstituted benzamide compound, and preparation method and application thereof Download PDFInfo
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- CN102746241A CN102746241A CN2012102248125A CN201210224812A CN102746241A CN 102746241 A CN102746241 A CN 102746241A CN 2012102248125 A CN2012102248125 A CN 2012102248125A CN 201210224812 A CN201210224812 A CN 201210224812A CN 102746241 A CN102746241 A CN 102746241A
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- China
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- replacement
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- compd
- carbox amide
- trisubstituted benzene
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- -1 benzamide compound Chemical class 0.000 title claims abstract description 75
- 238000002360 preparation method Methods 0.000 title claims abstract description 61
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 title claims abstract description 54
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 239000002904 solvent Substances 0.000 claims description 19
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 239000002246 antineoplastic agent Substances 0.000 claims description 9
- 229940041181 antineoplastic drug Drugs 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 101150003085 Pdcl gene Proteins 0.000 claims description 6
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
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- 239000000463 material Substances 0.000 claims description 6
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Abstract
The invention discloses a 2, 3, 5-trisubstituted benzamide compound, and a preparation method and application thereof. A formamide structure is used to substitute nitrogen atoms on a pyridyl ring of a 6-(3-pyridyl) quinoline (or quinazoline) compound, so as to obtain a novel compound with antitumor activity. The 2, 3, 5-trisubstituted benzamide compound provided by the invention has activity to restrain proliferation of tumor cells.
Description
Technical field
The invention belongs to the antitumor drug technical field, relate to 2,3,5-trisubstituted benzene Carbox amide.
Background technology
Tumour is one of malignant disease of serious threat human health.Over nearly 20 years, the M & M of China's malignant tumour constantly rises, and tumor incidence is about 2,00/,100,000 people, and annual new cases reach more than 2,200,000 people, and is dead about more than 160 ten thousand, controlling more than patient 6,000,000 people.
The tumor treatment means remain conventional surgical treatment, radiotherapy and pharmacological agent at present, are main but be still to a great extent with pharmacological agent.Therefore, the new antitumor drug of research and development is significant.
In recent years; Along with the oncomolecularbiology progress of research; Tumor invasion mechanism there has been more understanding, has found the novel targets of many antitumor drug effects, made the development of antitumor drug obtain many new achievements; Like topoisomerase enzyme inhibitor, kinases inhibitor, PI3K suppressor factor, mTOR suppressor factor etc.
In the most tumors cell, some kinases present high expression level or excessive activation.To these characteristics, ZD1939, imatinib, erlotinib, dust gram have been developed for kinase whose antitumor drugs of target such as Buddhist nun, Xarelto, Sutent and lapatinibditosylates.But some medicinal application finds that in clinical back it is efficient not high, and some medicine that acts on single target spot is easy to generate resistance.Therefore, the new antitumor drug of research and development or to act on the antitumor drug of a plurality of target spots simultaneously significant.
Document J.Med.Chem.2011; 54; 1789-1811 report 2-acetylaminohydroxyphenylarsonic acid 5-(3-pyridyl) benzothiazole compound has the activity of good restraining kinases PI3K and mTOR; It has good antitumor activity the experimentation on animals proof, and still, 2-ethanoyl instability and benzothiazole compound toxicity are bigger.
Document WO 2008157191A2; ACS Med.Chem.Lett.2010,1,39-43 and J.Med.Chem.2011; Report 6-(3-pyridyl) quinolines such as 54,4735 – 4751 also have activity and the anti-tumor activity of good restraining kinases PI3K and mTOR.
Summary of the invention
The problem that the present invention solves is to provide 2,3,5-trisubstituted benzene Carbox amide and its production and use, this compounds has anti-tumor activity, can be applicable to preparing anti-tumor medicine, and its synthesis material is easy to get, compound method realizes easily.
