CN108047231B - Hydrochloride of [1,2,4] triazino [6,1-a ] isoindole compound and application thereof - Google Patents
Hydrochloride of [1,2,4] triazino [6,1-a ] isoindole compound and application thereof Download PDFInfo
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- CN108047231B CN108047231B CN201810002521.9A CN201810002521A CN108047231B CN 108047231 B CN108047231 B CN 108047231B CN 201810002521 A CN201810002521 A CN 201810002521A CN 108047231 B CN108047231 B CN 108047231B
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- -1 [1,2,4] triazino [6,1-a ] isoindole compound Chemical class 0.000 title abstract description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title abstract description 3
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- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 1
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- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- CRXFROMHHBMNAB-UHFFFAOYSA-N methyl 2-isocyanoacetate Chemical compound COC(=O)C[N+]#[C-] CRXFROMHHBMNAB-UHFFFAOYSA-N 0.000 description 1
- CEOILRYKIJRPBZ-UHFFFAOYSA-N methyl cyclopent-3-ene-1-carboxylate Chemical compound COC(=O)C1CC=CC1 CEOILRYKIJRPBZ-UHFFFAOYSA-N 0.000 description 1
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- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
- IRWXYFWBGITFAG-UHFFFAOYSA-N piperidin-4-yl methanesulfonate Chemical compound CS(=O)(=O)OC1CCNCC1 IRWXYFWBGITFAG-UHFFFAOYSA-N 0.000 description 1
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- FVNAFVGZFQMIQX-UHFFFAOYSA-N pyrrolo[2,1-f][1,2,4]triazin-6-ylmethanol Chemical compound N=1N2C(C=NC1)=CC(=C2)CO FVNAFVGZFQMIQX-UHFFFAOYSA-N 0.000 description 1
- SFUIIJZOWVIBHA-UHFFFAOYSA-N pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid Chemical compound C1=NC=NN2C=C(C(=O)O)C=C21 SFUIIJZOWVIBHA-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention belongs to the field of chemical medicine, and relates to a [1,2,4] triazino [6,1-a ] isoindole compound with ALK/C-MET kinase dual inhibitory activity, a pharmaceutical composition containing the compound and application of the compound or the composition in medicine preparation, in particular to hydrochloride of the [1,2,4] triazino [6,1-a ] isoindole compound and application thereof, wherein the compound has good solubility and stability, and provides a better choice for formulation research.
Description
Technical Field
The invention belongs to the field of chemical medicine, and particularly relates to a [1,2,4] triazino [6,1-a ] isoindole compound with ALK/C-MET kinase dual inhibitory activity, a pharmaceutical composition containing the compound, and application of the compound or the composition in preparation of medicines.
Background
Receptor-type tyrosine kinase Anaplastic Lymphoma Kinase (ALK) was first discovered in Anaplastic Large Cell Lymphoma (ALCL) as a fusion protein formed by translocation of chromosomes 2 and 5, and includes the 3 '-terminal intracellular domain of ALK and the 5' -terminal domain of Nucleophosmin (NPM). The research shows that in the non-small cell lung cancer, the ALK positive rate is about 3% -5%, and the patient can generate specific chromosome translocation to form EML4 and ALK fusion protein, so that the tumor cells can proliferate and survive due to gene expression and signal disorder.
C-MET is a protein product encoded by C-MET protooncogene, is a Hepatocyte Growth Factor (HGF) receptor, has tyrosine kinase activity, is related to various oncogene products and regulatory proteins, participates in the regulation of cell information transduction and cytoskeleton rearrangement, and is an important factor of cell proliferation, differentiation and movement. Research shows that C-MET is closely related to the occurrence and metastasis of various cancers, and a large number of tumor patients have C-MET transient expression and gene amplification in the tumor mode and the metastasis process.
