CN107235897A - Tyrosine kinase inhibitor and its application - Google Patents
Tyrosine kinase inhibitor and its application Download PDFInfo
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- CN107235897A CN107235897A CN201610857372.5A CN201610857372A CN107235897A CN 107235897 A CN107235897 A CN 107235897A CN 201610857372 A CN201610857372 A CN 201610857372A CN 107235897 A CN107235897 A CN 107235897A
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- 0 C*C(*c1c(*C(C)c(ccc(*C(*)*2(CC2)C(*(C)C(C=C2)=CC[C@@]2I)=O)c2)c2F)ccnc1*1)=C1OCCC*1CCOCC1 Chemical compound C*C(*c1c(*C(C)c(ccc(*C(*)*2(CC2)C(*(C)C(C=C2)=CC[C@@]2I)=O)c2)c2F)ccnc1*1)=C1OCCC*1CCOCC1 0.000 description 7
- ZWOAQWKNPRTQKP-UHFFFAOYSA-N OS(c1cccnc1)(O)=O Chemical compound OS(c1cccnc1)(O)=O ZWOAQWKNPRTQKP-UHFFFAOYSA-N 0.000 description 1
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
- C07D213/71—Sulfur atoms to which a second hetero atom is attached
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/11—Esters of phosphoric acids with hydroxyalkyl compounds without further substituents on alkyl
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
- C07F9/3834—Aromatic acids (P-C aromatic linkage)
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
Abstract
The invention discloses a kind of salt compounds with following logical formula (I)s.The invention also discloses comprising the tyrosine kinase inhibitor of the salt compounds and the compound application in the medicine for preparing treating cancer.The tyrosine kinase inhibitor of the present invention, the bioactivity of the multi-signal transduction kinase such as C MET, VEGF, KDR can be suppressed, cell propagation can effectively be suppressed, there is good therapeutic effect to a variety of disorders such as cancers, especially there is significant therapeutic effect to lung cancer, stomach cancer, oophoroma, glioblastoma etc., application prospect is boundless.
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to a kind of tyrosine kinase inhibitor and its application.
Background technology
Protein kinase is a kind of phosphotransferase, shifts the gamma phosphoric acid ester group of adenosine triphosphate atp to specific amino
Sour residue, to realize the phosphorylation of albumen, so as to realize its physiology and biochemical function.
Protein kinase has critical function on Information Conduction.Unusual protein kinase can not carry out normal signal biography
Pass, lesion may be caused, for example：The protein kinases such as tumor cell proliferation, cell death, inflammation, angiocardiopathy.Albumen swashs
Enzyme is broadly divided into two classes：Protein tyrosine kinase PTKs and receptor tyrosine kinase RTKs.ROS1/ in MET races protein kinase
C-MET is a RTPs important subbreed, also referred to as hHGFR and RON；ROS1/C-MET can be to initial tumor cell growth
Played an important role with metabolism, be the target of multi-medicament clinical research.
Therefore, the junket of ROS1/C-MET kinase inhibitors, especially micromolecular compound is badly in need of in bio-medical technology field
Histidine kinase inhibitor.
The content of the invention
The technical problem to be solved in the present invention is to provide a kind of tyrosine kinase inhibitor, the kinase inhibitor can suppress
The activity of a variety of EGFR-TKs for participating in signal transduction such as C-MET, VEGF, KDR, RON, KIT, PDGF, FGF, SRC, can have
Effect suppresses the propagation of tumour cell, clinical cancer therapy is obtained more preferable effect.
In order to solve the above-mentioned technical problem, the present invention is achieved through the following technical solutions:
In one aspect of the invention there is provided a kind of salt compounds for having and leading to formula (I),
Wherein,
R1 is selected from halogen, halogen anion, lower halogenated alkyl, lower alkyl alkyl, light alkene base, Lower alkyne
Base, substitution saturation or unsaturation ring alkyl, substitution or not substituted aroma alkyl, substitution or substituted aromatic base, substitution or do not take
For heterocyclic radical, substitution or not substituted heterocycle alkyl or for sky；
Y is selected from C, O, N, S or is sky；
X is selected from carbonate, sulfate radical, inferior sulfate radical, bisulfate ion, phosphate radical, orthophosphite, hydrogen phosphate, di(2-ethylhexyl)phosphate
Hydrogen radical, molybdate, chlorate anions are sky.
It is preferred that, the logical formula (I) compound includes the compound of following concrete structures：
In another aspect of this invention, a kind of pharmaceutical composition is additionally provided, said composition is upper comprising safe and effective amount
State compound and pharmaceutically acceptable carrier.