The present invention realizes through following technical scheme:
A kind of 2,3,5-trisubstituted benzene Carbox amide, the structural formula of this compounds is:
Wherein, R
1Be 6-quinolyl, 6-benzothiazolyl, 4-replacement-6-quinolyl, 4-replacement-6-quinazolyl, 2,4-two replacement-6-quinazolyls or 2-replacement-6-benzothiazolyl; R
2Be cyclopropyl, phenyl or substituted-phenyl; R
3Be methoxyl group, chlorine or hydrogen.
Substituting group in described 4-replacement-6-quinolyl, the 4-replacement-6-quinazolyl is the 4-morpholinyl.
Described 2,2 of 4-two replacement-6-quinazolyls, 4-two are substituted by 2-amino-4-morpholinyl.
Described 2-replacement-6-benzothiazolyl is 2-cyclopropyl carbonyl amino-6-benzothiazolyl.
Described R
2In substituted-phenyl be single the replacement or two replacement, substituting group is halogen or methyl, such as to fluorophenyl, rubigan, p-methylphenyl, 2,4 difluorobenzene base etc.
A kind of 2,3, the preparation method of 5-trisubstituted benzene Carbox amide may further comprise the steps:
Carry out suzuki reaction with compd A and compd B and obtain 2,3,5-trisubstituted benzene Carbox amide, its reaction formula is following:
Wherein, R in the compd A
2Be cyclopropyl, phenyl or substituted-phenyl; R
3Be methoxyl group, chlorine or hydrogen; In the compd B
Be 6-quinolyl, 6-isoquinolyl, 6-benzothiazolyl, 4-replacement-6-quinolyl, 4-replacement-6-quinazolyl, 2,4-two replacement-6-quinolyls, 2,4-two replacement-6-quinazolyls or 2-replacement-6-benzothiazolyl.
At PdCl
2(pddf)
2Under the catalysis, compd A, compd B are mixed in solvent with an alkali metal salt, stirring and refluxing reaction 2～10h steams solvent under protective atmosphere, from reaction product, separates obtaining 2,3,5-trisubstituted benzene Carbox amide;
Described compd A is 2-methoxyl group-3-sulfonamido-5-brombenzamide, 2-chloro-3-sulfonamido-5-brombenzamide or 3-sulfonamido-5-brombenzamide;
Described compd B is 6-quinazolyl boric acid pinacol ester, 6-quinolyl boric acid pinacol ester or 6-benzothiazole ylboronic acid pinacol ester;
Described solvent is one or more in THF, dioxane, glycol dimethyl ether, N, the water.
Described an alkali metal salt is yellow soda ash, salt of wormwood, cesium carbonate or sodium-acetate, and the mol ratio of itself and compd A is 1:1～5:1.
Described 1 mole compd A joins in the solvent of 5～10L and reacts.
2,3, the application of 5-trisubstituted benzene Carbox amide in the preparation antitumor drug.
2,3,5-trisubstituted benzene Carbox amide adds auxiliary material and processes tablet, capsule, soft capsule or injection, wherein every or a preparation in contain 2,3 of 10～500mg, 5-trisubstituted benzene Carbox amide;
Described auxiliary material comprises one or more in additive, stablizer, solubilizing agent, lubricant, the disintegrating agent.
Compared with prior art, the present invention has following beneficial technical effects:
Provided by the invention 2; 3,5-trisubstituted benzene Carbox amide is the innovation on 6-(3-pyridyl) quinoline (or quinazoline) compounds architecture basics: the nitrogen-atoms of pyridine nitrogen atom and quinoline (or quinazoline) 1-position is its main pharmacodynamics unity structure in 6-(3-pyridyl) quinoline (or quinazoline) compounds; The protonated back of pyridine nitrogen atom forms hydrogen bond through water molecules mediation and acceptor in the activity conformation.The present invention has replaced the nitrogen-atoms on the pyridine ring with the structure of formyl ammonia, can obtain new antineoplastic compound 2,3,5-trisubstituted benzene Carbox amide.In this compounds, the structure of benzene carbon amide can be directly and acceptor form hydrogen bond.2,3,5-trisubstituted benzene Carbox amide and 6-(3-pyridyl) quinoline (or quinazoline) compounds has identical pharmacophore, also has the activity and the anti-tumor activity that suppress kinases PI3K and mTOR.And its synthesis material is easy to get, compound method realizes easily.
