CN102363618A - Novel inhibitor of epidermal growth factor receptor (EGFR) and application thereof - Google Patents
Novel inhibitor of epidermal growth factor receptor (EGFR) and application thereof Download PDFInfo
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- CN102363618A CN102363618A CN2011101847469A CN201110184746A CN102363618A CN 102363618 A CN102363618 A CN 102363618A CN 2011101847469 A CN2011101847469 A CN 2011101847469A CN 201110184746 A CN201110184746 A CN 201110184746A CN 102363618 A CN102363618 A CN 102363618A
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Abstract
The invention relates to a novel inhibitor of an EGFR and an application thereof. The general formula of the EGFR inhibitor is represented by a formula shown in the specification. In the formula, L is a C1-4 lower alkyl group, a C1-4 lower alkyloxy group, a C1-4 lower alkylamino group, O, OR4, S, SR4, NH or NR4, wherein R4 is a C1-4 lower alkyl group, a C1-4 lower alkyloxy group, or a C1-4 lower monoalkylamino group; R1 is a phenyl group, a substituted phenyl group, a substituted five-nine-membered aromatic cycle, a substituted five-nine-membered aromatic heterocycle or a substituted aromatic bicycle; R2 is hydrogen, a C1-9 alkyl group, a C1-9 alkyloxy group, OH, NH2, NO2, SH, or NR5R6, wherein R5R6 is hydrogen, a C1-9 alkyl group, a C1-9 alkyloxy group or a C1-9 monoalkylamino group, a three-nine-membered substituted aliphatic cycle, an aliphatic heterocycle, a substituted aromatic cycle, a substituted aromatic heterocycle, or a three-nine-membred bicycle; and R3 is halogen, H, SH, OH or NO2. The virtual screening of a computer, EGFR kinase activity inhibition experiments, and cancer cell inhibition experiments confirm that compounds of above formula are the EGFR inhibitor and have good curative effects and prevention effects on cancers related with the EGFR.
Description
[technical field]
The present invention relates to suppress skin factor acceptor and associated receptor technical field, specifically, is a kind of new inhibitor and application thereof of EGF-R ELISA.
[background technology]
EGF-R ELISA (EGFR) is one type of important film Tyrosylprotein kinase growth factor receptors of striding, and is positioned cytolemma, is equal to HER2/ErbB-2/Neu/pl85, HER3/ErbB-3, HER4/ErbB-4 and is included into HER/ErbB family.By extracellular region, stride the film district and intracellular region three parts are formed.Its part comprises Urogastron (epidermal growth factor; EGF), transforming growth factor-alpha (transforming growth factor-α; TGF-α), the plain (betacellulin of beta cell; BTC), amphiregulin (amphiregulin), epidermin (epiregulin), heparin-bounding Urogastron (heparin-binding EGF, HB-EGF) etc., important with EGF and TGF-α.EGFR combines the back interaction to form homodimer or heterodimer with its ligand extracellular region.Compare with homodimer, heterodimer plays a part even more important in signal transmission such as mediated cell propagation, differentiation, migration.Dimeric formation causes the activation in Tyrosylprotein kinase district in the born of the same parents, and then through changeing phosphorylation and phosphorylation, impels receptor tyrosine residue phosphorylation, starts a series of cascade reactions such as ras-MAPK, PI3K, PLC γ/PKC, STAT.Signal is passed in the nucleus.Finally cause a series of genes involved activation, promote cell from G
1Phase carries out the transition to the S phase, thereby genetic expression in examining and cell Growth and Differentiation are produced regulating effect.
At present existing broad research confirms the mistake of EGFR to be expressed in SCCHN, and (head and neck squamous cell carcinoma HNSCC) reaches 90%～100%, and kidney reaches 50%～9O%; Lung cancer reaches 40%～8O%; Mammary cancer reaches 14%～90%, and colorectal cancer (colorectal cancer) reaches 25%～77%, and ovarian cancer reaches 25%～70%; Prostate cancer reaches 39%～47%; 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 cancer cell multiplication that the objective of the invention is to utilize imidazo [1,2-a] pyrazine analog derivative to suppress the active of EGFR and regulated and control.
[summary of the invention]
The objective of the invention is to overcome the deficiency of prior art, a kind of new inhibitor and application thereof of EGF-R ELISA are provided.
