CN104725319A - 1H-indazole-3-aminobphenyl urea compound with anti-tumor activity as well as preparation method and application of 1H-indazole-3-aminobphenyl urea compound - Google Patents

1H-indazole-3-aminobphenyl urea compound with anti-tumor activity as well as preparation method and application of 1H-indazole-3-aminobphenyl urea compound Download PDF

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CN104725319A
CN104725319A CN201510107375.2A CN201510107375A CN104725319A CN 104725319 A CN104725319 A CN 104725319A CN 201510107375 A CN201510107375 A CN 201510107375A CN 104725319 A CN104725319 A CN 104725319A
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indazole
compound
phenylaniline
ring
tumor activity
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贺浪冲
张�杰
高洪平
苏萍
卢闻
张涛
王嗣岑
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Xian Jiaotong University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D417/12—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 linked by a chain containing hetero atoms as chain links

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Abstract

The invention provides a 1H-indazole-3-aminobphenyl urea compound with anti-tumor activity as well as a preparation method and an application of the 1H-indazole-3-aminobphenyl urea compound. A structural formula of the compound is as follows: FORMULA, wherein R1 is hydrogen, alkane, haloalkane or halogen; R2 is hydrogen, alkane, alkoxy, haloalkane, halogen or a tertiary amine segment; A is a benzene ring, a pyridine ring, a thiazole ring or a benzodioxolane ring; the urea structure is positioned on a meta-position or a para-position of the benzene ring. The compound can be prepared through organic synthesis reaction with four steps, has the advantages of being simple in reaction process operation, easily available in raw material, gentle in reaction condition, cheap in a used reagent and the like, and is suitable for large-scale production and manufacturing of pharmaceutical enterprises. The compound has good inhibitory activity on VEGFR-2 kinase, can be used for inhibiting proliferative activity of tumor cells, can be used for preparing anti-tumor drugs and drugs for inhibiting activity of the VEGFR-2 kinase, and is good in application prospect and high in scientific research value.

Description

A kind of 1H-indazole-3-phenylaniline carbamide compounds with anti-tumor activity and its preparation method and application
Technical field
The present invention relates to biomedicine technical field, relate to a kind of antineoplastic compound, be specifically related to a kind of 1H-indazole-3-phenylaniline carbamide compounds with anti-tumor activity and its preparation method and application.
Background technology
Malignant tumour as one of larger public health problem in the whole world, the greatly health of harm humans, and will first killer of the new millennium mankind be become.Malignant tumour is no longer the serious disease of advanced industrial country, and developing country is faced with larger Disease Spectrum.
Chemotherapy, as one of important means for the treatment of tumour, has had huge development and progress at nearly 30 years, has obtained large quantities of clinical antitumor agents with different mechanism of action.But antitumour drug also exists many untoward reactions, such as alopecia, vomiting, generation bone marrow depression, fast generation resistance etc., these all cause chemicals cannot reach the result for the treatment of of expection.The research and development of therefore new antitumor drug are one of the focus and difficulties of current pharmaceutical field.
Summary of the invention
The object of the present invention is to provide a kind of 1H-indazole-3-phenylaniline carbamide compounds with anti-tumor activity and its preparation method and application, this compound embodies good anti-tumor activity in vitro, can be applied to the preparation of antitumor drug.
The present invention is achieved through the following technical solutions:
Have a 1H-indazole-3-phenylaniline carbamide compounds for anti-tumor activity, its structural formula is as follows:
Wherein R 1for hydrogen, alkyl, halogenated alkane or halogen, R 2for hydrogen, alkyl, alkoxyl group, halogenated alkane, halogen or tertiary amine moieties, A ring is phenyl ring, pyridine ring, thiazole ring or the luxuriant ring of benzene Pian bis-Evil, and urea structure is positioned at position or contraposition between phenyl ring.
Described tertiary amine moieties is the Dimethylaminoethoxy that dimethylamino methyl, Diethylaminomethyl, piperidino methyl or phenyl ring have fluorine to replace.
Described R 1for H, 4-F, 4-CH 3, 6-CH 3, 4-F, 4-Cl, 5-CF 3or 3-F.
Described R 2for 2-F, 3-F, H, 2-Cl, 3-CH (CH 3) 2, 3-CF 3, 3-OCH 3, 2-CH 3, 3-Cl, 4- 4- 4- or 4-
There is a preparation method for the 1H-indazole-3-phenylaniline carbamide compounds of anti-tumor activity, comprise the following steps:
1) 2-fluoro-6-iodobenzene formonitrile HCN reacts with hydrazine hydrate under the effect of sodium bicarbonate, obtains the iodo-1H-indazole of 4--3-amine;
2) 3-amino-benzene boric acid is reacted with tetramethyl ethylene ketone under the catalysis of magnesium sulfate, obtain 3-amino-benzene pinacol borate;
3) aniline containing substituted radical and triphosgene are formed isocyanic ester, then with the condensation of 3-amino-benzene pinacol borate, obtain the carbamide compounds containing phenylo boric acid pinacol ester;
4) under the catalysis of tetrakis triphenylphosphine palladium, the carbamide compounds and the iodo-1H-indazole of 4--3-amine that contain phenylo boric acid pinacol ester are reacted by Suzuki, generates the 1H-indazole-3-phenylaniline carbamide compounds with anti-tumor activity.