Provided by the invention 2,3,5-trisubstituted benzene Carbox amide has the activity of inhibition tumour cell (such as human glioma cell U87) propagation, wherein part of compounds active even be superior to the positive drug of going on the market.IC such as compound 2-methoxyl group-3-(4-fluorobenzene sulfoamido)-5-(4-morpholinyl-6-quinazolyl) BM
50=1.54 μ mol/L, and the IC of positive drug Carmustine
50=3.97 μ mol/L.
Provided by the invention 2,3,5-trisubstituted benzene Carbox amide can be used in the preparation anti-tumor medicinal preparation, wherein every or this pharmaceutical prepn in contain 10-500mg.When the active compound that utilizes the present invention to provide prepares anti-tumor medicinal preparation, can this medicine be processed tablet, capsule, soft capsule or injection.These pharmaceutical prepns can be processed according to the conventional preparation technology of various preparations.For tablet or capsule, preferred content is 20-150mg.And can contain pharmaceutical excipient in the oral prepns that the present invention relates to; Comprise additive, stablizer, solubilizing agent, lubricant, disintegrating agent etc., like starch, dextrin, glucose, lactose, Mierocrystalline cellulose, Vinylpyrrolidone polymer, cross-linked polyvinylpyrrolidone, pectin, Schardinger dextrins, soil temperature-80, Z 150PH, Magnesium Stearate, talcum powder etc.
Description of drawings
Fig. 1 is 2,3, and 5-trisubstituted benzene Carbox amide is to the half-inhibition concentration contrast histogram of tumour cell.
Embodiment
The present invention provides 2; 3; 5-trisubstituted benzene Carbox amide replaces the nitrogen-atoms on the pyridine ring in 6-(3-pyridyl) quinoline (or quinazoline) compounds with the structure of methane amide, thereby obtains having the compound of anti-tumor activity.Further specify in the face of this compound down.Should be noted that, following examples be used for explanation of the present invention and and unrestricted the present invention.Although with preferred embodiment the present invention has been carried out detailed explanation, those of ordinary skill in the art should be appreciated that and under not departing from the scope of the present invention, can make amendment, be out of shape the present invention or be equal to replacement, all belongs to protection scope of the present invention.
A kind of 2,3,5-trisubstituted benzene Carbox amide, the structural formula of this compounds is:
Wherein, R
1Be 6-quinolyl, 6-benzothiazolyl, 4-replacement-6-quinolyl, 4-replacement-6-quinazolyl, 2,4-two replacement-6-quinazolyls or 2-replacement-6-benzothiazolyl; R
2Be cyclopropyl, phenyl or substituted-phenyl; R
3Be methoxyl group, chlorine or hydrogen.
Concrete 4-replacement-6-quinolyl, the substituting group in the 4-replacement-6-quinazolyl are the 4-morpholinyl.
Described 2,4-two replacement-6-quinolyls, 2,2 of 4-two replacement-6-quinazolyls, 4-two are substituted by 2-amino-4-morpholinyl.
Described 2-replacement-6-benzothiazolyl is 2-cyclopropyl carbonyl amino-6-benzothiazolyl.
Described R
2In substituted-phenyl be single the replacement or two replacement, substituting group is halogen or methyl, such as to fluorophenyl, rubigan, p-methylphenyl, 2,4 difluorobenzene base etc.
Provide some representative compound numberings, structure and HRMS data (structure of target compound is confirmed through high resolution mass spectrum HRMS) below, specifically as shown in table 1.
Some concrete compound number of table 1., structure and HRMS data
Synthesizing of above-claimed cpd:
Carry out suzuki reaction with compd A and compd B and obtain 2,3,5-trisubstituted benzene Carbox amide, its reaction formula is following:
Wherein, R in the compd A
2Be cyclopropyl, phenyl or substituted-phenyl; R
3Be methoxyl group, chlorine or hydrogen; In the compd B
Be 6-quinolyl, 6-isoquinolyl, 6-benzothiazolyl, 4-replacement-6-quinolyl, 4-replacement-6-quinazolyl, 2,4-two replacement-6-quinolyls, 2,4-two replacement-6-quinazolyls or 2-replacement-6-benzothiazolyl.
