CN102503945A - Compound capable of inhibiting epidermal growth factor receptor and application thereof - Google Patents
Compound capable of inhibiting epidermal growth factor receptor and application thereof Download PDFInfo
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- CN102503945A CN102503945A CN2011103860881A CN201110386088A CN102503945A CN 102503945 A CN102503945 A CN 102503945A CN 2011103860881 A CN2011103860881 A CN 2011103860881A CN 201110386088 A CN201110386088 A CN 201110386088A CN 102503945 A CN102503945 A CN 102503945A
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Abstract
The invention relates to a compound capable of inhibiting an epidermal growth factor receptor and an application thereof. The invention also relates to a medicament composition which comprises the compound capable of inhibiting the epidermal growth factor receptor or pharmaceutically acceptable salts and at least one pharmaceutically acceptable carrier. According to the invention, the administration route of the medicament composition comprises oral administration, nasal cavity inhalation, percutaneous absorption, lung administration and non-intestinal injection administration. The invention further relates to an application of the compound in the aspect of preventing and treating cancers related to EGFR (epidermal growth factor receptor) and related diseases thereof and an application of the medicament composition in the aspect of preventing and treating cancers related to EGFR and related diseases thereof.
Description
[technical field]
The present invention relates to suppress the EGF-R ELISA technical field, specifically, is some compound and application thereof that can suppress EGF-R ELISA.
[background technology]
EGF-R ELISA (epidermal growth factor receptor.EGFR) and part thereof came to light since 1962 and have just caused extensive attention.The neurogliocyte and the smooth muscle cell of epidermic cell that the research demonstration is nearly all and stroma cell and part all can be expressed EGFR..EGFR combines to make Src homology 2 district's protein phosphorylations under the physiological conditions with part, induces normal mitosis reaction, promotes cytodifferentiation, migration and homeostasis etc.; And aspects such as its abnormal expression and malignant cell breed, stick, vascularization, transfer, radiosensitivity are in close relations, also become in the present antibumor molecules target research pay close attention to the most extensively, research the most deeply, one of the most promising treatment target spot.
Urogastron (EGF) is the precursor of one big type of relative growth factor family.This family comprise transforming growth factor (Transforming Growth Factor, TGF), the two-ways regulation factor, heparin-bounding EGF and tunicin.TGF is considered to the crucial regulatory factor of normal cell and malignant cell propagation.TGF combines with specific receptors EGFR on the cytolemma, causes the catalytic activity of EGFR Tyrosylprotein kinase to be activated, and tenuigenin and nuclear signal transduction pathway are opened, thus cell beginning division growth.
(HERl erbB1) belongs to transmembrane receptor tyrosine family member in the cell proliferation and differentiation process to EGFR.EGFR also has the outer rich halfcystine district of two born of the same parents except that single kinases zone, above-mentioned part (EGF, TGF-a, the two-ways regulation factor, heparin-bounding EGF) and some other endogenic ligand all are combined in these zones.The known member of other in the EGFR family have HER2 (the similar acceptor 2 of Urogastrone), HER3 and HER4 (be erB2, erB3, erB4).The part of hypotype erB3 and erB4 mainly is heregulin, and the part of erB2 it be not immediately clear.Though do not find the part of erB2, it can connect into dimer through part with the HER family member and participate in cell signaling.In addition, the sudden change of the carinogenicity of erB2 can form an acceptor that is activated, and this receptor does not need to combine to get final product conducted signal with part.EGFR and HER2, HER3 are closely related, and HERR4 is only relevant with HER2.
At present, existing broad research confirms the mistake of EGFR to be expressed in SCCHN (head and neck squamous cell carcinoma HNSCC) reaches 90%～100%; Kidney reaches 50%～9O%, and lung cancer reaches 40%～8O%, and mammary cancer reaches 14%～90%; Colorectal cancer (colorectal cancer) reaches 25%～77%; Ovarian cancer reaches 25%～70%, and prostate cancer reaches 39%～47%, and neurogliocytoma reaches 40%～63%; Carcinoma of the pancreas reach 30%～50% and bladder cancer reach 31%～48%, in the multiple noumenal tumour such as cancer of the stomach, thymus neoplasms relevant report is also arranged all in addition.The over-expresses of EGFR often indicates that prognosis of patients is poor, shift fast, to chemicotherapy resistances, hormone resistance, existence weak point etc.Therefore, suppress propagation and the transfer that the EGFR Tyrosylprotein kinase can stop tumour cell effectively.
The objective of the invention is the activity of utilizing said compound to suppress EGFR and the cancer cell multiplication of being regulated and control thereof.
[summary of the invention]
The objective of the invention is to overcome the deficiency of prior art, some compound that can suppress EGF-R ELISA and application thereof are provided.