There is the application of 1H-indazole-3-phenylaniline carbamide compounds in preparation suppression VEGFR-2 kinase activity medicine of anti-tumor activity.
1H-indazole-3-phenylaniline the carbamide compounds with anti-tumor activity is preparing the application in antitumor drug.
The medicine that described antitumor drug is is target spot with VEGFR-2 kinases, comprises the medicine of anti-lung cancer, anti-liver cancer, anti-cancer of the stomach, leukemia, anti-neural cancer, inhibitor against colon carcinoma cells, anti-breast cancer, anti-cervical cancer and anti-carcinoma of the pancreas.
Described antitumor drug is the medicine of inhibition tumor cell proliferation activity.
Described antitumor drug is the medicine suppressing lung cell A549 and liver cancer cell SMCC-7721 proliferation activity.
Compared with prior art, the present invention has following beneficial effect:
1H-indazole-3-phenylaniline the carbamide compounds with anti-tumor activity provided by the invention, it is a kind of novel compound with anti-tumor activity obtained through chemosynthesis, it has good inhibit activities to VEGFR-2 kinases, and can the proliferation activity of inhibition tumor cell.Scientific research has found that the generation of the generation of blood vessel and tumour, development and migration have substantial connection, suppress the formation of new vessel can the effectively growth of Tumor suppression and migration, many somatomedins all participate in the generation of new vessel, and wherein VEGFR-2 is the strongest known positive regulatory factor.1H-indazole-3-phenylaniline the carbamide compounds with anti-tumor activity provided by the invention passes through to suppress the kinase whose activity of VEGFR-2, block the signal path of its induction, thus can the hyperplasia of inhibition tumor cell and migration, therefore the 1H-indazole-3-phenylaniline carbamide compounds with anti-tumor activity provided by the invention can be used for antitumor drug and suppresses the preparation of VEGFR-2 kinase activity medicine, has a good application prospect and scientific research value.
The preparation method with the 1H-indazole-3-phenylaniline carbamide compounds of anti-tumor activity provided by the invention, target compound can be obtained by the conventional organic synthesis of four steps, there is the advantages such as reaction process is simple to operate, raw material is easy to get, reaction conditions gentle, agents useful for same is cheap, be suitable for the scale operation manufacture of pharmacy corporation.
In addition, 1H-indazole-3-phenylaniline the carbamide compounds with anti-tumor activity provided by the invention, to its cell-proliferation activity of inhibiting tumour cells comprising Non-small cell lung carcinoma cell (A549) and liver cancer cell (SMCC-7721), the preparation of antitumor drug can be can be applicable to.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of the 1H-indazole-3-phenylaniline carbamide compounds with anti-tumor activity;
Wherein compound 1 is 2-fluoro-6-iodobenzene formonitrile HCN, and compound 2 is the iodo-1H-indazole of 4--3-amine, and compound 3 is 3-amino-benzene boric acid, and compound 4 is 3-amino-benzene pinacol borate; Compound is 5 is the carbamide compounds containing phenylo boric acid pinacol ester, and compound 6 is for having the 1H-indazole-3-phenylaniline carbamide compounds of anti-tumor activity.What mark in figure is specially: a:EtOH, NaHCO 3, NH 2nH 2h 2o; B:MgSO 4, THF; C:BTC, Et 3n, DCM:d:Pd (PPh 3) 4, Na 2cO 3, H 2o, dioxane.
Embodiment
The invention provides a kind of 1H-indazole-3-phenylaniline carbamide compounds with anti-tumor activity, this 1H-indazole-3-phenylaniline carbamide compounds embodies anti-tumor activity in vitro, can be applied to the preparation of antitumor drug.
Be described in detail the present invention below in conjunction with drawings and Examples, the explanation of the invention is not limited.
1H-indazole-3-phenylaniline the carbamide compounds with anti-tumor activity provided by the invention, its chemical structural formula is:
Wherein, R 1, R 2be respectively the one in hydrogen, alkyl, alkoxyl group, halogenated alkane, halogen or tertiary amine moieties, A ring is phenyl ring, pyridine ring, thiazole ring or the luxuriant ring of benzene Pian bis-Evil, and urea structure is positioned at position or contraposition between phenyl ring.Tertiary amine moieties is the Dimethylaminoethoxy that dimethylamino methyl, Diethylaminomethyl, piperidino methyl or phenyl ring have fluorine to replace.
Concrete, R 1for H, 4-F, 4-CH 3, 6-CH 3, 4-F, 4-Cl, 5-CF 3or 3-F, R 2for 2-F, 3-F, H, 2-Cl, 3-CH (CH 3) 2, 3-CF 3, 3-OCH 3, 2-CH 3, 3-Cl, 4- 4- 4- or 4-
Preparation method and the method for screening active ingredients thereof with the drug candidate 1H-indazole-3-phenylaniline carbamide compounds of anti-tumor activity of the present invention is described in detail below in conjunction with the synthetic route shown in Fig. 1 and concrete synthetic example.