Provide the synthetic embodiment of above-claimed cpd below.
The preparation of embodiment 12-methoxyl group-3-(4-fluorobenzene sulfoamido)-5-(4-morpholinyl-6-quinazolyl) BM (1)
Compd A: the preparation of 2-methoxyl group-3-(4-fluorobenzene sulfoamido)-5-brombenzamide (1A)
In the 100mL round-bottomed flask, add 2-methoxyl group-3-amino-5-brombenzamide (0.9g; 3.7mmol); Pyridine (2mL) and THF (20mL), system adds fluorobenzene SULPHURYL CHLORIDE (0.86g under the ice bath cooling in batches; 4.4mmol), then mixture is stirred 24h (being warming up to room temperature naturally).Steam solvent, in residue, add the hydrochloric acid 10mL of 1mol/L, leave standstill 2h, suction filtration gets solid, and the gained solid is used ethyl alcohol recrystallization, gets product 2-methoxyl group-3-(4-fluorobenzene sulfoamido)-5-brombenzamide 0.73g, productive rate 49.3%.
Compd B: the preparation of 4-morpholinyl-6-quinazoline boric acid pinacol ester (1B)
In the 100mL round-bottomed flask, add 4-morpholinyl-6-amido quinazoline (0.95g), tetramethyl ethylene ketone couplet boric acid ester (1.23g), potassium acetate (0.95g) and PdCl
2(pddf)
2(0.117g), mixture is in 50C vacuum-drying 30min, and nitrogen protection adds exsiccant dioxane 20mL, stirring and refluxing 3h down.Steam solvent, resistates adds 5% sodium hydrogencarbonate 50mL, changes separating funnel over to, and with ethyl acetate extraction (50mL * 3), anhydrous sodium sulfate drying steams solvent and gets crude product 4-morpholinyl-6-quinazoline boric acid pinacol ester and can directly be used as down going on foot and react.
The preparation of 2-methoxyl group-3-(4-fluorobenzene sulfoamido)-5-(4-morpholinyl-6-quinazolyl) BM (1):
In the 50mL round-bottomed flask, add 2-methoxyl group-3-(4-fluorobenzene sulfoamido)-5-brombenzamide (0.15g), 4-morpholinyl-6-quinazoline boric acid pinacol ester (crude product 0.40g), PdCl
2(pddf)
2(25mg), yellow soda ash (0.15g), water (3mL) and glycol dimethyl ether (6mL), mixture stirring and refluxing 3 hours under nitrogen protection steams solvent, the resistates silica gel column chromatography separate (chloroform: methyl alcohol=30:1) product 70mg, productive rate 35.0%.
The preparation of embodiment 22-methoxyl group-3-(4-chlorobenzene sulfonamide base)-5-(4-morpholinyl-6-quinazolyl) BM (2)
2A.2-methoxyl group-3-(4-chlorobenzene sulfonamide base)-5-brombenzamide
The preparation method is synthetic with embodiment 1 compd A, replaces to the fluorobenzene SULPHURYL CHLORIDE productive rate productive rate 46.0% with parachloroben-zenesulfonyl chloride.
The preparation of 2-methoxyl group-3-(4-chlorobenzene sulfonamide base)-5-(4-morpholinyl-6-quinazolyl) BM (2):
In the 50mL round-bottomed flask, add 2-methoxyl group-3-(4-chlorobenzene sulfonamide base)-5-brombenzamide (0.16g), 4-morpholinyl-6-quinazoline boric acid pinacol ester (crude product 0.40g), PdCl
2(pddf)
2(25mg), salt of wormwood (0.15g) water (3mL) and THF (6mL), mixture stirring and refluxing 3 hours under nitrogen protection steams solvent, the resistates silica gel column chromatography separate (chloroform: methyl alcohol=30:1) product, productive rate 37.4%.