The objective of the invention is to realize through following technical scheme:
A kind of new inhibitor of EGF-R ELISA, its chemical structural formula is:
I：
Wherein
L is C
1-4Low alkyl group, C
1-4Lower alkoxy, C
1-4Lower alkyl amino, O or OR
4, S or SR
4, NH or NR
4, R
4Be C
1-4Low alkyl group, C
1-4Lower alkoxy or C
1-4Rudimentary alkyl monosubstituted amino;
R
1For phenyl, substituted-phenyl, replacement 5-9 unit aromatic nucleus, replace 5-9 membered aromatic heterocycle or the assorted dicyclo of substituted aroma and (contain 1-3 heteroatoms that is selected from oxygen, sulphur, nitrogen, can and close, or by one or more halogen, C of being selected from by phenyl and aromatic heterocycle
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 can be that (substituting group can be 1-4 and be selected from halogen, C for phenyl, substituted-phenyl, substituted benzyl, substituted benzyloxy, replacement benzyl amino, replacement 5-9 unit's aromatic base or fragrant heterocyclic radical
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), Nai Ji, Lian Naiji;
R
2Be hydrogen, C
1-9Alkyl, C
1-9Alkoxyl group, OH, NH
2, NO
2, SH, NR
5R
6, R
5R
6Be hydrogen, C
1-9Alkyl, C
1-9Alkoxyl group or C
1-9Alkyl monosubstituted amino, 3-9 unit replace cycloaliphatic ring, aliphatic heterocycle, replacement aromatic ring, substituted aroma heterocycle or 3-9 unit and replace assorted dicyclo;
R3 is halogen, H, SH, OH or NO
2In a kind of.
A kind of pharmaceutical composition is characterized in that, contains compound or the combination of formula I; The pharmaceutically acceptable salt that perhaps contains the compound of formula I such as the salt of receiving of the compound that contains formula I, contains the sylvite of the compound of formula I; The hydrochloride that contains the compound of formula I; The vitriol that contains the compound of formula I contains the calcium salt of the compound of formula I, contains the hydrochloride of the compound of formula I.
A kind of route of administration of pharmaceutical composition comprises oral, nasal cavity suction, Transdermal absorption, pulmonary administration and parenteral drug administration by injection.
Medicine or the pharmaceutical composition that contains formula I structural formula is in prevention and treatment cancer relevant with EGFR and the medicinal application in the relative disease thereof.
Cancer can be lung cancer, mammary cancer, kidney, head and neck cancer, the rectum cancer.
Relevant disease can be for expressing the relative disease of lacking of proper care with EGFR.
Compared with prior art, positively effect of the present invention is:
The present invention suppresses experiment and confirms that all this compounds is the EGFR suppressor factor through computer virtual screening, EGFR kinase activity inhibition experiment, cancer cells, and the cancer relevant to EGFR has curative effect and prophylactic effect preferably.
The present invention is a kind of new texture, has certain EGFR and suppresses activity and antitumour activity, has couple VEGFR that effect is also arranged, and is a kind of novel EGFR tyrosine kinase inhibitor.
[description of drawings]
Fig. 1 is that 3-(3-chloro-4-fluorobenzene methylamino-)-6-(the 4-anisole is amino) imidazo [1,2-a] pyrazine is to A431 cell inhibiting curve;
Fig. 2 is the inhibition curve of 3-(3-chloro-4-fluorobenzene methylamino-)-6-(the 4-anisole is amino) imidazo [1,2-a] pyrazine to the EGFR kinase activity;
Fig. 3 is the structural formula of the new inhibitor of EGF-R ELISA of the present invention.
[embodiment]
The new inhibitor of a kind of EGF-R ELISA of the present invention and the embodiment of application thereof below are provided.
Embodiment 1
3-(1,1,3,3-tetramethyl-butylamine base)-6-chlorine imidazo [1,2-a] pyrazine
Under the nitrogen protection, in the 150mL there-necked flask, add ethanol and methylene dichloride mixed solution 100mL and 2-amino-5-chloropyrazine (2.00g, 15mmol), add after the stirring and dissolving formaldehyde (5.33,75mmol) and the trifluoromethayl sulfonic acid scandium (0.74g, 1.5mmol).Stir 1h under the room temperature.Add 1,1,3 again, (2.33g 15mmol), stirs 48h under the room temperature to 3-tetramethyl butyl isonitrile.TLC shows that raw material reaction is complete, and solvent is removed in underpressure distillation, and residuum water (100mL) and ETHYLE ACETATE (150mL) separatory behind the organic layer anhydrous sodium sulfate drying, concentrate and obtain product (2.10g, bullion).Directly be used for next step reaction without purifying.