The marketed Crizotinib (Crizotinib) is approved by FDA 2011 in the United states, can inhibit C-MET and ALK tumor cells in a dose-dependent manner, and also has a strong inhibition effect on tumor cells with translocation or inversion of ALK genes. Clinical researches show that the crizotinib has a remarkable improvement effect on the survival condition of ALK-positive non-small cell lung cancer patients, has good tolerance and higher safety, and can effectively treat ALK-positive locally advanced or metastatic non-small cell lung cancer.
Therefore, the development of the medicine with the double inhibitory activity of C-MET and ALK certainly has good application prospect in clinic.
Disclosure of Invention
One object of the present invention is to provide furan-2-methyl 4- (1- (piperidin-4-yl) 1H-pyrazol-3 yl) -5,6,7, 8-tetrahydro- [1,2,4] triazino [6,1-a ] isoindol-7-methyl ether hydrochloride or a solvate, crystal or prodrug thereof, which is a compound having dual ALK/C-MET inhibitory activity, and which has good solubility and stability and provides a better choice for formulation studies.
Another object of the present invention is to provide a pharmaceutical composition comprising furan-2-methyl 4- (1- (piperidin-4-yl) 1H-pyrazol-3 yl) -5,6,7, 8-tetrahydro- [1,2,4] triazino [6,1-a ] isoindol-7-methyl ether hydrochloride or a solvate, crystal or prodrug thereof and a pharmaceutically acceptable carrier, and compositions comprising furan-2-methyl 4- (1- (piperidin-4-yl) 1H-pyrazol-3-yl) -5,6,7, 8-tetrahydro- [1,2,4] triazino [6,1-a ] isoindol-7-methyl ether hydrochloride, or a solvate, crystal, or prodrug thereof, and one or more protein tyrosine kinase inhibitors.
Still another object of the present invention is to provide a method for treating and/or preventing tumors by furan-2-methyl 4- (1- (piperidin-4-yl) 1H-pyrazol-3-yl) -5,6,7, 8-tetrahydro- [1,2,4] triazino [6,1-a ] isoindol-7-methyl ether hydrochloride or solvate, crystal or prodrug, or a pharmaceutical composition thereof, and use thereof for preparing a medicament for treating and/or preventing tumors.
Aiming at the above purpose, the invention provides the following technical scheme:
in a first aspect, the present invention provides a compound of formula I or a solvate, crystal or prodrug thereof,
in a second aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier.
In some embodiments, the present invention provides pharmaceutical compositions comprising a compound, solvate, crystal or prodrug of the present invention, further comprising one or more selected from the group consisting of: tyrosine protease inhibitors, EGFR inhibitors, VEGFR inhibitors, BCR-ABL inhibitors, c-kit inhibitors, c-Met inhibitors, Raf inhibitors, MEK inhibitors, histone deacetylase inhibitors, VEGF antibodies, EGF antibodies, HIV protein kinase inhibitors, HMG-CoA reductase inhibitors, and the like.
The compound, solvate, crystal or prodrug of the present invention may be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare a pharmaceutical preparation suitable for oral or parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulations may be administered by any route, for example by infusion or bolus injection, by a route of absorption through epithelial or cutaneous mucosa (e.g. oral mucosa or rectum, etc.). Administration may be systemic or local. Examples of the formulation for oral administration include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations may be prepared by methods known in the art and include carriers, diluents or excipients conventionally used in the art of pharmaceutical formulation.
In a third aspect, the present invention provides a method for treating and/or preventing tumors by using the compound, solvate, crystal or prodrug of the present invention or the pharmaceutical composition of the present invention, and an application in preparing a drug for preventing and/or treating tumors, comprising administering the compound, solvate, crystal or prodrug of the present invention or the pharmaceutical composition comprising the compound, solvate, crystal or prodrug of the present invention to a population prone to tumor or a tumor patient, so as to effectively reduce the incidence of tumors and prolong the life of the tumor patient.
Detailed Description
The following representative examples are intended to better illustrate the present invention and are not intended to limit the scope of the present invention.