The objective of the invention is to realize through following technical scheme:
The compound that can suppress EGF-R ELISA, its chemical structural formula are I, II, and a kind of among the III,
Wherein
In the I formula:
R
1Single the replacement or polysubstituted group (wherein polysubstituted group is the replacement of 2-5 position at random) on the phenyl ring of place, can be independently selected from hydrogen, halogen, C
1-9Low alkyl group, C
3-9Naphthenic base, C
1-9Alkoxyl group, C
3-9Cycloalkyloxy, C
1-4Low-grade acyloxy, OH, NH
2, NO
2, SH, COOH, carbonate group (promptly-OC (O) OR
8), NR
8R
9, C=O R
8, O R
8, COO R
8, S R
8(R wherein
8R
9Be hydrogen, C
1-9Low alkyl group, C
3-9Naphthenic base, C
1-9Alkoxyl group, C
3-9Cycloalkyloxy, C
1-9Alkyl monosubstituted amino, 3-9 unit replace cycloaliphatic ring, 3-9 unit aliphatic heterocycle, replacement aromatic ring, substituted aroma heterocycle or 3-9 unit and replace assorted dicyclo); Or
The urethane that urea groups or thioureido or N-or O-connect, they are all optionally by one or two-C
1-9Low alkyl group or-C
3-9Cycloalkyl substituted;
Work as R
1During for two substituted radicals linking to each other, can form 3-9 unit's cycloaliphatic ring and and R
1The place phenyl ring and with, also can form five yuan or hexa-atomic aromatic ring or fragrant heterocycle and R
1The place phenyl ring and with.
L
1Be C
1-4Low alkyl group, C
1-4Lower alkoxy, C
1-4Lower alkyl amino, O or OX, S or SX, NH or NX, X are C
1-4Low alkyl group, C
1-4Lower alkoxy or C
1-4Rudimentary alkyl monosubstituted amino;
R
2For phenyl, substituted-phenyl, replacement 5-9 unit aromatic nucleus, replacement 5-9 membered aromatic heterocycle or the assorted dicyclo of substituted aroma, for containing 1-3 heteroatoms that is selected from oxygen, sulphur, nitrogen, can and close by phenyl ring and 5-6 membered aromatic heterocycle, or by one or more halogen, C of being selected from
1-C
6Straight or branched alkyl, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C
1-C
4Alkoxyl group, sulfydryl, C
1-C
4Acyl group, 5-9 unit's aromatic base or fragrant heterocyclic radical Ar replace;
Aromatic base or fragrant heterocyclic radical Ar are phenyl, substituted-phenyl, substituted benzyl, substituted benzyloxy, replacement benzyl amino, replace 5-9 unit aromatic base, replace 5-9 membered aromatic heterocycle base or replace the assorted bicyclic of the first substituted aroma of 5-9, Nai Ji, Lian Naiji; Substituting group is 1-4 and is selected from halogen, C
1-C
6Straight or branched alkyl, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C
1-C
4Alkoxyl group, sulfydryl, C
1-C
4The group of acyl group;
In the II formula:
R
3Single the replacement or polysubstituted group (wherein polysubstituted group is the replacement of 2-5 position at random) on the phenyl ring of place, can be independently selected from hydrogen, halogen, C
1-9Low alkyl group, C
3-9Naphthenic base, C
1-9Alkoxyl group, C
3-9Cycloalkyloxy, C
1-4Low-grade acyloxy, OH, NH
2, NO
2, SH, COOH, carbonate group (promptly-OC (O) OR
8), NR
8R
9, C=O R
8, O R
8, COO R
8, S R
8(R wherein
8R
9Be hydrogen, C
1-9Low alkyl group, C
3-9Naphthenic base, C
1-9Alkoxyl group, C
3-9Cycloalkyloxy, C
1-9Alkyl monosubstituted amino, 3-9 unit replace cycloaliphatic ring, 3-9 unit aliphatic heterocycle, replacement aromatic ring, substituted aroma heterocycle or 3-9 unit and replace assorted dicyclo); Or
The urethane that urea groups or thioureido or N-or O-connect, they are all optionally by one or two-C
1-9Low alkyl group or-C
3-9Cycloalkyl substituted;
Work as R
3During for two substituted radicals linking to each other, can form 3-9 unit's cycloaliphatic ring and and R
3The place phenyl ring and with, also can form five yuan or hexa-atomic aromatic ring or fragrant heterocycle and R
3The place phenyl ring and with.