MS(EI)m/z(％)：280.2(100％)，282.2(33％)
1H?NMR(DMSO-d
6，400MHz)δ：8.71(s，1H)，δ：8.46(s，1H)，δ：7.52(s，1H)，δ：6.76(s，1H)，δ：1.72(s，2H)，δ：1.35-1.33(m，6H)，1.06(s，9H)
Embodiment 2
3-amino-6-chlorine imidazo [1,2-a] pyrazine
(1.00g, 3.6mmol) and exsiccant methylene dichloride (45mL), after the dissolving, ice bath adds trifluoroacetic acid (100mL) down, stirs 1h under the room temperature in the 250mL round-bottomed flask, to add 3-(1,1,3,3-tetramethyl-butylamine base)-6-chlorine imidazo [1,2-a] pyrazine.After having reacted, solvent is removed in underpressure distillation, uses saturated NaHCO
3(200mL) after the solution-treated, methylene dichloride (200mL) extraction behind the organic layer anhydrous sodium sulfate drying, is removed dichloromethane solvent, and thick product column chromatography is purified and obtained white solid 3-amino-6-chlorine imidazo [1,2-a] pyrazine (0.30g, 50%).
MS(EI)m/z(％)：168.0(100％)，170.0(33％)
1H?NMR(DMSO-d
6，400MHz)δ：8.62(s，1H)，δ：8.35(s，1H)，δ：7.20(s，1H)，δ：6.84(s，2H)
Embodiment 3
3-(3-chloro-4-fluorobenzene methylamino-)-6-chlorine imidazo [1,2-a] pyrazine
In the 25mL round-bottomed flask, add 3-amino-6-chlorine imidazo [1,2-a] pyrazine (0.20g, 1.2mmol), (3-chloro-4-fluorine Bian bromine (and 0.40g, 1.8mmol) and the 10mL dioxane, heated and stirred backflow 3h.After having reacted, solvent is removed in distillation, adds ETHYLE ACETATE 100mL, after the dissolving, uses saturated NaHCO
3(100mL) behind the solution washing, anhydrous sodium sulfate drying, behind the removal solvent, column chromatography is purified, and obtains white solid 3-(3-chloro-4-fluorobenzene methylamino-)-6-chlorine imidazo [1,2-a] pyrazine (0.28g, 75%).
MS(EI)m/z(％)：310.0(100％)，312.0(65％)
1H?NMR(DMSO-d
6，400MHz)δ：8.72(s，1H)，δ：8.45(s，1H)，δ：7.10-6.79(m，4H)，δ：6.68(t，1H)，δ：4.29(d，2H)
Embodiment 4
3-(3-chloro-4-fluorobenzene methylamino-)-6-(the 4-anisole is amino) imidazo [1,2-a] pyrazine
In the 25mL round-bottomed flask, add 3-(3-chloro-4-fluorobenzene methylamino-)-6-chlorine imidazo [1,2-a] pyrazine (0.10g, 0.32mmol), to anisidine (0.06g, 0.48mmol) and the 10mL dioxane, splash into a concentrated hydrochloric acid after, heated and stirred backflow 5h.After having reacted, solvent is removed in distillation, adds ETHYLE ACETATE 100mL, after the dissolving, uses saturated NaHCO
3(100mL) behind the solution washing, anhydrous sodium sulfate drying, behind the removal solvent, column chromatography is purified, and obtains white solid 3-(3-chloro-4-fluorobenzene methylamino-)-6-(the 4-anisole is amino) imidazo [1,2-a] pyrazine (0.07g, 58%).
MS(EI)m/z(％)：397.1(100％)，399.1(33％)
1H?NMR(DMSO-d
6，400MHz)δ：10.40(s，1H)，δ：8.84(s，1H)，δ：8.53(s，1H)，δ：7.36-6.47(m，9H)，δ：4.29(d，2H)，δ：3.78(s，3H)，
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, 10000 cells in every hole, 200 μ L/ holes.After 24 hours, add 3-(3-chloro-4-fluorobenzene methylamino-)-6-(the 4-anisole is amino) imidazo [1,2-a] pyrazine of preparation among the embodiment 4, 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 it is 4.07 μ mol/L that the half inhibiting rate is obtained in mapping.
Embodiment 6
The test of EGFR kinase activity adopts the homogeneous phase time discrimination fluorescence HTRFKinase-TK test kit of Cisbio company to measure.Operation instruction according to test kit; The 3-of gradient concentration (3-chloro-4-fluorobenzene methylamino-)-6-(the 4-anisole is amino) imidazo [1; 2-a] pyrazine, 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, obtaining the half inhibiting rate is 90nM.
