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CN107235897B - Tyrosine kinase inhibitor and its application - Google Patents

Tyrosine kinase inhibitor and its application Download PDF

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Publication number
CN107235897B
CN107235897B CN201610857372.5A CN201610857372A CN107235897B CN 107235897 B CN107235897 B CN 107235897B CN 201610857372 A CN201610857372 A CN 201610857372A CN 107235897 B CN107235897 B CN 107235897B
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cancer
tyrosine kinase
compound
kinase inhibitor
compounds
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CN107235897A (en
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孙芳
占有妮
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Lixin Pharmaceutical Technology Shanghai Co Ltd
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Shanghai Xiang Jin Biotechnology Co Ltd
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Abstract

The invention discloses a kind of salt compounds with the following general formula (I).The invention also discloses the applications comprising the tyrosine kinase inhibitor of the salt compounds and the compound in the drug of preparation treating cancer.Tyrosine kinase inhibitor of the invention, it is able to suppress the bioactivity of the multi-signals transduction kinase such as C-MET, VEGF, KDR, cell Proliferation can effectively be inhibited, there is good therapeutic effect to a variety of disorders such as cancers, especially there is significant therapeutic effect to lung cancer, gastric cancer, oophoroma, glioblastoma etc., application prospect is boundless.

Description

Tyrosine kinase inhibitor and application thereof
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a tyrosine kinase inhibitor and application thereof.
Background
Protein kinase is a phosphotransferase that transfers the gamma phosphate group of ATP to specific amino acid residues to effect phosphorylation of proteins and thus their physiological and biochemical functions.
Protein kinases have an important function in information transduction. Abnormal protein kinases fail to perform normal signaling and may cause pathologies such as: tumor cell proliferation, cell death, inflammation, cardiovascular diseases and other protein kinases. Protein kinases are largely divided into two categories: protein tyrosine kinases PTKs and receptor tyrosine kinases RTKs. ROS1/C-MET in MET family protein kinases is an important subline of RTPs, also known as hHGFR and RON; ROS1/C-MET can play an important role in initiating the growth and metabolism of tumor cells, and is a target for clinical research of various drugs.
Therefore, there is an urgent need in the biomedical technology field for ROS1/C-MET kinase inhibitors, especially tyrosine kinase inhibitors of small molecule compounds.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a tyrosine kinase inhibitor, which can inhibit the activity of a plurality of tyrosine kinases involved in signal transduction, such as C-MET, VEGF, KDR, RON, KIT, PDGF, FGF, SRC and the like, can effectively inhibit the proliferation of tumor cells, and can achieve better effect on clinical cancer treatment.
In order to solve the technical problems, the invention is realized by the following technical scheme:
in one aspect of the invention, there is provided a salt compound having the general formula (I),
wherein,
r1 is selected from halogen, halogen anion, lower haloalkane, lower alkane, lower alkylene, lower alkynyl, substituted saturated or unsaturated cycloalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocycloalkyl, or is null;
y is selected from C, O, N, S or is null;
x is selected from carbonate, sulfate, sulfite, bisulfate, phosphate, phosphite, hydrogen phosphate, dihydrogen phosphate, molybdate, chlorate or blank.
Preferably, the compounds of formula (I) include compounds of the following specific structure:
in another aspect of the present invention, there is also provided a pharmaceutical composition comprising a safe and effective amount of the above compound and a pharmaceutically acceptable carrier.
Such acceptable carriers are non-toxic, can be adjunctive to administration, and do not adversely affect the therapeutic efficacy of the compounds. Such carriers can be any solid, liquid, semi-solid or gaseous vehicle commonly available to those skilled in the art in aerosol compositions. Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glyceryl stearyl ester, sodium chloride, anhydrous skim milk, and the like. The liquid and semi-solid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil and the like, preferably liquid carriers, particularly for injectable solutions, including water, saline, aqueous dextrose and glycols. Other adjuvants such as flavoring agent, sweetener, etc. can also be added into the composition.
The compounds of the invention are administered in therapeutically effective amounts by oral, systemic (e.g., transdermal, nasal inhalation, or by suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration. The preferred mode of administration is oral, which may be modulated by the extent of the disease.
The actual amount of the compound of the invention administered (i.e., the active ingredient) will depend on a number of factors, such as the severity of the disease to be treated, the age and relative health of the subject being treated, the potency of the compound used, the route and form of administration, and other factors.
Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional methods in the pharmaceutical field. For example, the compounds can be combined with one or more carriers and then formulated into the desired dosage form, e.g., tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, formulations, aerosols, and the like.
In another aspect of the present invention, there is also provided a tyrosine kinase inhibitor comprising the above salt compound.
The tyrosine kinase comprises C-MET, VEGF, KDR, RON, KIT, PDGF, FGF, SRC kinase.