Embodiment 1
In the structural formula of this compound, A ring is phenyl ring, R 1for 4-fluorine, R 2for hydrogen, urea structure is positioned at position between phenyl ring, by following steps preparation (see Fig. 1):
1) 2-fluoro-6-iodobenzene formonitrile HCN (compound 1) prepares the iodo-1H-indazole of compound 4--3-amine (compound 2)
60ml dissolve with ethanol 10g 2-fluoro-6-iodobenzene formonitrile HCN (compound 1) and 5.2g sodium bicarbonate, add 12.5ml hydrazine hydrate, and reflux 8 hours, is cooled to 25 DEG C, adds 60ml water, and 25 DEG C are stirred 2 hours, and 0 DEG C is stirred 2 hours.By reaction solution suction filtration, drying obtains the iodo-1H-indazole of white-yellowish solid compound 4--3-amine (compound 2) 8.6g, productive rate: 83%;
2) 3-amino-benzene boric acid (compound 3) and tetramethyl ethylene ketone react and prepare compound 3-amino-benzene pinacol borate (compound 4)
By 20g 3-amino-benzene boric acid (compound 3), 19.2g tetramethyl ethylene ketone, 46.6g anhydrous magnesium sulfate joins in 500ml round-bottomed flask, add 250ml tetrahydrofuran (THF), stirring at room temperature 5 hours, filter, organic phase saturated sodium-chloride washes twice, anhydrous sodium sulfate drying.Tawny crude product 3-amino-benzene pinacol borate (compound 4) 21.5g is obtained, productive rate 76% after being spin-dried for liquid;
3) 3-amino-benzene pinacol borate (compound 4) and para-fluoroaniline prepare 1-(4-fluorophenyl)-3-(3-(4 by condensation reaction, 4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-base) phenyl) urea (compound 5)
Under condition of ice bath, heavily steam methylene dichloride with 20mL two for 0.80g (2.7mmol) (trichloromethyl) carbonic ether (BTC) is dissolved and stir 5min, slowly drip the dichloromethane solution of 0.76g (6.8mmol) para-fluoroaniline again, dropwise and stir 15min, the dichloromethane solution 10mL dripping 0.83mL (8.2mmol) triethylamine is continued in turbid solution, dropwise rear continuation and stir 15min, then in reaction soln, drip the dichloromethane solution 10mL of 1.50g (6.8mmol) 3-amino-benzene pinacol borate (compound 4) and 0.83mL (8.2mmol) triethylamine, dropwise rear continuation and stir 20min, reaction solution is used saturated sodium bicarbonate solution successively, saturated common salt water washing, anhydrous sodium sulfate drying, be spin-dried for and obtain red residue, be separated with chromatography column and obtain light yellow solid 1-(4-fluorophenyl)-3-(3-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxy boron penta ring-2-base) phenyl) urea (compound 5) 1.06g, productive rate 43.3%,
4) the iodo-1H-indazole of compound 4--3-amine (compound 2) and 1-(4-fluorophenyl)-3-(3-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-base) phenyl) urea (compound 5) prepares 1-(3-(3-amino-1 h-indazole-4-base) phenyl)-3-(4-fluorophenyl) urea (compound 6) by Suzuki linked reaction
By 1-(4-fluorophenyl)-3-(3-(4; 4; 5; 5-tetramethyl--1; 3; 2-dioxaborolan-2-yl) phenyl) urea (compound 5) 1.0g (2.8mmol); the iodo-1H-indazole of 4--3-amine (compound 2) 0.7g (2.7mmol); sodium carbonate 0.7g (6.6mmol); tetrakis triphenylphosphine palladium 0.3g (0.26mmol) is dissolved in 20mL 1; in 4-dioxane and 5ml water, spend the night in 100 DEG C of reactions under nitrogen protection.Be cooled to room temperature, suction filtration, 1,4-dioxane washing leaching cake, collect filtrate, be spin-dried for obtain yellow residue, be separated (eluting solvent is by sherwood oil: ethyl acetate=1:1) through chromatography column and obtain white solid 1-(3-(3-amino-1 h-indazole-4-base) phenyl)-3-(4-fluorophenyl) urea (compound 6) 0.56g, productive rate 56%;
Gained compound structure is shown below:
Physico-chemical property: mp:204 ~ 206 DEG C, MS (ESI) [M-H] +: m/z=360.10
Hydrogen spectrum nuclear magnetic resonance data is: 1h NMR (400MHz, DMSO) δ 11.77 (s, 1H), 8.85 (s, 1H), 8.77 (s, 1H), 7.62 (s, 1H), 7.48 (dd, J=5.7,3.5Hz, 1H), 7.45 (dd, J=6.8,2.6Hz, 1H), 7.41 (d, J=8.1Hz, 1H), 7.30 (d, J=3.9Hz, 2H), 7.12 (s, 1H), 7.10 (d, J=3.6Hz, 1H), 6.84 – 6.80 (m, 1H), 4.48 (s, 2H).
Embodiment 2
In the structural formula of this compound, A ring is phenyl ring, R 1for hydrogen, R 2for 3-sec.-propyl, urea structure is positioned at position between phenyl ring.