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 (5)
1. the new inhibitor of an EGF-R ELISA is characterized in that, its chemical structural formula is:
I：
Wherein
L is C
1-4Low alkyl group, C
1-4Lower alkoxy, C
1-4Lower alkyl amino, O or OR
4, S or SR
4, NH or NR
4, R
4Be C
1-4Low alkyl group, C
1-4Lower alkoxy or C
1-4Rudimentary alkyl monosubstituted amino;
R
1For phenyl, substituted-phenyl, replacement 5-9 unit aromatic nucleus, replace 5-9 membered aromatic heterocycle or the assorted dicyclo of substituted aroma and (contain 1-3 heteroatoms that is selected from oxygen, sulphur, nitrogen, can and close, or by one or more halogen, C of being selected from by phenyl and aromatic heterocycle
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 can be that (substituting group can be 1-4 and be selected from halogen, C for phenyl, substituted-phenyl, substituted benzyl, substituted benzyloxy, replacement benzyl amino, replacement 5-9 unit's aromatic base or fragrant heterocyclic radical
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), Nai Ji, Lian Naiji;
R
2Be hydrogen, C
1-9Alkyl, C
1-9Alkoxyl group, OH, NH
2, NO
2, SH, NR
5R
6, R
5R
6Be hydrogen, C
1-9Alkyl, C
1-9Alkoxyl group or C
1-9Alkyl monosubstituted amino, 3-9 unit replace cycloaliphatic ring, aliphatic heterocycle, replacement aromatic ring, substituted aroma heterocycle or 3-9 unit and replace assorted dicyclo;
R3 is halogen, H, SH, OH or NO
2In a kind of.
2. a pharmaceutical composition is characterized in that, contains compound or the combination of formula I, perhaps contains the pharmacy acceptable salt of the compound of formula I.
3. the route of administration of a kind of pharmaceutical composition as claimed in claim 2 is characterized in that, comprises oral, nasal cavity suction, Transdermal absorption, pulmonary administration and parenteral drug administration by injection.
4. the new inhibitor of a kind of EGF-R ELISA as claimed in claim 1 is in prevention and treatment cancer relevant with EGFR and the medicinal application in the relative disease thereof.
5. a kind of medicine as claimed in claim 2 or pharmaceutical composition are in prevention and treatment cancer relevant with EGFR and the medicinal application in the relative disease thereof.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO2016070816A1 (en) * | 2014-11-05 | 2016-05-12 | 上海页岩科技有限公司 | Pyrimidine or pyridine compounds, preparation method therefor and pharmaceutical uses thereof |
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|---|---|---|---|---|
| CN101370811A (en) * | 2005-11-10 | 2009-02-18 | 先灵公司 | Imidazopyrazines as protein kinase inhibitors |
| WO2009097233A1 (en) * | 2008-01-28 | 2009-08-06 | Schering Corporation | Imidazopyrazines as protein kinase inhibitors |
-
2011
- 2011-07-04 CN CN2011101847469A patent/CN102363618A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101370811A (en) * | 2005-11-10 | 2009-02-18 | 先灵公司 | Imidazopyrazines as protein kinase inhibitors |
| WO2009097233A1 (en) * | 2008-01-28 | 2009-08-06 | Schering Corporation | Imidazopyrazines as protein kinase inhibitors |
Non-Patent Citations (1)
| Title |
|---|
| MICHAEL A. LYON等: "Glyoxylic Acid and MP-Glyoxylate:Efficient Formaldehyde Equivalents in the 3-CC of 2-Aminoazines, Aldehydes, and Isonitriles", 《ORGANIC LETTERS》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO2016070816A1 (en) * | 2014-11-05 | 2016-05-12 | 上海页岩科技有限公司 | Pyrimidine or pyridine compounds, preparation method therefor and pharmaceutical uses thereof |
| US10179784B2 (en) | 2014-11-05 | 2019-01-15 | Inventisbio Shanghai Ltd. | Pyrimidine or pyridine compounds, preparation method therefor and pharmaceutical uses thereof |
| US11203589B2 (en) | 2014-11-05 | 2021-12-21 | InventisBio Co., Ltd. | Pyrimidine or pyridine compounds, preparation method therefor and pharmaceutical uses thereof |
| US11498921B1 (en) | 2014-11-05 | 2022-11-15 | InventisBio Co., Ltd. | Pyrimidine or pyridine compounds, preparation method therefor and pharmaceutical uses thereof |
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Application publication date: 20120229 |