The preparation of embodiment 32-methoxyl group-3-(4-Methyl benzenesulfonyl amido)-5-(4-morpholinyl-6-quinazolyl) BM (3)
3A.2-methoxyl group-3-(4-Methyl benzenesulfonyl amido)-5-brombenzamide
The preparation method is synthetic with midbody 1A's among the embodiment 1, replaces fluorobenzene SULPHURYL CHLORIDE productive rate with Tosyl chloride.Productive rate 45.9%.
The preparation of 2-methoxyl group-3-(4-Methyl benzenesulfonyl amido)-5-(4-morpholinyl-6-quinazolyl) BM (3):
In the 50mL round-bottomed flask, add 2-methoxyl group-3-(4-Methyl benzenesulfonyl amido)-5-brombenzamide (0.16g), 4-morpholinyl-6-quinazoline boric acid pinacol ester (crude product 0.40g), PdCl
2(pddf)
2(25mg), sodium-acetate (0.15g) water (3mL) and dioxane (6mL), mixture stirring and refluxing 3 hours under nitrogen protection steams solvent, the resistates silica gel column chromatography separate product, productive rate 37.4%.
The preparation of embodiment 4 3-(4-fluorobenzene sulfoamido)-5-(4-morpholinyl-6-quinazolyl) BM (4)
(4A.3-4-fluorobenzene sulfoamido)-5-brombenzamide
The preparation method is synthetic with midbody 1A's among the embodiment 1, replaces 2-methoxyl group-3-amino-5-brombenzamide with 3-amino-5-brombenzamide.Productive rate 83.1%.
The preparation of 3-(4-fluorobenzene sulfoamido)-5-(4-morpholinyl-6-quinazolyl) BM (4):
The preparation method is synthetic with compound 1 among the embodiment 1.Replace 2-methoxyl group-3-(4-fluorobenzene sulfoamido)-5-brombenzamide with 3-(4-fluorobenzene sulfoamido)-5-brombenzamide.Productive rate 47.2%.
The preparation of embodiment 5 3-(4-chlorobenzene sulfonamide base)-5-(4-morpholinyl-6-quinazolyl) BM (5)
(5A.3-4-chlorobenzene sulfonamide base)-5-brombenzamide
The preparation method is synthetic with midbody 1A's among the embodiment 1, replaces 2-methoxyl group-3-amino-5-brombenzamide with 3-amino-5-brombenzamide, replaces the fluorobenzene SULPHURYL CHLORIDE with parachloroben-zenesulfonyl chloride.Productive rate 95.0%.
The preparation of 3-(4-chlorobenzene sulfonamide base)-5-(4-morpholinyl-6-quinazolyl) BM (5):
The preparation method is synthetic with compound 1 among the embodiment 1.Replace 2-methoxyl group-3-(4-fluorobenzene sulfoamido)-5-brombenzamide with 3-(4-chlorobenzene sulfonamide base)-5-brombenzamide.Productive rate 43.1%.
The preparation of embodiment 6 3-(4-fluorobenzene sulfoamido)-5-(2-amino-4-morpholinyl-6-quinazolyl) BM (6)
The preparation method is synthetic with compound 1 among the embodiment 1.Replace 1A with 4A, replace 4-morpholinyl-6-quinazoline boric acid pinacol ester with 2-amino-4-morpholinyl-6-quinazoline boric acid pinacol ester.Productive rate 80.8%.
The preparation of embodiment 7 2-methoxyl group-3-(4-fluorobenzene sulfoamido)-5-(2-amino-4-morpholinyl-6-quinazolyl) BM (7)
The preparation method is synthetic with compound 1 among the embodiment 1.Replace 4-morpholinyl-6-quinazoline boric acid pinacol ester with 2-amino-4-morpholinyl-6-quinazoline boric acid pinacol ester.Productive rate 65.7%.