L
2Be C
1-4Low alkyl group, C
1-4Lower alkoxy, C
1-4Lower alkyl amino, O or OX, S or SX, NH or NX, X are C
1-4Low alkyl group, C
1-4Lower alkoxy or C
1-4Rudimentary alkyl monosubstituted amino;
R
4For phenyl, substituted-phenyl, replacement 5-9 unit aromatic nucleus, replacement 5-9 membered aromatic heterocycle or the assorted dicyclo of substituted aroma, for containing 1-3 heteroatoms that is selected from oxygen, sulphur, nitrogen, can and close by phenyl ring and 5-6 membered aromatic heterocycle, or by one or more halogen, C of being selected from
1-C
6Straight or branched alkyl, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C
1-C
4Alkoxyl group, sulfydryl, C
1-C
4Acyl group, 5-9 unit's aromatic base or fragrant heterocyclic radical Ar replace;
Aromatic base or fragrant heterocyclic radical Ar are phenyl, substituted-phenyl, substituted benzyl, substituted benzyloxy, replacement benzyl amino, replace 5-9 unit aromatic base, replace 5-9 membered aromatic heterocycle base or replace the assorted bicyclic of the first substituted aroma of 5-9, Nai Ji, Lian Naiji; Substituting group is 1-4 and is selected from halogen, C
1-C
6Straight or branched alkyl, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C
1-C
4Alkoxyl group, sulfydryl, C
1-C
4The group of acyl group;
R
5Be H, halogen, hydroxyl or amino;
In the III formula:
R
6Single the replacement or polysubstituted group (wherein polysubstituted group is the replacement of 2-5 position at random) on the phenyl ring of place, can be independently selected from hydrogen, halogen, C
1-9Low alkyl group, C
3-9Naphthenic base, C
1-9Alkoxyl group, C
3-9Cycloalkyloxy, C
1-4Low-grade acyloxy, OH, NH
2, NO
2, SH, COOH, carbonate group (promptly-OC (O) OR
8), NR
8R
9, C=O R
8, O R
8, COO R
8, S R
8(R wherein
8R
9Be hydrogen, C
1-9Low alkyl group, C
3-9Naphthenic base, C
1-9Alkoxyl group, C
3-9Cycloalkyloxy, C
1-9Alkyl monosubstituted amino, 3-9 unit replace cycloaliphatic ring, 3-9 unit aliphatic heterocycle, replacement aromatic ring, substituted aroma heterocycle or 3-9 unit and replace assorted dicyclo); Or
The urethane that urea groups or thioureido or N-or O-connect, they are all optionally by one or two-C
1-9Low alkyl group or-C
3-9Cycloalkyl substituted;
Work as R
6During for two substituted radicals linking to each other, can form 3-9 unit's cycloaliphatic ring and and R
6The place phenyl ring and with, also can form five yuan or hexa-atomic aromatic ring or fragrant heterocycle and R
6The place phenyl ring and with.
L
3Be C
1-4Low alkyl group, C
1-4Lower alkoxy, C
1-4Lower alkyl amino, O or OX, S or SX, NH or NX, X are C
1-4Low alkyl group, C
1-4Lower alkoxy or C
1-4Rudimentary alkyl monosubstituted amino;
R
7For phenyl, substituted-phenyl, replacement 5-9 unit aromatic nucleus, replacement 5-9 membered aromatic heterocycle or the assorted dicyclo of substituted aroma, for containing 1-3 heteroatoms that is selected from oxygen, sulphur, nitrogen, can and close by phenyl ring and 5-6 membered aromatic heterocycle, or by one or more halogen, C of being selected from
1-C
6Straight or branched alkyl, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C
1-C
4Alkoxyl group, sulfydryl, C
1-C
4Acyl group, 5-9 unit's aromatic base or fragrant heterocyclic radical Ar replace;
Aromatic base or fragrant heterocyclic radical Ar are phenyl, substituted-phenyl, substituted benzyl, substituted benzyloxy, replacement benzyl amino, replace 5-9 unit aromatic base, replace 5-9 membered aromatic heterocycle base or replace the assorted bicyclic of the first substituted aroma of 5-9, Nai Ji, Lian Naiji; Substituting group is 1-4 and is selected from halogen, C
1-C
6Straight or branched alkyl, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C
1-C
4Alkoxyl group, sulfydryl, C
1-C
4The group of acyl group;
A kind of pharmaceutical composition comprises combination of compounds or the pharmacy acceptable salt and at least a pharmaceutically acceptable carrier that can suppress EGF-R ELISA.Such as, hydrochloride, vitriol, benzene sulfonate etc.
Said pharmaceutically acceptable carrier is selected from ionite, aluminum oxide, StAl, Yelkin TTS, serum proteins; Buffer substance such as phosphoric acid salt, glycerine, Sorbic Acid, POTASSIUM SORBATE GRANULAR WHITE, the partial glycerol ester mixture of saturated vegetable fatty acid; Water, salt or ionogen, Sodium phosphate, dibasic, potassium hydrogen phosphate, sodium-chlor; Zinc salt, colloided silica, Magnesium Trisilicate, Vinylpyrrolidone polymer, cellulosic material; Polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, one or more combinations in beeswax and the yolk.
That a kind of route of administration of pharmaceutical composition, route of administration comprise is oral, nasal cavity suction, Transdermal absorption, pulmonary administration and parenteral drug administration by injection.