Example 14 Synthesis of chloro-6, 7-dihydro-5H-cyclopenta [3,4] pyrrolo [2,1-f ] [1,2,4] triazine-6-methanol
Step 11-iodine-2-p-toluenesulfonyl-4-methyl formate-cyclopentane synthesis
Weighing 5g of methyl 3-cyclopentene-1-formate and 12.6g of sodium p-toluenesulfinate into a reaction bottle at the temperature of-5 ℃, adding 300mL of dichloromethane/water mixed solvent (volume ratio is 1:1), reacting for 1.5h, and adding 10g I
2And heating to room temperature for reaction for 2 hours, separating an organic phase after the reaction is finished, extracting a water phase, combining, washing with a sodium bisulfite aqueous solution, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution in sequence, drying with anhydrous sodium sulfate, filtering, and spin-drying to obtain the title compound, wherein the title compound is directly used for the next reaction without purification.
ESI-MS m/z:409[M+H]
+,447[M+K]
+。
Step 21 Synthesis of methyl p-toluenesulfonyl-4-carboxylate-cyclopentene
Weighing 10.6g of the compound obtained in the step 1 into a reaction bottle, slowly adding 3.5g of triethylamine and 200mL of acetonitrile, reacting at 70 ℃ for 2.5 hours, carrying out spin-drying after the reaction is finished, adding 100mL of ethyl acetate for dissolving, sequentially washing with a saturated sodium bicarbonate aqueous solution and a saturated saline solution, drying with anhydrous sodium sulfate, filtering, and carrying out spin-drying to obtain the title compound, wherein the compound is directly used for the next reaction without purification.
ESI-MS m/z:281[M+H]
+。
Step Synthesis of 32, 4-Methyldicarboxylate-Pentao [3,4] pyrrole
Weighing 1g of NaH, putting the NaH into a reaction bottle, adding 70mL of anhydrous THF, adding 100mL of anhydrous THF solution dissolved with 2.8g of the compound obtained in the step 2 and 1.88g of methyl isocyanoacetate in batches at 0-5 ℃, continuing to react for 1.5 hours at 0-5 ℃, adding 1mL of anhydrous methanol after the reaction is finished, stirring, spinning, drying, adding ethyl acetate into the residue to dissolve, filtering by using kieselguhr, washing the filter cake by using ethyl acetate, combining organic phases, washing by using saturated saline, drying by using anhydrous sodium sulfate, filtering, spinning to obtain black oily matter, and purifying by column chromatography to obtain the title compound.
ESI-MS m/z:224[M+H]
+,262[M+K]
+。
Step 4 Synthesis of N-amino-2, 4-dicarboxylic acid methyl ester-cyclopenta [3,4] pyrrole
Weighing 24mg of NaH, putting the NaH into a reaction bottle, adding 5mL of anhydrous DMF, dripping 2mL of anhydrous DMF solution dissolved with 90mg of the compound obtained in the step 3 at 0-5 ℃, continuously reacting for 0.5h at 0-5 ℃, adding 120mg of diphenylphosphinoylhydroxylamine in batches, continuously reacting for 0.5h at room temperature, after the reaction is finished, adding ethyl acetate and ice water for extraction, taking an organic layer, extracting a water layer by using ethyl acetate, combining the organic layers, washing the organic layer once by using saturated saline, drying the anhydrous sodium sulfate, filtering, spin-drying and purifying by column chromatography to obtain the title compound.
ESI-MS m/z:239[M+H]
+。
Step 54 Synthesis of methyl hydroxy-6, 7-dihydro-5H-cyclopenta [3,4] pyrrolo [2,1-f ] [1,2,4] triazine-6-carboxylate
Weighing 0.7g of the compound obtained in the step 4 in a reaction bottle, adding 5mL of formamide for dissolving, reacting at 180 ℃ for 2 hours, after the reaction is finished, pouring the reaction solution into 10mL of ice water, extracting with ethyl acetate, combining the ethyl acetate, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, spin-drying, and purifying by column chromatography to obtain the title compound.