The preparation of embodiment 8 3-(4-chlorobenzene sulfonamide base)-5-(2-amino-4-morpholinyl-6-quinazolyl) BM (8)
The preparation method is synthetic with compound 1 among the embodiment 1.Replace 1A with midbody 5A, replace 4-morpholinyl-6-quinazoline boric acid pinacol ester with 2-amino-4-morpholinyl-6-quinazoline boric acid pinacol ester.Productive rate 72.2%.
The preparation of embodiment 9 2-chloro-3-(4-fluorobenzene sulfoamido)-5-(2-amino-4-morpholinyl-6-quinazolyl) BM (9)
9A 2-chloro-3-(4-fluorobenzene sulfoamido)-5-brombenzamide
The preparation method is synthetic with 1A's among the embodiment 1.Replace 2-methoxyl group-3-amino-5-brombenzamide with 2-chloro-3-amino-5-brombenzamide.Productive rate 75.1%.
The preparation of 2-chloro-3-(4-fluorobenzene sulfoamido)-5-(2-amino-4-morpholinyl-6-quinazolyl) BM (9):
The preparation method is synthetic with compound 1 among the embodiment 1.Replace 1A with 9A, replace 4-morpholinyl-6-quinazoline boric acid pinacol ester with 2-amino-4-morpholinyl-6-quinazoline boric acid pinacol ester.Productive rate 71.8%.
The preparation of embodiment 10 2-chloro-3-(4-fluorobenzene sulfoamido)-5-(4-morpholinyl-6-quinazolyl) BM (10)
The preparation method is synthetic with compound 1 among the embodiment 1.Replace 1A with 9A.Productive rate 62.7%.
The preparation of embodiment 11 2-methoxyl group-3-cyclopropyl-sulfonylamide base-5-(4-morpholinyl-6-quinazolyl) BM (11)
11A 2-methoxyl group-3-cyclopropyl-sulfonylamide base-5-brombenzamide
The preparation method is synthetic with 1A's among the embodiment 1.Replace 4-fluorobenzene SULPHURYL CHLORIDE with ring third SULPHURYL CHLORIDE.Productive rate 24.8%.
The preparation of 2-methoxyl group-3-cyclopropyl-sulfonylamide base-5-(4-morpholinyl-6-quinazolyl) BM (11):
The preparation method is synthetic with compound 1 among the embodiment 1.Replace 1A with 11A.Productive rate 72.2%.
The preparation of embodiment 122-methoxyl group-3-(4-fluorobenzene sulfoamido)-5-(4-morpholinyl-6-quinolyl) BM (12)
The preparation method is synthetic with compound 1 among the embodiment 1.Replace 4-morpholinyl-6-quinazoline boric acid pinacol ester with 4-morpholinyl-6-quinoline boric acid pinacol ester.Productive rate 69.8%.
The preparation of embodiment 132-methoxyl group-3-(2,4 difluorobenzene sulfoamido)-5-(4-morpholinyl-6-quinolyl) BM (13)
13A 2-methoxyl group-3-(2,4 difluorobenzene sulfoamido)-5-brombenzamide
The preparation method is synthetic with 1A's among the embodiment 1.Replace 4-fluorobenzene SULPHURYL CHLORIDE with the 2,4 difluorobenzene SULPHURYL CHLORIDE.Productive rate 57.8%.
2-methoxyl group-3-(2,4 difluorobenzene sulfoamido)-5-(4-morpholinyl-6-quinolyl) BM (13)
The preparation method is synthetic with compound 1 among the embodiment 1.Replace 1A to replace 4-morpholinyl-6-quinazoline boric acid pinacol ester with 13A with 4-morpholinyl-6-quinoline boric acid pinacol ester.Productive rate 52.8%.
The preparation of embodiment 142-methoxyl group-3-(2,4 difluorobenzene sulfoamido)-5-(4-morpholinyl-6-quinazolyl) BM (14)
The preparation method is synthetic with compound 1 among the embodiment 1.Synthetic with 13A and 1B reaction.Productive rate 61.5%.