Described medicine or pharmaceutical composition are in prevention and treatment cancer relevant with EGFR and the application in the relative disease thereof.
Compared with prior art, positively effect of the present invention is:
The computer virtual screening suppresses experiment with synthetic, EGFR kinase activity, cancer cells suppresses experiment and confirms that all this compounds is the EGFR suppressor factor, and the cancer relevant to EGFR has curative effect and prophylactic effect preferably.
[embodiment]
The compound of some inhibition EGF-R ELISAs of the present invention and the embodiment of application thereof below are provided.
Embodiment 1
Synthesizing of 5-phenyl-7 (1H)-[1,2,4] triazole [1,5-a] pyrimidones (1)
It is amino-1,2 in the 250mL round-bottomed flask, to add 3-, and (4.20g, 50.0mmol), (11.00g, 57.2mmol), (7.98g, 11.7mmol) and ethanol (150mL), stirring heating refluxed 4 hours sodium ethylate ethyl benzoylacetate the 4-triazole.After reaction is accomplished, to neutral, be positioned over 4 ℃ of refrigerator overnight with acetic acid neutralization reaction liquid, suction filtration obtains solid, and N, dinethylformamide and water mixed solvent recrystallization obtain 5-phenyl-7 (1H)-[1,2,4] triazole [1,5-a] pyrimidone (4.00g, 38%).
MS(EI)m/z(％)：212.1(100％)
1H?NMR(DMSO-d
6，400MHz)δ：8.26(s，1H)，δ：7.91(s，1H)，δ：7.13-7.42(m，5H)，δ：6.02(s，1H)
Embodiment 2
Synthesizing of 4-N-(4-benzene phenetole ethyl)-5-phenyl-7 (1H)-[1,2,4] triazole [1,5-a] pyrimidones (2)
Adding 5-phenyl-7 (1H)-[1,2,4] triazole [1,5-a] pyrimidone in the 250mL round-bottomed flask (1.00g, 4.7mmol); 4-benzene oxyethyl group Bian bromine (1.97g, 7.1mmol), salt of wormwood (2.07g, 15.0mmol) and propyl carbinol (45mL); Reflux 8 hours, solvent is removed in underpressure distillation, adds acetic acid ethyl dissolution, with saturated common salt water washing three times; After the organic solution drying, remove solvent, column chromatography is purified, and obtains white solid 4-N-(4-benzene phenetole ethyl)-5-phenyl-7 (1H)-[1; 2,4] triazole [1,5-a] pyrimidone (0.58g, 30%).
MS(EI)m/z(％)：408.2(100％)
1H?NMR(DMSO-d
6，400MHz)δ：7.92(s，1H)，δ：6.65-7.47(m，14H)，δ：6.07(s，1H)，δ：5.20(s，2H)，δ：4.78(s，2H)
Embodiment 3
Synthesizing of 2-(4-phenol methylene) ethyl malonate (3)
In the 150mL round-bottomed flask, add PARA HYDROXY BENZALDEHYDE (5.20g, 42.6mmol), ethyl malonate (6.82g, 42.6mmol), piperidines (0.5mL), phenylformic acid (0.2g, 1.4mmol) and benzene (60mL), heated and stirred refluxes, fraction water device water-dividing, reaction is spent the night.The pressure reducing and steaming solvent adds chloroform and moisture liquid, and organic layer is water, 2M hydrochloric acid and saturated sodium bicarbonate solution washing successively; Behind the anhydrous sodium sulfate drying; Remove solvent, obtain red oil 2-(4-phenol methylene) ethyl malonate (8.78g, 78%).
MS(EI)m/z(％)：264.1(100％)
1H?NMR(DMSO-d
6，400MHz)δ：7.75(s，1H)，δ：7.45-7.35(m，5H)，δ：4.32(q，2H)，δ：4.30(q，2H)，δ：1.32(t，3H)，δ：1.27(t，3H)
Embodiment 4
Synthesizing of 2-(4-benzene phenetole methylene radical) ethyl malonate (4)
In the 150mL round-bottomed flask, add 2-(4-phenol methylene) ethyl malonate (5.30g, 20.1mmol), the Bian bromine (4.33g, 25.3mmol); Salt of wormwood (4.14g, 30.0mmol) and ethanol (100mL), microwave heating refluxed 1 hour, after having reacted; Solvent is removed in underpressure distillation, adds ETHYLE ACETATE and moisture liquid, organic layer with water washing three times after, anhydrous magnesium sulfate drying; After removing solvent, column chromatography is purified and is obtained 2-(4-benzene phenetole methylene radical) ethyl malonate (5.00g, 70%).