1H NMR(300M Hz,DMSO-d
6):δ12.45(s,1H),7.68(s,1H),7.26(s,1H),3.72-3.66(m,1H),3.63(s,3H),3.20-3.02(m,4H)。
ESI-MS m/z:234[M+H]
+。
Step Synthesis of methyl 64-chloro-6, 7-dihydro-5H-cyclopenta [3,4] pyrrolo [2,1-f ] [1,2,4] triazine-6-carboxylate
Weighing 100mg of the compound obtained in the step 5 into a reaction bottle, adding 20mL of toluene for dissolving, sequentially adding 5 equivalents of phosphorus oxychloride and 5 equivalents of N, N-diisopropylethylamine, reacting at 110 ℃ for 6 hours, carrying out spin-drying, adding ethyl acetate for dissolving, adding a saturated sodium bicarbonate aqueous solution under ice bath to adjust the pH value to 6-7, separating an organic layer, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, and carrying out spin-drying to obtain the title compound.
ESI-MS m/z:252[M+H]
+。
Step Synthesis of 74-chloro-6, 7-dihydro-5H-cyclopenta [3,4] pyrrolo [2,1-f ] [1,2,4] triazine-6-methanol
Adding 20mL of tetrahydrofuran and 54mg of lithium aluminum hydride into a reaction bottle, dropwise adding 20mL of anhydrous tetrahydrofuran solution in which 400mg of the compound obtained in the step 6 is dissolved while stirring, stirring for 0.5h, after the reaction is finished, quenching, extracting with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, filtering, and spin-drying to obtain the title compound.
1H NMR(300M Hz,DMSO-d
6):δ10.05(s,1H),6.11(s,1H),3.65-3.62(m,2H),3.40-3.36(m,1H),2.55-2.52(m,3H),2.28-2.25(m,2H)。
ESI-MS m/z:224[M+H]
+。
EXAMPLE 21 Synthesis of N-Boc-piperidin-4-yl) -3-iodo-1H-pyrazole
Step 1 Synthesis of piperidin-4-yl methanesulfonate
10g 4-hydroxypiperidine was weighed into a reaction flask, and 200mL of anhydrous tetrahydrofuran was added and dissolved, and 100mL of a solution containing 25g (Boc) was slowly added dropwise at 0 deg.C
2And (3) reacting the solution of O in anhydrous tetrahydrofuran at room temperature for 12h after dripping, spin-drying, adding a dichloromethane solution, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and spin-drying to obtain the title compound, wherein the title compound is directly used in the next step without purification.
ESI-MS m/z:180[M+H]
+。
Step 2 Synthesis of N-BOC piperidin-4-yl methanesulfonate
Weighing 5.4g of the product obtained in the step 1 in a reaction bottle, adding 100mL of dichloromethane for dissolving, slowly dropwise adding 4.2mL of triethylamine at 0 ℃, after dropwise adding, slowly dropwise adding 2.32mL of methanesulfonyl chloride and 40mg of DMAP, after dropwise adding, reacting at room temperature for 8h, adding water and dichloromethane for extraction, combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and spin-drying to obtain the title compound, wherein the compound is directly used in the next step without purification.
ESI-MS m/z:218[M+H]
+。
Synthesis of step 31- (N-Boc-piperidin-4-yl) -3-iodo-1H-pyrazole
Weighing 9.7g of 4-iodopyrazole in a reaction bottle, adding 100mL of DMF to dissolve the 4-iodopyrazole, adding 2.4g of sodium hydride in batches at 0 ℃, reacting for 1h at 0 ℃, adding 15.3g of the product obtained in the step 2, reacting for 12h at 100 ℃, adding water to quench the reaction, extracting with ethyl acetate, combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, spin-drying, and purifying by column chromatography to obtain the title compound.