Step 1) ~ 3) with step 1 in embodiment 1) ~ 3) identical, just step 3) in raw material para-fluoroaniline is replaced to 3-isopropyl aniline, namely the iodo-1H-indazole of compound 4--3-amine (compound 2) is prepared by initial compounds 2-fluoro-6-iodobenzene formonitrile HCN (compound 1), prepare compound 1-(3-isopropyl phenyl)-3-(3-(4 by 3-amino-benzene boric acid (compound 3) simultaneously, 4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-base) phenyl) urea (compound 5).
4) 1-(3-isopropyl phenyl)-3-(3-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-base) phenyl) urea (compound 5) and the iodo-1H-indazole of 4--3-amine (compound 2) prepare compound 1-(3-(3-amino-1 h-indazole-4-base) phenyl)-3-(3-isopropyl phenyl) urea (compound 6) by Suzuki linked reaction, and concrete operation steps is:
By 1-(3-isopropyl phenyl)-3-(3-(4; 4; 5; 5-tetramethyl--1; 3; 2-dioxy boron penta ring-2-base) phenyl) urea (compound 5) 0.9g (1.9mmol); the iodo-1H-indazole of 4--3-amine (compound 2) 0.5g (1.9mmol); sodium carbonate 0.42g (3.9mmol); tetrakis triphenylphosphine palladium 0.3g (0.15mmol) is dissolved in 20mL 1; in 4-dioxane and 5ml water, spend the night in 100 DEG C of reactions under nitrogen protection.Be cooled to room temperature, suction filtration, 1,4-dioxane washing leaching cake, collect filtrate, be spin-dried for obtain yellow residue, be separated (eluting solvent is by sherwood oil: ethyl acetate=1:1) through chromatography column and obtain white solid 1-(3-(3-amino-1 h-indazole-4-base) phenyl)-3-(3-isopropyl phenyl) urea (compound 6) 0.47g, productive rate 52%;
Gained compound structure is shown below:
Physico-chemical property: mp:197 ~ 198 DEG C, MS (ESI) [M-H] +: m/z=384.20.
Hydrogen spectrum nuclear magnetic resonance data is: 1h NMR (400MHz, DMSO) δ 11.77 (s, 1H), 8.81 (s, 1H), 8.68 (s, 1H), 7.63 (d, J=1.8Hz, 1H), 7.46 – 7.40 (m, 2H), 7.35 (d, J=1.7Hz, 1H), 7.30 – 7.28 (m, 2H), 7.27 – 7.25 (m, 1H), 7.19 (t, J=7.8Hz, 1H), 7.09 – 7.06 (m, 1H), 6.86 (d, J=7.5Hz, 1H), 6.84 – 6.81 (m, 1H), 4.45 (s, 2H), 2.88 – 2.81 (m, 1H), 1.19 (d, J=6.9Hz, 6H).
Embodiment 3
In the structural formula of this compound, A ring is phenyl ring, R 1for 5-trifluoromethyl, R 2for 3-trifluoromethyl, urea structure is positioned at position between phenyl ring.
Step 1) ~ 3) with step 1 in embodiment 1) ~ 3) identical, just step 3) in raw material para-fluoroaniline is replaced to 3,5-bis-(trifluoromethyl) aniline, namely the iodo-1H-indazole of compound 4--3-amine (compound 2) is prepared by initial compounds 2-fluoro-6-iodobenzene formonitrile HCN (compound 1), prepare compound 1-(3 by 3-amino-benzene boric acid (compound 3) simultaneously, 5-bis-(trifluoromethyl) phenyl)-3-(3-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-base) phenyl) urea (compound 5).
4) 1-(3,5-bis-(trifluoromethyl) phenyl)-3-(3-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-base) phenyl) urea (compound 5) and the iodo-1H-indazole of 4--3-amine (compound 2) prepare compound 1-(3-(3-amino-1 h-indazole-4-base) phenyl)-3-(3 by Suzuki linked reaction, 5-bis-(trifluoromethyl) phenyl) urea (compound 6), concrete operation steps is:
By 1-(3; 5-bis-(trifluoromethyl) phenyl)-3-(3-(4; 4; 5; 5-tetramethyl--1; 3; 2-dioxy boron penta ring-2-base) phenyl) urea (compound 5) 0.9g (1.9mmol); the iodo-1H-indazole of 4--3-amine (compound 2) 0.5g (1.9mmol); sodium carbonate 0.42g (3.9mmol); tetrakis triphenylphosphine palladium 0.3g (0.15mmol) is dissolved in 20mL Isosorbide-5-Nitrae-dioxane and 5ml water, spends the night under nitrogen protection in 100 DEG C of reactions.Be cooled to room temperature, suction filtration, 1,4-dioxane washing leaching cake, collect filtrate, be spin-dried for obtain yellow residue, be separated (eluting solvent is by sherwood oil: ethyl acetate=1:1) through chromatography column and obtain white solid 1-(3-(3-amino-1 h-indazole-4-base) phenyl)-3-(3,5-bis-(trifluoromethyl) phenyl) urea (compound 6) 0.47g, productive rate 53%;
Gained compound structure is shown below:
Physico-chemical property: mp:203 ~ 204 DEG C, MS (ESI) [M-H] +: m/z=478.10
Hydrogen spectrum nuclear magnetic resonance data is: 1h NMR (400MHz, DMSO) δ 11.78 (s, 1H), 9.47 (s, 1H), 9.19 (s, 1H), 8.15 (s, 2H), 7.65 (t, J=4.3Hz, 2H), 7.53 – 7.51 (m, 1H), 7.45 (t, J=4.3Hz, 1H), 7.31 (t, J=4.3Hz, 2H), 7.13 (d, J=7.5Hz, 1H), 6.85 – 6.82 (m, 1H), 4.43 (s, 2H).