The preparation of embodiment 152-methoxyl group-3-(4-fluorobenzene sulfoamido)-5-(2-cyclopropyl carbonyl amino-6-benzothiazolyl) BM (15)
The preparation method is synthetic with compound 1 among the embodiment 1.Replace 4-morpholinyl-6-quinazoline boric acid pinacol ester with 2-cyclopropyl carbonyl amino-6-benzothiazole ylboronic acid pinacol ester.Productive rate 68.2%.
The preparation of embodiment 162-methoxyl group-3-cyclopropyl-sulfonylamide base-5-(2-cyclopropyl carbonyl amino-6-benzothiazolyl) BM (16)
The preparation method is synthetic with compound 1 among the embodiment 1.Replace 1A with 11A.Replace 4-morpholinyl-6-quinazoline boric acid pinacol ester with 2-cyclopropyl carbonyl amino-6-benzothiazole ylboronic acid pinacol ester.Productive rate 50.3%.
The checking of anti-tumor activity
In order to verify 2,3, the anti-tumor activity of 5-trisubstituted benzene Carbox amide specifically with the positive control drug of Carmustine, adopts external mtt assay to measure the growth-inhibiting effect of compound 1-16 to U87.
Verification method: tumour cell U87 is cultivated in containing the RPMI1640 substratum of 10% calf serum, include mould and have 100UmL
-1, Streptomycin sulphate 100 μ gmL
-1, in 37 ℃, 5%CO
2The cultivation of going down to posterity in the incubator.Get the adherent tumour cell of 0.3% trysinization, contain the RPMI1640 nutrient solution preparation cell suspension of 10% calf serum, concentration is 6 * 10
3Individual cells/ml.200 μ L (containing 1000 tumour cells approximately) are inoculated in every hole in 96 well culture plates, cultivate 24h for 37 ℃.The administration group adds the different concns medicine, and every medicine sets 10
-4, 10
-5, 10
-6, 10
-7, 10
-8MolL
-15 concentration are established 5 parallel holes for every group.Control group adds and the isopyknic solvent of medicine, places 37 ℃, 5%CO
2Discard nutrient solution after cultivating 48h in the incubator, every hole adds 20 μ l5mgmL
-1MTT solution, hatch 4h after, abandoning supernatant, every hole adds DMSO150 μ L, under 570nm, measures OD value (OD) with ELIASA behind the gentle agitation.
The result calculates:
The tumour cell of handling with solvent control is a control group, asks the inhibiting rate of medicine to tumour cell according to following formula.
And further adopt the improvement karber's method to obtain half-inhibition concentration (IC
50).
IC
50Detected result as shown in Figure 1, can see that most compounds has the obvious suppression effect to the growth of U87, wherein the IC of some compound
50Be worth suitable with the medicine Carmustine, the IC of compound 1 especially
50=1.54 μ mol/L; The IC of positive drug Carmustine
50=3.97 μ mol/L, effect is superior to Carmustine.
Claims (10)
1. one kind 2,3,5-trisubstituted benzene Carbox amide is characterized in that, the structural formula of this compounds is:
Wherein, R
1Be 6-quinolyl, 6-isoquinolyl, 6-benzothiazolyl, 4-replacement-6-quinolyl, 4-replacement-6-quinazolyl, 2,4-two replacement-6-quinazolyls or 2-replacement-6-benzothiazolyl; R
2Be cyclopropyl, phenyl or substituted-phenyl; R
3Be methoxyl group, chlorine or hydrogen.
2. as claimed in claim 12,3,5-trisubstituted benzene Carbox amide is characterized in that, the substituting group in described 4-replacement-6-quinolyl, the 4-replacement-6-quinazolyl is a morpholinyl.
3. as claimed in claim 12,3,5-trisubstituted benzene Carbox amide is characterized in that, and is described 2, and 2 of 4-two replacement-6-quinazolyls, 4-two are substituted by 2-amino-4-morpholinyl.
4. as claimed in claim 12,3,5-trisubstituted benzene Carbox amide is characterized in that, described 2-replacement-6-benzothiazolyl is 2-cyclopropyl carbonyl amino-6-benzothiazolyl.