1H NMR(400MHz,CDCl
3,δppm):7.53(s,1H),7.47(s,1H),4.23(m,3H),2.85-2.88(m,2H),2.07-2.09(m,2H),1.88(m,2H),1.44(s,9H)。
ESI-MS m/z:378[M+H]
+。
EXAMPLE 3 Synthesis of furan-2-methyl 4- (1- (piperidin-4-yl) 1H-pyrazol-3 yl) -5,6,7, 8-tetrahydro- [1,2,4] triazino [6,1-a ] isoindol-7-methyl ether
Step 1 Furan-2-methyl 4-chloro-5, 6,7, 8-tetrahydro- [1,2,4] triazino [6,1-a ] isoindol-7-methyl ether
Weighing 10g of the product obtained in example 1, placing the product in a reaction bottle, adding 200mL of tetrahydrofuran to dissolve the product, sequentially adding 8.6g of 2-hydroxymethyl furan and 18.6g of triphenylphosphine, reacting at room temperature for 5h, cooling to 0 ℃, adding 15mL of DIAD, reacting at 0 ℃ for 12h, after the reaction is finished, spin-drying, and purifying by column chromatography to obtain the title compound.
1H NMR(400MHz,CDCl
3,δppm):10.08(s,1H),7.67-7.68(m,1H),6.47-6.49(m,1H),6.39-6.41(m,1H),6.08(s,1H),4.48(s,2H),3.46-3.49(m,1H),3.19-3.22(m,1H),2.52-2.58(m,3H),2.27-2.29(m,2H)。
ESI-MS m/z:304[M+H]
+。
Step 2 Furan-2-methyl 4- (1- (N-Boc-piperidin-4-yl) 1H-pyrazol-3-yl) -5,6,7, 8-tetrahydro- [1,2,4] triazino [6,1-a ] isoindol-7-methyl ether
Weighing 4.09g of PdCl
2(dppf) is put into a reaction bottle, 9.4g of the product obtained in the example 2, 9.5g of pinacol ester diboron borate, 9.7g of potassium acetate and 150mL of dimethyl sulfoxide are added, the mixture is reacted for 3 hours at 80 ℃, cooled to room temperature, 30mL of dimethyl sulfoxide solution in which 7.6g of the product obtained in the step 1 is dissolved and 20mL of aqueous solution in which 6.6g of sodium carbonate is dissolved are added, the reaction is carried out for 4 hours at 80 ℃, the mixture is cooled to room temperature after the reaction is finished, filtered, the filter cake is washed by ethyl acetate, the filtrate is taken, water is added, ethyl acetate is extracted, organic layers are combined, the mixture is washed by saturated common salt solution, dried by anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to obtain the title.
1H NMR(400MHz,CDCl
3,δppm):10.05(s,1H),7.94-7.97(m,2H),7.67-7.68(m,1H),6.47-6.49(m,1H),6.37-6.39(m,1H),6.08(s,1H),4.48(s,2H),3.69-3.71(m,1H),3.21-3.46(m,6H),2.55-2.58(m,2H),2.48-2.51(m,2H),2.27-2.33(m,1H),2.06-2.09(m,2H),1.81-1.83(m,2H),1.38(s,9H)。
ESI-MS m/z:519[M+H]
+。
Step 3 Furan-2-methyl 4- (1- (piperidin-4-yl) 1H-pyrazol-3 yl) -5,6,7, 8-tetrahydro- [1,2,4] triazino [6,1-a ] isoindol-7-ylether
Weighing 1.0g of the product obtained in the step 2 into a reaction bottle, adding 2mL of dichloromethane, adding 5mL of trifluoroacetic acid, stirring at room temperature for 8h, evaporating to remove the solvent and the trifluoroacetic acid, adding dichloromethane for dissolution, adjusting the pH to 12-13 with 20% sodium hydroxide aqueous solution, separating an organic layer, continuously extracting a water layer with dichloromethane, combining the organic layers, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, concentrating, and purifying by column chromatography to obtain the title compound.