In another aspect of the invention, the application of the salt compound in preparing a medicament for treating cancer is also provided.
Tyrosine kinase is an antitumor drug target with obvious effect at present, and the salt compound has obvious tyrosine kinase inhibition activity, and experiments prove that the compounds have inhibition effect on the proliferation of various cancer cells, so the salt compound is suitable for treating various cancers. Especially has better treatment effect on lung cancer, gastric cancer, ovarian cancer, colon cancer and malignant glioma.
In another aspect of the invention, the application of the salt compound in preparing a medicament for treating inflammation is also provided.
The salt compound of the invention has good biological activity with a plurality of signal transduction kinases such as C-MET, VEGF, KDR, RON, KIT, PDGF, FGF, SRC and the like, and is associated with a plurality of signal transduction paths, thereby having treatment effect on a plurality of diseases such as cancer, inflammation, lymphedema, diabetes and the like.
The tyrosine kinase inhibitor can inhibit the biological activity of various signal transduction kinases such as C-MET, VEGF, KDR and the like, can effectively inhibit cell proliferation, has good treatment effect on various diseases such as cancers, especially has obvious treatment effect on lung cancer, gastric cancer, ovarian cancer, malignant glioma and the like, and has very wide application prospect.
Drawings
The present invention will be described in further detail with reference to the accompanying drawings and specific embodiments.
FIG. 1 is a graph fitted with compound 6 of example 7 of the present invention on the inhibition of proliferation of human lung adenocarcinoma cell HCC 78;
FIG. 2 is a graph fitted with Compound 6 of example 7 of the present invention on the inhibition of proliferation of human glioblastoma cell U87 MG;
FIG. 3 is a graph fitted with Compound 6 of example 7 of the present invention for the inhibition of proliferation of human umbilical vein endothelial cells HUVEC;
FIG. 4 is a graph fitted with proliferation inhibition of human glioblastoma cell U87MG by Compounds 2 and 4 of example 7 of the invention;
FIG. 5 is a graph fitted with the proliferation inhibition of human gastric cancer cells MKN-45 by Compounds 2 and 4 of example 7 of the present invention;
FIG. 6 is a graph fitted with proliferation inhibition curves of human lung adenocarcinoma cell HCC78 for Compounds 2 and 4 of example 7 of the present invention;
FIG. 7 is a graph fitted with proliferation inhibition curves of compounds 2, 4 and 6 of example 7 of the present invention on human ovarian cancer cells SK-OV-3;
FIG. 8 is a graph fitted to the proliferation inhibition of human colon cancer cell HCT116 by Compounds 2, 4, 6 of example 7 of the invention;
fig. 9 is a fitted curve of the proliferation inhibition of human lung adenocarcinoma cells a549 by compounds 2, 4 and 6 of example 7 of the present invention.
Detailed Description
EXAMPLE 1 Synthesis of tyrosine kinase inhibitor p-toluenesulfonate Compound
Dissolving a compound 1(N- [ 3-fluoro-4- [ [ 6-methoxy-7- [ [3- (morpholin-4-yl) propyl ] oxy ] quinolin-4-yl ] oxy ] phenyl ] -N '- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide) (632mg,1mmol) in tetrahydrofuran (10mL), adding p-toluenesulfonic acid (173mg, 1mmol) after an ice-water bath is carried out and the internal temperature is 0 ℃, reacting for 2h at room temperature, filtering after the reaction is finished to obtain a white solid N- [ 3-fluoro-4- [ [ 6-methoxy-7- [ [3- (morpholin-4-yl) propyl ] oxy ] quinolin-4-yl ] oxy ] phenyl ] -N' - (4-fluorophenyl) cyclopropane-1, 1-Dimethylamide p-toluenesulfonate (Compound 2)650mg, yield 81%.
1H NMR(500MHz,DMSO-d6):δ10.41(s,1H),9.99(s,1H),9.48(brs,1H),8.50(d,J＝5Hz,1H),7.92(dd,1H),7.52-7.65(m,4H),7.40-7.48(m,4H),7.10-7.18(m,4H),6.46(d,J＝5.5Hz,1H),4.26(t,2H),4.10(d,2H),4.10(m,1H),3.97(s,3H),3.66(t,2H),3.60(m,2H),3.15(m,2H),2.21-2.36(m,5H),1.45-1.51(m,4H)。
LC-MS(ESI)m/z 633(M+H)。
Example 2 Synthesis of tyrosine kinase inhibitor glutamate Compounds
Compound 1(N- [ 3-fluoro-4- [ [ 6-methoxy-7- [ [3- (morpholin-4-yl) propyl ] oxy ] quinolin-4-yl ] oxy ] phenyl ] -N '- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide) (632mg,1mmol) is dissolved in tetrahydrofuran/water (10mL,1:1), L-glutamic acid (147mg, 1mmol) is added after the ice-water bath temperature reaches 0 ℃, the reaction is carried out for 8h at room temperature, after the reaction is finished, white solid N- [ 3-fluoro-4- [ [ 6-methoxy-7- [ [3- (morpholin-4-yl) propyl ] oxy ] quinolin-4-yl ] oxy ] phenyl ] -N' - (4-fluorophenyl) cyclopropane-1 is obtained by filtration, 1-Dimethylaminoglutamate (Compound 3)450mg, 58% yield.