Embodiment 4
In the structural formula of this compound, A ring is pyridine ring, R 1for 4-methyl, R 2for hydrogen, urea structure is positioned at the contraposition of phenyl ring.
Step 1) ~ 3) with step 1 in embodiment 1) ~ 3) identical, just step 3) in raw material para-fluoroaniline is replaced to 2-amido 4-picoline, namely the iodo-1H-indazole of compound 4--3-amine (compound 2) is prepared by initial compounds 2-fluoro-6-iodobenzene formonitrile HCN (compound 1), prepare compound 1-(4-picoline-2-base)-3-(4-(4 by 3-amino-benzene boric acid (compound 3) simultaneously, 4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-base) phenyl) urea (compound 5).
4) 1-(4-picoline-2-base)-3-(4-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-base) phenyl) urea (compound 5) and the iodo-1H-indazole of 4--3-amine (compound 2) prepare compound 1-(4-(3-amino-1 h-indazole-4-base) phenyl)-3-(4-picoline-2-base) urea (compound 6) by Suzuki linked reaction, and concrete operation steps is:
By 1-(4-picoline-2-base)-3-(4-(4; 4; 5; 5-tetramethyl--1; 3; 2-dioxy boron penta ring-2-base) phenyl) urea (compound 5) 1.5g (4.2mmol); the iodo-1H-indazole of 4--3-amine (compound 2) 1.2g (4.6mmol); sodium carbonate 1.1g (10.3mmol); tetrakis triphenylphosphine palladium 0.5g (0.43mmol) is dissolved in 20mL 1; in 4-dioxane and 5ml water, spend the night in 100 DEG C of reactions under nitrogen protection.Be cooled to room temperature, suction filtration, 1,4-dioxane washing leaching cake, collect filtrate, be spin-dried for obtain yellow residue, be separated (eluting solvent is by sherwood oil: ethyl acetate=1:1) through chromatography column and obtain white solid 1-(4-(3-amino-1 h-indazole-4-base) phenyl)-3-(4-picoline-2-base) urea (compound 6) 0.79g, productive rate 52.5%;
Gained compound is shown below
Physico-chemical property: mp:228 ~ 229 DEG C, MS (ESI) [M-H] +: m/z=357.10
Hydrogen spectrum nuclear magnetic resonance data is: 1h NMR (400MHz, DMSO) δ 11.74 (s, 1H), 10.89 (s, 1H), 9.50 (s, 1H), 8.17 (d, J=5.2Hz, 1H), 7.68 (d, J=8.5Hz, 2H), 7.43 (d, J=8.5Hz, 2H), 7.30 (d, J=5.2Hz, 2H), 7.27 (s, 1H), 6.88 (d, J=5.0Hz, 1H), 6.81-6.79 (m, 1H), 4.35 (s, 2H), 2.31 (s, 3H).
Embodiment 5
In the structural formula of this compound, A ring is the luxuriant ring of benzene Pian bis-Evil, R 1for hydrogen, R 2for hydrogen, urea structure is positioned at the contraposition of phenyl ring.
Step 1) ~ 3) with step 1 in embodiment 1) ~ 3) identical, just step 3) in raw material para-fluoroaniline is replaced to namely the iodo-1H-indazole of compound 4--3-amine (compound 2) is prepared by initial compounds 2-fluoro-6-iodobenzene formonitrile HCN (compound 1), prepare compound 1-(benzo [d] (1 by 3-amino-benzene boric acid (compound 3) simultaneously, 3) dioxa penta ring-5-base)-3-(4-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-base) phenyl) urea (compound 5).