MS(EI)m/z(％)：354.2(100％)
1H?NMR(DMSO-d
6，400MHz)δ：7.76(s，1H)，δ：7.65-6.95(m，9H)，δ：5.20(s，2H)，δ：4.32(q，2H)，δ：4.30(q，2H)，δ：1.32(t，3H)，δ：1.27(t，3H)
Embodiment 5
N-p-methoxyphenyl-3-(4-benzene phenetole methylene radical)-3,5-diketone pyrazolidine (5) synthetic
In the 50mL round-bottomed flask, add 2-(4-benzene phenetole methylene radical) ethyl malonate (1.20g, 3.4mmol), phenylhydrazine (0.57g, 4.1mmol); Sodium ethylate (0.49g, 7.2mmol) and ethanol (20mL), reflux 6 hours is after having reacted; Be cooled to room temperature, to neutral, hold over night is filtered and is obtained thick product with acetic acid neutralization reaction liquid; Column chromatography is purified and is obtained N-p-methoxyphenyl-3-(4-benzene phenetole methylene radical)-3,5-diketone pyrazolidine (0.54g, 40%).
MS(EI)m/z(％)：400.2(100％)
1H?NMR(DMSO-d
6，400MHz)δ：8.16(s，1H)，7.89(s，1H)，δ：7.64-6.91(m，13H)，δ：5.21(s，2H)，δ：3.72(s，3H)
Embodiment 6
Synthesizing of 3-ethoxycarbonyl-5-phenyl-4,7 [2H]-pyrazoles [1,5-a] pyrimidone (6)
(2.50g, 16.1mmol), (3.10g, 16.1mmol) and acetic acid (18mL), stirring heating refluxed 10 hours ethyl benzoylacetate in the 50mL round-bottomed flask, to add 3-amino-4-ethoxycarbonyl pyrazoles.Reaction obtains solid 3-ethoxycarbonyl-5-phenyl-4,7 [2H]-pyrazoles [1,5-a] pyrimidone (2.74g, 60%) after accomplishing after the underpressure distillation, directly be used for next step without purifying.
MS(EI)m/z(％)：283.1(100％)
1H?NMR(DMSO-d
6，400MHz)δ：8.16-8.05(m，3H)，7.49-7.38(m，3H)，δ：7.21(br?s，1H)，δ：6.21(s，1H)，δ：4.22(q，2H)，δ：1.32(t，3H)
Embodiment 7
Synthesizing of 3-carboxyl-5-phenyl-4,7 [2H]-pyrazoles [1,5-a] pyrimidone (7)
Adding 3-carboxyl-5-phenyl-4,7 [2H]-pyrazoles [1,5-a] pyrimidone in the 50mL round-bottomed flask (2.50g, 8.8mmol), KOH (9.88g, 176.5mmol), the mixed solution of water and THF (25mL), stirring heating refluxed 12 hours.After reaction is accomplished, with the Hydrocerol A acidifying after, filtration, solid with water washing after, the dioxane recrystallization obtains 3-carboxyl-5-phenyl-4,7 [2H]-pyrazoles [1,5-a] pyrimidone (1.57g, 70%).
MS(EI)m/z(％)：255.1(100％)
1H?NMR(DMSO-d
6，400MHz)δ：10.32(s，1H)，δ：8.15-8.01(m，3H)，7.45-7.35(m，3H)，δ：7.20(br?s，1H)，δ：6.22(s，1H)
Embodiment 8
Synthesizing of 3-(4-benzene phenetidine acyl group)-5-phenyl-4,7 [2H]-pyrazoles [1,5-a] pyrimidone (8)
Adding 3-carboxyl-5-phenyl-4,7 [2H]-pyrazoles [1,5-a] pyrimidone in the 50mL round-bottomed flask (0.80g, 3.1mmol); 4-benzene phenetidine (1.25g, 6.3mmol), EDC (1.20g, 6.3mmol); (0.85g, 6.3mmol) and dry DMF (15mL), lucifuge stirred 12 hours HOBt.After having reacted, water down, add the saturated aqueous solution of sodium bicarbonate separatory with 100mL ETHYLE ACETATE; Organic layer with brine wash after, anhydrous magnesium sulfate drying removes ETHYLE ACETATE; The residuum column chromatography is purified and is obtained 3-(4-benzene phenetidine acyl group)-5-phenyl-4; 7 [2H]-pyrazoles [1,5-a] pyrimidones (0.34g, 25%).