LC-MS(ESI)m/z 633(M+H)。
EXAMPLE 3 Synthesis of tyrosine kinase inhibitor n-butyl phosphate Compound
Dissolving a compound 1(N- [ 3-fluoro-4- [ [ 6-methoxy-7- [ [3- (morpholin-4-yl) propyl ] oxy ] quinolin-4-yl ] oxy ] phenyl ] -N '- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide) (632mg,1mmol) in dichloromethane (10mL), adding N-butyl phosphoric acid (154mg, 1mmol) after an ice-water bath is carried out and the internal temperature is 0 ℃, reacting for 4h at room temperature, filtering after the reaction is finished to obtain white solid N- [ 3-fluoro-4- [ [ 6-methoxy-7- [ [3- (morpholin-4-yl) propyl ] oxy ] quinolin-4-yl ] oxy ] phenyl ] -N' - (4-fluorophenyl) cyclopropane-1, 1-Dimethylamide n-butyl phosphate (Compound 4)650mg, yield 83%.
1H NMR(500MHz,DMSO-d6):δ10.43(s,1H),9.94(s,1H),9.20(brs,1H),8.51(d,J＝5Hz,1H),7.92(dd,1H),7.52-7.65(m,4H),7.40-7.48(m,4H),7.10-7.18(m,4H),6.46(d,J＝5.5Hz,1H),4.21(t,2H),4.15(d,2H),4.08(m,1H),3.77(m,2H),3.66(t,2H),3.60(m,2H),3.15(m,2H),2.21-2.36(m,5H),1.45-1.51(m,4H),1.23(m,4H).1.10(t,3H),
LC-MS(ESI)m/z 633(M+H)。
Example 4 Synthesis of tyrosine kinase inhibitor malate Compound
Dissolving a compound 1(N- [ 3-fluoro-4- [ [ 6-methoxy-7- [ [3- (morpholin-4-yl) propyl ] oxy ] quinolin-4-yl ] oxy ] phenyl ] -N '- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide) (632mg,1mmol) in tetrahydrofuran (10mL), adding malic acid (134mg, 1mmol) after an ice-water bath is carried out and the internal temperature is 0 ℃, reacting for 8h at room temperature, filtering after the reaction is finished to obtain white solid N- [ 3-fluoro-4- [ [ 6-methoxy-7- [ [3- (morpholin-4-yl) propyl ] oxy ] quinolin-4-yl ] oxy ] phenyl ] -N' - (4-fluorophenyl) cyclopropane-1, 1-Dimethylamidomalate (Compound 5)550mg, 72% yield.
LC-MS(ESI)m/z 633(M+H)。
Example 5 Synthesis of tyrosine kinase inhibitor alendronate Compounds
Dissolving a compound 1(N- [ 3-fluoro-4- [ [ 6-methoxy-7- [ [3- (morpholin-4-yl) propyl ] oxy ] quinolin-4-yl ] oxy ] phenyl ] -N '- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide) (632mg,1mmol) in N, N-dimethylformamide (10mL), adding alendronic acid (249mg, 1mmol) after the internal temperature of ice-water bath is 0 ℃, reacting for 8h at room temperature, filtering after the reaction is finished to obtain white solid N- [ 3-fluoro-4- [ [ 6-methoxy-7- [ [3- (morpholin-4-yl) propyl ] oxy ] quinolin-4-yl ] oxy ] phenyl ] -N' - (4-fluorophenyl) cyclopropane-1, 150mg of 1-dimethylamide alendronate (Compound 6) in 17% yield.
LC-MS(ESI)m/z 633(M+H)。
Example 6 detection of tyrosine kinase inhibitory Activity
The salt compounds of the above embodiments are applied to the detection and screening of C-MET and KDR kinase inhibitory activity.
1. Method of producing a composite material
(1) Add 4. mu.L of formulated kinase buffer solution, or 4. mu.L of kinase solution (100% inhibition control) to 384-well plates; add 2. mu.L of compound to the well, or 2. mu.L of buffer without compound (0% inhibition control); all samples or controls above were plated in 2 replicates.