1H NMR(400MHz,CDCl
3,δppm):10.05(s,1H),7.94-7.97(m,2H),7.67-7.68(m,1H),6.47-6.48(m,1H),6.39-6.41(m,1H),6.08(s,1H),4.48(s,2H),3.70-3.72(m,1H),3.45-3.47(m,1H),3.21-3.23(m,1H),2.69-2.79(m,4H),2.52-2.58(m,3H),2.27-2.30(m,2H),2.00-2.06(m,3H),1.81-1.83(m,2H)。
ESI-MS m/z:419[M+H]
+。
EXAMPLE 4 Synthesis of furan-2-methyl 4- (1- (piperidin-4-yl) 1H-pyrazol-3-yl) -5,6,7, 8-tetrahydro- [1,2,4] triazino [6,1-a ] isoindol-7-methyl ether hydrochloride
Weighing 15g of the product obtained in example 3 into a reaction bottle, adding 50ml of ethyl acetate to dissolve, dropwise adding a hydrogen chloride ethyl acetate solution until the pH value reaches 6, stirring at 0 ℃ for 10min, pouring out the supernatant, adding 50ml of acetone, stirring at room temperature for 0.5h, separating out a solid, filtering, and drying in vacuum at 40 ℃ for 2h to obtain the title compound.
Experimental example 1 stability test
0.5g of the compound of example 4 are weighed out in 4 portions and placed under the conditions of light 4500Lx, RH 70% 75 deg.C, RH 70% 60 deg.C and RH 70% room temperature for 6 months, and the experimental results are shown in Table 1.
TABLE 1
The experimental results show that the compound of the invention in the example 4 has very high stability.
Experimental example 2 solubility experiment
The solubility was determined by HPLC and the results are shown in Table 2.
TABLE 2
| Water (W) | |
| Example 3 Compounds | 15.2mg/ml |
| Example 4 Compounds | 207.6mg/ml |
Experimental example 3 evaluation of enzyme Activity in vitro
The ALK kinase used was a human recombinant protein, which was reacted with a polypeptide substrate and test compounds of various concentrations (25 ℃ C., 45min) in a reaction system containing 50mM HEPES (pH7.5), 10mM MgCl2, 2MDTT (1000X) in a buffer solution and 30. mu.M ATP, followed by the FAM-labeled antibody pairLabeling substrate, quantitatively determining ALK kinase activity in time-resolved fluorescence mode, and determining IC
50The values (the concentration of the compound required to inhibit the enzyme activity at a certain concentration to 50%) are shown in Table 3.
TABLE 3
| Compound (I) | ALK kinase inhibition IC 50Value (nM) |
| Crizotinib | 0.52 |
| Example 3 Compounds | 0.35 |
| Example 4 Compounds | 0.31 |
From the experimental results, the compound has better inhibitory activity on ALK kinase.
Although the present invention has been described in detail above, those skilled in the art will appreciate that various modifications and changes can be made to the present invention without departing from the spirit and scope of the invention. The scope of the invention is not to be limited by the above detailed description but is only limited by the claims.
Claims (6)
1. A compound of the formula I, wherein,
2. a pharmaceutical formulation comprising a compound of claim 1, and one or more pharmaceutically acceptable carriers.
3. The pharmaceutical formulation according to claim 2, formulated to be suitable for oral or parenteral administration.
4. The pharmaceutical formulation according to claim 3, which is a tablet, pill, granule, powder, capsule, syrup, emulsion, suspension.
5. Use of a compound according to claim 1 or a pharmaceutical preparation according to any one of claims 2 to 4 for the preparation of a medicament for the treatment and/or prophylaxis of tumours.
6. The use of claim 5, wherein the neoplasm is lung cancer.
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