MS(EI)m/z(％)：436.2(100％)
1H?NMR(DMSO-d
6，400MHz)δ：8.24(s，1H)，δ：8.15-8.02(m，4H)，δ：7.85-7.66(m，5H)，7.55-7.35(m，6H)，δ：7.23(br?s，1H)，δ：6.23(s，1H)，δ：5.20(s，2H)
Embodiment 9
In the moist incubator that carbonic acid gas 5% is 37 ℃, with DMEM nutrient solution (adding 10% foetal calf serum, the Stimulina of 2mM, the Streptomycin sulphate of the penicillium mould of 50U/mL and 50 μ g/mL) conventional culturing human epidermal carcinoma cell (A431).The A431 cell of taking the logarithm vegetative period adds in 96 orifice plates, 3000 cells in every hole, 200 μ L/ holes.After 24 hours, add the compound 2,5,8 for preparing among the embodiment, concentration is 0.1-20 μ mol, and each concentration is provided with 3 parallel holes, puts 37 ℃ of cultivations.After 72 hours, discard nutrient solution, every hole adds the DMEM nutrient solution 200 μ L of 10%MTT; Cultivated again 4 hours, and discarded nutrient solution, add the DMSO of 200 μ L; After first is collected together dissolution of crystals; Under 492nm on the ELIASA and 570nm wavelength, detect the OD value in every hole, more by formula: growth inhibition ratio (%)=((1-dosing group OD value)/average OD value of control group) * 100% calculates the growth inhibition ratio of each concentration, and the half inhibiting rate is obtained in mapping.Accomplish three times independently the experiment after, the half inhibiting rate that calculates compound is as shown in table 1.Embodiment 10
The test of EGFR kinase activity adopts the homogeneous phase time discrimination fluorescence HTRFKinase-TK test kit of Cisbio company to measure.According to the operation instruction of test kit, the compound 2,5 of gradient concentration; 8, can be hatched in advance 2 hours by the substrate of phosphorylation and EGFR kinases, add ATP and start enzyme reaction; 37 ℃ the reaction half a hour after; Add anti-tyrosine phosphorylation antibody that has EU-BHHCT and the Streptavidin EDTA solution that has fluorophore XL665, room temperature was placed after 1 hour, and test sample is in the fluorescence intensity of 620nm and 665nm on the fluorescence microplate reader.The ratio of every hole two Wavelength strengths divided by the empty ratio of negative control, is inhibiting rate.The corresponding inhibiting rate mapping of different concns obtains the half inhibiting rate.Accomplish three times independently the experiment after, the half inhibiting rate that calculates compound is as shown in table 2.
Table 1
| Compound | To A431 cell inhibiting rate IC 50(μM) |
| 2 | 1.32±0.12 |
| 5 | 1.59±0.20 |
| 8 | 2.77±0.41 |
Table 2
| Compound | Inhibiting rate IC to EGFR 50(nM) |
| 2 | 120±13 |
| 5 | 151±20 |
| 8 | 202±11 |
The above only is a preferred implementation of the present invention; Should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the present invention's design; Can also make some improvement and retouching, these improvement and retouching also should be regarded as in protection scope of the present invention.
Claims (6)
1. can suppress the compound of EGF-R ELISA, it is characterized in that, its chemical structural formula is I, II, and a kind of among the III,
Wherein
In the I formula:
R
1Be single the replacement or polysubstituted group on the phenyl ring of place, wherein polysubstituted group is the replacement of 2-5 position at random, is independently selected from hydrogen, halogen, C
1-9Low alkyl group, C
3-9Naphthenic base, C
1-9Alkoxyl group, C
3-9Cycloalkyloxy, C
1-4Low-grade acyloxy, OH, NH
2, NO
2, SH, COOH, carbonate group, NR
8R
9, C=O R
8, O R
8, COO R
8, S R
8, R wherein
8R
9Be hydrogen, C
1-9Low alkyl group, C
3-9Naphthenic base, C
1-9Alkoxyl group, C
3-9Cycloalkyloxy, C
1-9Alkyl monosubstituted amino, 3-9 unit replace cycloaliphatic ring, 3-9 unit aliphatic heterocycle, replacement aromatic ring, substituted aroma heterocycle or 3-9 unit and replace assorted dicyclo; Or
The urethane that urea groups or thioureido or N-or O-connect, they are all optionally by one or two-C
1-9Low alkyl group or-C
3-9Cycloalkyl substituted;
Work as R
1During for two substituted radicals linking to each other, form 3-9 unit's cycloaliphatic ring and and R
1The place phenyl ring and with, also or form five yuan or hexa-atomic aromatic ring or fragrant heterocycle and R
1The place phenyl ring and with;
L
1Be C
1-4Low alkyl group, C
1-4Lower alkoxy, C
1-4Lower alkyl amino, O or OX, S or SX, NH or NX, X are C
1-4Low alkyl group, C
1-4Lower alkoxy or C
1-4Rudimentary alkyl monosubstituted amino;
R