(2) Incubating at 25 deg.C for 5 min;
(3) add 2. mu.L of ATP/substrate/MgCl to the wells2/MnCl2A mixed solution of SEB and DTT;
(4) centrifuging at 1000rpm for 1min, and incubating at 30 deg.C with shaking for 30 min;
(5) add 8. mu.L XL-665/antibody mixture to the well;
(6) incubating for 1h at 25 ℃;
(7) reading signals of 665nm and 620nm by a PHERAStar FS instrument;
(8) data were analyzed according to kit instructions and IC50 was calculated using GraphPad Prism5 fit.
Ratio＝665nm/620nm
2. Results of the experiment
The results of the test of the tested compounds and the reference compounds are summarized in the following tables 1 and 2, wherein the reference compound is the existing C-MET kinase inhibitor Foretinib (the structural formula is shown below). The chemical structural formulas of For-Oxide and For-Methyl are also respectively as follows.
TABLE 1 inhibitory Activity of Compound 6 on C-MET
TABLE 2 inhibitory Activity of Compound 6 on KDR
TABLE 3 inhibitory Activity of Compounds 2 and 4 on C-Met/KDR
As is clear from the data in tables 1 to 3, the salt compounds of the present invention according to the above examples have inhibitory activities against tyrosine kinases such as C-MET and KDR.
Example 7 inhibition of tumor cell proliferation assay
1. Method of producing a composite material
(1) Cell culture: culturing tumor cells (such as human lung adenocarcinoma cell HCC78, human malignant glioma cell U87MG, human gastric cancer cell MKN-45, human umbilical vein endothelial cell HUVEC, human lung adenocarcinoma cell A549, etc.) in cell culture medium at 37 deg.C and 5% CO2。
(2) Cell inoculation: taking cells in an exponential growth phase with good state, adding a proper amount of pancreatin digestive cells, collecting the cells, centrifuging, and removing supernatant. The cells were resuspended in serum-containing medium, and the cell suspension was counted and plated at 3000/well in 96-well plates at 90. mu.L/well. Transfer the plates to constant temperature CO2In an incubator at 37 ℃ with 5% CO2And culturing under saturated humidity condition for 24 hours.
(3) The test compound was added: 10 μ L/well, cultured for 72 hours, each set of 3 parallel wells.
(4) And (4) determining the result: after 72 hours of compound action, 10. mu.L/well of CCK8 was added, incubated in an incubator for an appropriate time and absorbance measured at 450 nm.
2. Results of the experiment
The results of the test for each test compound are summarized in tables 4-6 below:
TABLE 4 proliferation inhibition results of Compound 6 on human lung adenocarcinoma cell HCC78, human glioblastoma cell U87MG, human umbilical vein endothelial cell HUVEC, and human gastric cancer cell MKN-45 (corresponding fitting curves are shown in FIGS. 1-3)
TABLE 5 proliferation inhibition results of Compounds 2 and 4 on human glioblastoma U87MG, human gastric carcinoma cells MKN-45, and human lung adenocarcinoma cells HCC78 (corresponding fitting curves are shown in FIGS. 4-6)
TABLE 6 proliferation inhibition results of compounds 2, 4 and 6 on human ovarian cancer SK-OV-3, human colon cancer HCT116 and human lung adenocarcinoma A549 (corresponding fitting curves are shown in FIGS. 7-9)
From the data in tables 4 to 6, it is understood that the salt compound of the present invention can effectively inhibit the proliferation of various cancer cells such as human lung adenocarcinoma cells, human gastric cancer cells, human colon cancer cells, human ovarian cancer cells, and human malignant glioma cells by inhibiting the activities of tyrosine kinases such as C-MET and KDR, and is particularly suitable for the treatment of cancer.
The above-mentioned embodiments only express the embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (8)

1. Salt compounds with a general formula (I),
wherein, theSelected from:
2. a pharmaceutical composition comprising a safe and effective amount of a salt of a compound of claim 1 and a pharmaceutically acceptable carrier.
3. A tyrosine kinase inhibitor comprising a salt compound of claim 1.
4. A tyrosine kinase inhibitor according to claim 3, wherein the tyrosine kinase comprises C-MET, VEGFR, KDR, RON, KIT, PDGF, FGF, SRC kinase.
5. Use of a salt compound according to claim 1 for the manufacture of a medicament for the treatment of cancer.
6. The use of claim 5, wherein the cancer comprises lung cancer, gastric cancer, ovarian cancer, colon cancer, pancreatic cancer, esophageal adenocarcinoma, glioblastoma.
7. Use of a pharmaceutical composition according to claim 2 for the manufacture of a medicament for the treatment of cancer.
8. Use of a salt compound according to claim 1 for the manufacture of a medicament for the treatment of inflammation.
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