4) 1-(benzo [d] (1,3) dioxa penta ring-5-base)-3-(4-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-base) phenyl) urea (compound 5) and the iodo-1H-indazole of 4--3-amine (compound 2) prepare compound 1-(4-(3-amino-1 h-indazole-4-base) phenyl)-3-(benzo [d] (1 by Suzuki linked reaction, 3) dioxa penta ring-5-base) urea (compound 6), concrete operation steps is:
By 1-(benzo [d] (1; 3) dioxa penta ring-5-base)-3-(4-(4; 4; 5; 5-tetramethyl--1; 3; 2-dioxy boron penta ring-2-base) phenyl) urea (compound 5) 0.75g (1.9mmol); the iodo-1H-indazole of 4--3-amine (compound 2) 0.56g (2.1mmol); sodium carbonate 0.52g (4.7mmol); tetrakis triphenylphosphine palladium 0.23g (0.20mmol) is dissolved in 20mL Isosorbide-5-Nitrae-dioxane and 5ml water, spends the night under nitrogen protection in 100 DEG C of reactions.Be cooled to room temperature, suction filtration, 1,4-dioxane washing leaching cake, collect filtrate, be spin-dried for obtain yellow residue, be separated (eluting solvent is by sherwood oil: ethyl acetate=1:1) through chromatography column and obtain white solid 1-(4-(3-amino-1 h-indazole-4-base) phenyl)-3-(benzo [d] (1,3) dioxa penta ring-5-base) urea (compound 6) 0.41g, productive rate 55%;
Gained compound is shown below
Physico-chemical property: mp:150 ~ 152 DEG C, MS (ESI) [M-H] +: m/z=386.10
Hydrogen spectrum nuclear magnetic resonance data is: 1h NMR (400MHz, DMSO) δ 11.73 (s, 1H), 8.77 (s, 1H), 8.63 (s, 1H), 7.58 (d, J=8.6Hz, 2H), 7.39 (d, J=8.5Hz, 2H), 7.27 (d, J=8.6Hz, 2H), 7.24 (d, J=2.1Hz, 1H), 6.58 (d, J=8.6Hz, 1H), 6.80 – 6.78 (m, 2H), 5.99 (s, 2H), 4.35 (s, 2H).
Embodiment 6
In the structural formula of this compound, A ring is phenyl ring, R 1for hydrogen, R 2for Diethylaminomethyl, urea structure is positioned at the contraposition of phenyl ring.
Step 1) ~ 3) with step 1 in embodiment 1) ~ 3) identical, just step 3) in raw material para-fluoroaniline is replaced to 4-Diethylaminomethyl aniline, namely the iodo-1H-indazole of compound 4--3-amine (compound 2) is prepared by initial compounds 2-fluoro-6-iodobenzene formonitrile HCN (compound 1), prepare compound 1-(4-((diethylin) methyl) phenyl)-3-(4-(4 by 3-amino-benzene boric acid (compound 3) simultaneously, 4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-base) phenyl) urea (compound 5).
4) 1-(4-((diethylin) methyl) phenyl)-3-(4-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-base) phenyl) urea (compound 5) and the iodo-1H-indazole of 4--3-amine (compound 2) prepare compound 1-(4-(3-amino-1 h-indazole-4-base) phenyl)-3-(4-((diethylin) methyl) phenyl) urea (compound 6) by Suzuki linked reaction, and concrete operation steps is:
By 1-(4-((diethylin) methyl) phenyl)-3-(4-(4; 4; 5; 5-tetramethyl--1; 3; 2-dioxy boron penta ring-2-base) phenyl) urea (compound 5) 0.8g (1.9mmol); the iodo-1H-indazole of 4--3-amine (compound 2) 0.61g (2.3mmol); sodium carbonate 0.65g (6.1mmol); tetrakis triphenylphosphine palladium 0.24g (0.20mmol) is dissolved in 20mL 1; in 4-dioxane and 5ml water, spend the night in 100 DEG C of reactions under nitrogen protection.Be cooled to room temperature, suction filtration, 1,4-dioxane washing leaching cake, collect filtrate, be spin-dried for obtain yellow residue, be separated (eluting solvent is by sherwood oil: ethyl acetate=1:1) through chromatography column and obtain white solid 1-(4-(3-amino-1 h-indazole-4-base) phenyl)-3-(4-((diethylin) methyl) phenyl) urea (compound 6) 0.46g, productive rate 58%;
Gained compound is shown below
Physico-chemical property: mp:200 ~ 202 DEG C, MS (ESI) [M-H] +: m/z=427.50
Hydrogen spectrum nuclear magnetic resonance data is: 1h NMR (400MHz, DMSO) δ 11.74 (s, 1H), 8.83 (s, 1H), 8.72 (s, 1H), 7.60 (d, J=8.5Hz, 2H), 7.41 (m, 4H), 7.27 (d, J=5.8Hz, 2H), 7.22 (d, J=8.4Hz, 2H), 6.79 (dd, J=5.9,1.8Hz, 1H), 4.36 (s, 2H), 3.47 (s, 2H), 2.48 – 2.42 (m, 4H), 0.98 (t, J=7.1Hz, 6H).
Embodiment 7
In the structural formula of this compound, A ring is thiazole ring, R 1for hydrogen, R 2for hydrogen, urea structure is positioned at the contraposition of phenyl ring.
Step 1) ~ 4) with step 1 in embodiment 1) ~ 4) identical, just step 3) in raw material para-fluoroaniline is replaced to 2-amino-thiazol, namely prepare the iodo-1H-indazole of compound 4--3-amine (compound 2) by initial compounds 2-fluoro-6-iodobenzene formonitrile HCN (compound 1), prepare compound 6 by 3-amino-benzene boric acid (compound 3) simultaneously.Gained compound 6 is shown below
The generation of blood vessel and the generation of tumour, development and migration have substantial connection, suppress the formation of new vessel can the growth of effective Tumor suppression.Many somatomedins all participate in the generation of new vessel, and wherein VEGFR-2 is the strongest known positive regulatory factor.By suppressing VEGFR-2 kinase whose activity, block the signal path of its induction, can the hyperplasia of inhibition tumor cell and migration, and then reach the object for the treatment of tumour.