2Be phenyl, substituted-phenyl, replacement 5-9 unit aromatic nucleus, replace 5-9 membered aromatic heterocycle or the assorted dicyclo of substituted aroma, for containing 1-3 heteroatoms that is selected from oxygen, sulphur, nitrogen, by phenyl ring and 5-6 membered aromatic heterocycle and close, or by one or more halogen, C of being selected from
1-C
6Straight or branched alkyl, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C
1-C
4Alkoxyl group, sulfydryl, C
1-C
4Acyl group, 5-9 unit's aromatic base or fragrant heterocyclic radical Ar replace;
Aromatic base or fragrant heterocyclic radical Ar are phenyl, substituted-phenyl, substituted benzyl, substituted benzyloxy, replacement benzyl amino, replace 5-9 unit aromatic base, replace 5-9 membered aromatic heterocycle base or replace the assorted bicyclic of the first substituted aroma of 5-9, Nai Ji, Lian Naiji; Substituting group is 1-4 and is selected from halogen, C
1-C
6Straight or branched alkyl, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C
1-C
4Alkoxyl group, sulfydryl, C
1-C
4The group of acyl group;
In the II formula:
R
3Be single the replacement or polysubstituted group on the phenyl ring of place, wherein polysubstituted group is the replacement of 2-5 position at random, is independently selected from hydrogen, halogen, C
1-9Low alkyl group, C
3-9Naphthenic base, C
1-9Alkoxyl group, C
3-9Cycloalkyloxy, C
1-4Low-grade acyloxy, OH, NH
2, NO
2, SH, COOH, carbonate group, NR
8R
9, C=O R
8, O R
8, COO R
8, S R
8, R wherein
8R
9Be hydrogen, C
1-9Low alkyl group, C
3-9Naphthenic base, C
1-9Alkoxyl group, C
3-9Cycloalkyloxy, C
1-9Alkyl monosubstituted amino, 3-9 unit replace cycloaliphatic ring, 3-9 unit aliphatic heterocycle, replacement aromatic ring, substituted aroma heterocycle or 3-9 unit and replace assorted dicyclo; Or
The urethane that urea groups or thioureido or N-or O-connect, they are all optionally by one or two-C
1-9Low alkyl group or-C
3-9Cycloalkyl substituted;
Work as R
3During for two substituted radicals linking to each other, form 3-9 unit's cycloaliphatic ring and and R
3The place phenyl ring and with, also or form five yuan or hexa-atomic aromatic ring or fragrant heterocycle and R
3The place phenyl ring and with;
L
2Be C
1-4Low alkyl group, C
1-4Lower alkoxy, C
1-4Lower alkyl amino, O or OX, S or SX, NH or NX, X are C
1-4Low alkyl group, C
1-4Lower alkoxy or C
1-4Rudimentary alkyl monosubstituted amino;
R
4Be phenyl, substituted-phenyl, replacement 5-9 unit aromatic nucleus, replace 5-9 membered aromatic heterocycle or the assorted dicyclo of substituted aroma, for containing 1-3 heteroatoms that is selected from oxygen, sulphur, nitrogen, by phenyl ring and 5-6 membered aromatic heterocycle and close, or by one or more halogen, C of being selected from
1-C
6Straight or branched alkyl, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C
1-C
4Alkoxyl group, sulfydryl, C
1-C
4Acyl group, 5-9 unit's aromatic base or fragrant heterocyclic radical Ar replace;
Aromatic base or fragrant heterocyclic radical Ar are phenyl, substituted-phenyl, substituted benzyl, substituted benzyloxy, replacement benzyl amino, replace 5-9 unit aromatic base, replace 5-9 membered aromatic heterocycle base or replace the assorted bicyclic of the first substituted aroma of 5-9, Nai Ji, Lian Naiji; Substituting group is 1-4 and is selected from halogen, C
1-C
6Straight or branched alkyl, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C
1-C
4Alkoxyl group, sulfydryl, C
1-C
4The group of acyl group;
R
5Be H, halogen, hydroxyl or amino;
In the III formula:
R
6Be single the replacement or polysubstituted group on the phenyl ring of place, wherein polysubstituted group is the replacement of 2-5 position at random, is independently selected from hydrogen, halogen, C
1-9Low alkyl group, C
3-9Naphthenic base, C
1-9Alkoxyl group, C
3-9Cycloalkyloxy, C
1-4Low-grade acyloxy, OH, NH
2, NO
2, SH, COOH, carbonate group, NR
8R
9, C=O R
8, O R
8, COO R
8, S R
8, R wherein
8R
9Be hydrogen, C
1-9Low alkyl group, C
3-9Naphthenic base, C
1-9Alkoxyl group, C
3-9Cycloalkyloxy, C
1-9Alkyl monosubstituted amino, 3-9 unit replace cycloaliphatic ring, 3-9 unit aliphatic heterocycle, replacement aromatic ring, substituted aroma heterocycle or 3-9 unit and replace assorted dicyclo; Or
The urethane that urea groups or thioureido or N-or O-connect, they are all optionally by one or two-C
1-9Low alkyl group or-C
3-9Cycloalkyl substituted;
Work as R
6During for two substituted radicals linking to each other, form 3-9 unit's cycloaliphatic ring and and R
6The place phenyl ring and with, also or form five yuan or hexa-atomic aromatic ring or fragrant heterocycle and R