5. as claimed in claim 12,3,5-trisubstituted benzene Carbox amide is characterized in that, described R
2In substituted-phenyl be single the replacement or two replacement, substituting group is halogen or methyl.
6. one kind 2,3, the preparation method of 5-trisubstituted benzene Carbox amide is characterized in that, may further comprise the steps:
Carry out suzuki reaction with compd A and compd B and obtain 2,3,5-trisubstituted benzene Carbox amide, its reaction formula is following:
Wherein, R in the compd A
2Be cyclopropyl, phenyl or substituted-phenyl; R
3Be methoxyl group, chlorine or hydrogen; In the compd B
Be 6-quinolyl, 6-quinazolyl, 6-benzothiazolyl, 4-replacement-6-quinolyl, 4-replacement-6-quinazolyl, 2,4-two replacement-6-quinazolyls or 2-replacement-6-benzothiazolyl.
7. as claimed in claim 62,3, the preparation method of 5-trisubstituted benzene Carbox amide is characterized in that, at PdCl
2(pddf)
2Under the catalysis, compd A, compd B are mixed in solvent with an alkali metal salt, stirring and refluxing reaction 2～10h steams solvent under nitrogen protection, from reaction, separates obtaining 2,3,5-trisubstituted benzene Carbox amide;
Described compd A is 2-methoxyl group-3-sulfonamido-5-brombenzamide, 2-chloro-3-sulfonamido-5-brombenzamide or 3-sulfonamido-5-brombenzamide;
Described compd B is 6-quinazolyl boric acid pinacol ester, 6-quinolyl boric acid pinacol ester or 6-benzothiazole ylboronic acid pinacol ester;
Described solvent is one or more in THF, dioxane, glycol dimethyl ether, N, the water.
8. as claimed in claim 62,3, the preparation method of 5-trisubstituted benzene Carbox amide is characterized in that, described an alkali metal salt is yellow soda ash, salt of wormwood, cesium carbonate or sodium-acetate, and the mol ratio of itself and compd A is 1:1～5:1;
Described 1 mole compd A joins in the solvent of 5～10L and reacts.
9. claim 1 is described 2,3, the application of 5-trisubstituted benzene Carbox amide in the preparation antitumor drug.
10. application as claimed in claim 9 is characterized in that 2; 3,5-trisubstituted benzene Carbox amide adds auxiliary material and processes tablet, capsule, soft capsule or injection, wherein every or a preparation in contain 2 of 10～500mg; 3,5-trisubstituted benzene Carbox amide;
Described auxiliary material comprises one or more in additive, stablizer, solubilizing agent, lubricant, the disintegrating agent.
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| US20090018131A1 (en) * | 2007-06-14 | 2009-01-15 | Adams Nicholas D | Quinazoline derivatives as p13 kinase inhibitors |
| WO2009111277A1 (en) * | 2008-02-29 | 2009-09-11 | Array Biopharma Inc. | Imdizo [4. 5-b] pyridine derivatives used as raf inhibitors |
| WO2009111277A9 (en) * | 2008-02-29 | 2009-12-30 | Array Biopharma Inc. | Imidazo [4. 5-b] pyridine derivatives used as raf inhibitors |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103772317A (en) * | 2014-01-06 | 2014-05-07 | 西安山川医药科技有限公司 | 2-methoxyl-3-substituted sulfonamido-5-(2-acetamido-6-benzothiazolyl) benzamide compound, preparation method and application thereof |
| CN103772317B (en) * | 2014-01-06 | 2016-04-06 | 西安山川医药科技有限公司 | 2-methoxyl group-3-replaces sulfonamido-5-(2-acetylaminohydroxyphenylarsonic acid 6-benzothiazolyl) benzamide compound and preparation method thereof and purposes |
| US11912668B2 (en) | 2020-11-18 | 2024-02-27 | Deciphera Pharmaceuticals, Llc | GCN2 and perk kinase inhibitors and methods of use thereof |
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| CN102746241B (en) | 2014-11-05 |
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