Anti-tumor activity experiment is carried out to the 1H-indazole-3-phenylaniline carbamide compounds with anti-tumor activity provided by the invention below.
1, there is the 1H-indazole-3-phenylaniline carbamide compounds of anti-tumor activity to the kinase whose inhibit activities screening of VEGFR-2
Kinases VEGFR-2 and substrate A bltide is purchased from Signal-Chem company, and select the ADP-GlobTM Kinase Assays detection kit of Promega company to detect the Inhibiting enzyme activity of target compound, working method illustrates according to test kit carries out.
By ATP (1mM) buffer (2 ×) (Tris 80mM, MgCl 220mM, BSA 0.2mg/mL, DTT2mM) dilute buffer (2 ×) solution that 80 times are mixed with ATP (125 μMs); The mixing solutions ATP solution of 125 μMs and Abltide liquor capacity 1:1 being hybridly prepared into ATP (62.5 μMs)-Abltide (0.5 μ g/ μ l) is for subsequent use; VEGFR-2 kinase solution buffer (1 ×) (Tris 40mM, MgCl 210mM, BSA 0.1mg/mL, DTT 1mM) dilute buffer (1 ×) solution for standby that 100 times are mixed with VEGFR-2 (10ng/ μ l); Target compound and positive control drug (Sorafinib) buffer (1 ×) are mixed with 6 × 10 respectively -5mol/L, 6 × 10 -6mol/L, 6 × 10 -7mol/L, 6 × 10 -8mol/L, 6 × 10 -9mol/L, 6 × 10 -10the sample solution of mol/L concentration gradient, on 384 orifice plates, every hole adds the mixing solutions of 2 μ L ATP-Abltide successively, 1 μ L sample solution, 2 μ L enzyme solution; Blank well adds the mixing solutions of 3 μ L damping fluids and 2 μ LATP-Abltide; Control wells adds the mixing solutions of 2 μ L ATP-Abltide, 1 μ L damping fluid, and 2 μ L enzyme solution, finish, hatch 60min at 30 DEG C; Add ADP-Glo reagent 5 μ L, at 25 DEG C, hatch 40min; Add Kinase detection reagent 10 μ L, at 25 DEG C, hatch 30min.
Adopt the chemoluminescence module of PerkinElmer multi-functional microplate reader to measure the luminous value in every hole, calculate the 1H-indazole-3-phenylaniline carbamide compounds with anti-tumor activity provided by the invention to the inhibiting rate of VEGFR-2 and IC 50.
The result obtained is as shown in table 1:
Table 1 1H-indazole-3-phenylaniline carbamide compounds is to the kinase whose IC of VEGFR-2 50
Wherein, the urea structure fragment of compound S 1 ~ S16 is positioned at position between phenyl ring, and the urea structure fragment of compound S 17 ~ S22 is positioned at the contraposition of phenyl ring.
Can find out that the individual compound had in the 1H-indazole-3-phenylaniline carbamide compounds of anti-tumor activity provided by the invention has the good kinase whose activity of suppression VEGFR-2 by table 1, can suppress to apply in the medicine of VEGFR-2 kinase activity in preparation.
2, there is the antitumor activity screening of the 1H-indazole-3-phenylaniline carbamide compounds of anti-tumor activity
Mtt assay is adopted to check 1H-indazole-3-phenylaniline carbamide compounds to be measured to the growth inhibitory activity of tumour cell:
1H-indazole-3-phenylaniline the carbamide compounds with anti-tumor activity provided by the invention has antitumor action, vitro inhibition proliferation activity is had to tumour cell, at lung carcinoma cell (A549), there is in liver cancer cell (SMCC-7721) clone the proliferation activity of inhibition tumor cell, may be used for the treatment to these cancers; Compared with positive drug BAY 43-9006 (Sorafinib), individual compound shows higher inhibition tumor cell proliferation activity.
To be in the lung carcinoma cell (A549) of logarithmic phase, liver cancer cell (SMCC-7721), the trysinization with 0.25% 3 ~ 5 minutes, being diluted to concentration after piping and druming is evenly 1 × 10 4~ 2 × 10 4the single cell suspension of individual/mL, is parallelly inoculated in 96 well culture plates, and every hole inoculation volume is 180 μ L; In 37 DEG C, 5%CO 2cultivate 24 hours in incubator; With the aqueous solution containing 0.25%DMSO (N, N-dimethyl sulfoxide (DMSO)) for negative control, take BAY 43-9006 as positive control, testing sample adds the 1H-indazole-3-phenylaniline carbamide compounds (8 × 10 of 4 different concns -7mol/L, 4 × 10 -6mol/L, 2 × 10 -5mol/L, 1 × 10 -4mol/L), each concentration establishes 3 multiple holes, continues cultivation 48 hours; Then every hole adds the MTT working fluid 22 μ L of 5mg/mL, mixing, 37 DEG C of incubators are hatched after 4 hours and are taken out, nutrient solution is abandoned in careful suction, every hole adds 150 μ L DMSO, vibration 10min, and euzymelinked immunosorbent assay (ELISA) detector measures 490nm place, each hole ultraviolet absorption value (OD value), then calculate cell inhibitory rate, and obtain IC according to inhibiting rate 50value.The calculation formula of cell inhibitory rate is:
Inhibiting rate %=(positive controls OD value-medication group OD value)/negative control cell OD value × 100%
Detected result shows: compared with negative control group, 1H-indazole-3-phenylaniline carbamide compounds has In-vitro Inhibitory Effect in various degree to above-mentioned 2 kinds of tumour cells, and result is as shown in table 2.