6The place phenyl ring and with;
L
3Be C
1-4Low alkyl group, C
1-4Lower alkoxy, C
1-4Lower alkyl amino, O or OX, S or SX, NH or NX, X are C
1-4Low alkyl group, C
1-4Lower alkoxy or C
1-4Rudimentary alkyl monosubstituted amino;
R
7Be phenyl, substituted-phenyl, replacement 5-9 unit aromatic nucleus, replace 5-9 membered aromatic heterocycle or the assorted dicyclo of substituted aroma, for containing 1-3 heteroatoms that is selected from oxygen, sulphur, nitrogen, by phenyl ring and 5-6 membered aromatic heterocycle and close, or by one or more halogen, C of being selected from
1-C
6Straight or branched alkyl, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C
1-C
4Alkoxyl group, sulfydryl, C
1-C
4Acyl group, 5-9 unit's aromatic base or fragrant heterocyclic radical Ar replace;
Aromatic base or fragrant heterocyclic radical Ar are phenyl, substituted-phenyl, substituted benzyl, substituted benzyloxy, replacement benzyl amino, replace 5-9 unit aromatic base, replace 5-9 membered aromatic heterocycle base or replace the assorted bicyclic of the first substituted aroma of 5-9, Nai Ji, Lian Naiji; Substituting group is 1-4 and is selected from halogen, C
1-C
6Straight or branched alkyl, cyanic acid, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C
1-C
4Alkoxyl group, sulfydryl, C
1-C
4The group of acyl group.
2. a pharmaceutical composition is characterized in that, comprises combination of compounds or the pharmacy acceptable salt and at least a pharmaceutically acceptable carrier that can suppress EGF-R ELISA.
3. a kind of pharmaceutical composition as claimed in claim 2 is characterized in that, said pharmaceutically acceptable carrier is selected from ionite, aluminum oxide, StAl, Yelkin TTS; Serum proteins, buffer substance such as phosphoric acid salt, glycerine, Sorbic Acid, POTASSIUM SORBATE GRANULAR WHITE; The partial glycerol ester mixture of saturated vegetable fatty acid, water, salt or ionogen, Sodium phosphate, dibasic, potassium hydrogen phosphate; Sodium-chlor, zinc salt, colloided silica, Magnesium Trisilicate, Vinylpyrrolidone polymer; Cellulosic material, polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, one or more combinations in beeswax and the yolk.
4. the route of administration of a kind of pharmaceutical composition as claimed in claim 2 is characterized in that, that route of administration comprises is oral, nasal cavity suction, Transdermal absorption, pulmonary administration and parenteral drug administration by injection.
5. the compound that can suppress EGF-R ELISA as claimed in claim 1 is in prevention and treatment cancer relevant with EGFR and the application in the relative disease thereof.
6. a kind of pharmaceutical composition as claimed in claim 2 is in prevention and treatment cancer relevant with EGFR and the application in the relative disease thereof.
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| CN2011103860881A CN102503945A (en) | 2011-11-28 | 2011-11-28 | Compound capable of inhibiting epidermal growth factor receptor and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103058959A (en) * | 2013-01-04 | 2013-04-24 | 华东理工大学 | N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl) amide compound and application thereof |
| CN112204029A (en) * | 2018-05-31 | 2021-01-08 | 豪夫迈·罗氏有限公司 | Therapeutic compounds |
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| US20040038993A1 (en) * | 2002-06-04 | 2004-02-26 | Neogenesis Pharmaceuticals, Inc. | Pyrazolo[1,5a]pyrimidine compounds as antiviral agents |
| WO2007048066A2 (en) * | 2005-10-21 | 2007-04-26 | Exelixis, Inc. | Pyrazolo-pyrimidines as casein kinase ii (ck2) modulators |
| WO2010139483A1 (en) * | 2009-06-04 | 2010-12-09 | Merz Pharma Gmbh & Co. Kgaa | Glycine b antagonists |
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| US20040038993A1 (en) * | 2002-06-04 | 2004-02-26 | Neogenesis Pharmaceuticals, Inc. | Pyrazolo[1,5a]pyrimidine compounds as antiviral agents |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103058959A (en) * | 2013-01-04 | 2013-04-24 | 华东理工大学 | N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl) amide compound and application thereof |
| CN103058959B (en) * | 2013-01-04 | 2014-09-10 | 华东理工大学 | N-(2-(4-methylpiperazine-1-yl)-5-formylphenyl) amide compound and application thereof |
| CN112204029A (en) * | 2018-05-31 | 2021-01-08 | 豪夫迈·罗氏有限公司 | Therapeutic compounds |
| CN112204029B (en) * | 2018-05-31 | 2024-03-01 | 豪夫迈·罗氏有限公司 | Therapeutic compounds |
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