Table 2.1H-indazole-3-phenylaniline carbamide compounds is to the IC of different cell strain 50(μM)
The suppression of result display section compound on tumor cell is suitable with positive control drug BAY 43-9006, even has some activity to be higher than positive control.Illustrate that the proliferation inhibiting effect of 1H-indazole-3-phenylaniline carbamide compounds to tumour cell (lung cell A549 and liver cancer cell SMCC-7721) with anti-tumor activity provided by the invention is obvious, can apply preparing in antitumor drug.
Because VEGFR-2 kinases is to the growth of tumour cell, and the 1H-indazole-3-phenylaniline carbamide compounds with anti-tumor activity provided by the invention is to the kinase whose restraining effect of VEGFR-2, therefore the 1H-indazole-3-phenylaniline carbamide compounds with anti-tumor activity provided by the invention can be applied in the antitumor drug being target spot with VEGFR-2 kinases, not only comprise anti-lung cancer and the medicines resistant to liver cancer of above-mentioned citing, in like manner, also can comprise anti-cancer of the stomach, leukemia, anti-neural cancer, inhibitor against colon carcinoma cells, anti-breast cancer, the medicine such as anti-cervical cancer and anti-carcinoma of the pancreas.

Claims (10)

1. have a 1H-indazole-3-phenylaniline carbamide compounds for anti-tumor activity, it is characterized in that, its structural formula is as follows:
Wherein R 1for hydrogen, alkyl, halogenated alkane or halogen, R 2for hydrogen, alkyl, alkoxyl group, halogenated alkane, halogen or tertiary amine moieties, A ring is phenyl ring, pyridine ring, thiazole ring or the luxuriant ring of benzene Pian bis-Evil, and urea structure is positioned at position or contraposition between phenyl ring.
2. the 1H-indazole-3-phenylaniline carbamide compounds with anti-tumor activity according to claim 1, is characterized in that: described tertiary amine moieties is the Dimethylaminoethoxy that dimethylamino methyl, Diethylaminomethyl, piperidino methyl or phenyl ring have fluorine to replace.
3. the 1H-indazole-3-phenylaniline carbamide compounds with anti-tumor activity according to claim 1, is characterized in that: described R 1for H, 4-F, 4-CH 3, 6-CH 3, 4-F, 4-Cl, 5-CF 3or 3-F.
4. the 1H-indazole-3-phenylaniline carbamide compounds with anti-tumor activity according to claim 1, is characterized in that: described R 2for 2-F, 3-F, H, 2-Cl, 3-CH (CH 3) 2, 3-CF 3, 3-OCH 3, 2-CH 3, 3-Cl,
5. the preparation method with the 1H-indazole-3-phenylaniline carbamide compounds of anti-tumor activity in claim 1-4 described in any one, is characterized in that, comprise the following steps:
1) 2-fluoro-6-iodobenzene formonitrile HCN reacts with hydrazine hydrate under the effect of sodium bicarbonate, obtains the iodo-1H-indazole of 4--3-amine;
2) 3-amino-benzene boric acid is reacted with tetramethyl ethylene ketone under the catalysis of magnesium sulfate, obtain 3-amino-benzene pinacol borate;
3) aniline containing substituted radical and triphosgene are formed isocyanic ester, then with the condensation of 3-amino-benzene pinacol borate, obtain the carbamide compounds containing phenylo boric acid pinacol ester;
4) under the catalysis of tetrakis triphenylphosphine palladium, the carbamide compounds and the iodo-1H-indazole of 4--3-amine that contain phenylo boric acid pinacol ester are reacted by Suzuki, generates the 1H-indazole-3-phenylaniline carbamide compounds with anti-tumor activity.
6. the 1H-indazole-3-phenylaniline carbamide compounds with anti-tumor activity in claim 1-4 described in any one suppresses the application in VEGFR-2 kinase activity medicine in preparation.
7. the 1H-indazole-3-phenylaniline carbamide compounds with anti-tumor activity in claim 1-4 described in any one is preparing the application in antitumor drug.
8. apply as claimed in claim 7, it is characterized in that: the medicine that described antitumor drug is is target spot with VEGFR-2 kinases, comprise the medicine of anti-lung cancer, anti-liver cancer, anti-cancer of the stomach, leukemia, anti-neural cancer, inhibitor against colon carcinoma cells, anti-breast cancer, anti-cervical cancer and anti-carcinoma of the pancreas.
9. apply as claimed in claim 7, it is characterized in that: described antitumor drug is the medicine of inhibition tumor cell proliferation activity.
10. apply as claimed in claim 9, it is characterized in that: described antitumor drug is the medicine suppressing lung cell A549 and liver cancer cell SMCC-7721 proliferation activity.
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