Above-mentioned acceptable carrier is nontoxic, can aid in using and not have unfavorable shadow to the therapeutic effect of compound
Ring.Examples of such carriers can be any solid excipient, liquid excipient, the semisolid that those skilled in the art usually leads to
Excipient or the gaseous excipient in aerosol combination.Solid pharmaceutical excipients include starch, cellulose, talcum, Portugal
Grape sugar, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, odium stearate, glyceryl stearate acyl ester,
Sodium chloride, anhydrous skimmed milk etc..Liquid and semisolid excipient can be selected from glycerine, propane diols, water, ethanol and various oil, bag
Include those and come from oil, animal, plant or artificial synthesized oil, for example, peanut oil, soya-bean oil, mineral oil, sesame oil etc., preferably
Liquid-carrier, particularly for Injectable solution, including water, salt solution, D/W and glycol.It can in addition contain
Other assistant agents such as flavouring agent, sweetener etc. are added in composition.
The compound of the present invention is applied with the effective dose on treating, and its method of application can be oral, systemic administration (example
Such as, it is transdermal, nasal inhalation or use suppository) or parenteral administration (for example, intramuscular, intravenously or subcutaneously).It is preferred that
Method of application be oral, it can be adjusted according to disease degree.
The actual amount of application (i.e. active component) of the compound of the present invention depends on many factors, and such as disease to be treated is tight
Principal characteristic, the age for the treatment of target and relative health, the efficiency of used compound, route of administration and form, Yi Jiqi
His factor.
The various formulations of pharmaceutical composition of the present invention can be prepared according to the conventional method of pharmaceutical field.For example make the chemical combination
Thing mix with one or more kinds of carriers, the formulation needed for being then made into, such as tablet, pill, capsule, semisolid, powder,
Slow release formulation, solution, suspension, ingredients, aerosol etc..
In another aspect of this invention, a kind of tyrosine kinase inhibitor for including above-mentioned salt compounds is additionally provided.
The EGFR-TK includes C-MET, VEGF, KDR, RON, KIT, PDGF, FGF, SRC kinases.
In another aspect of this invention, above-mentioned salt compounds answering in the medicine for preparing treating cancer is additionally provided
With.
Because EGFR-TK is the obvious antineoplastic target spot of current effect, and the salt compounds of the present invention have
Significant tyrosine-kinase enzyme inhibition activity, experiments prove that these compounds are inhibited to various cancer cell multiplications,
Therefore salt compounds of the present invention are applied to treat various cancers.Especially for lung cancer, stomach cancer, oophoroma, colon cancer, pernicious
Glioma has preferable therapeutic effect.
In another aspect of this invention, above-mentioned salt compounds answering in the medicine for preparing treatment inflammation is additionally provided
With.
Salt compounds of the present invention and multi-signal transduction kinase such as C-MET, VEGF, KDR, RON, KIT, PDGF, FGF,
SRC etc. has good biological action, and associated with multi-signal conducting path, therefore has treatment to a variety of diseases
Effect, such as cancer, inflammation, lymphedema, diabetes.
The tyrosine kinase inhibitor of the present invention, can suppress the life of the multi-signal transduction kinase such as C-MET, VEGF, KDR
Thing activity, can effectively suppress cell propagation, have good therapeutic effect to a variety of disorders such as cancers, especially to lung cancer, stomach
Cancer, oophoroma, glioblastoma etc. have significant therapeutic effect, and application prospect is boundless.
Brief description of the drawings
The present invention is further detailed explanation with reference to the accompanying drawings and detailed description.
Fig. 1 is Proliferation Ability matched curve figure of the compound 6 to human lung adenocarcinoma cell HCC78 of the embodiment of the present invention 7；
Fig. 2 is Proliferation Ability matched curve of the compound 6 of the embodiment of the present invention 7 to people's Malignant glioma cells U87MG
Figure；
Fig. 3 is Proliferation Ability matched curve of the compound 6 to Human umbilical vein endothelial cells HUVEC of the embodiment of the present invention 7
Figure；
Fig. 4 is the compound 2 of the embodiment of the present invention 7 and 4 couples of people's Malignant glioma cells U87MG Proliferation Ability fitting song
Line chart；
Fig. 5 is the compound 2 of the embodiment of the present invention 7 and 4 couples of gastric carcinoma cells MKN-45 Proliferation Ability matched curve figure；
Fig. 6 is compound 2 and the 4 couples of human lung adenocarcinoma cell HCC78 Proliferation Ability matched curve of the embodiment of the present invention 7
Figure；
Fig. 7 be the compound 2 of the embodiment of the present invention 7,4,6 couples of Proliferation of Human Ovarian Cell SK-OV-3 Proliferation Ability fitting it is bent
Line chart；
Fig. 8 is the compound 2 of the embodiment of the present invention 7,4,6 couples of human colon cancer cell HCT116 Proliferation Ability matched curve
Figure；
Fig. 9 is the compound 2 of the embodiment of the present invention 7, the Proliferation Ability matched curve of 4,6 pairs of human A549 cell lines.
Embodiment
The synthesis of the tyrosine kinase inhibitor p-methyl benzenesulfonic acid salt compound of embodiment 1
(N- [the fluoro- 4- of 3- [[6- methoxyl groups -7- [[3- (morpholine -4- bases) propyl group] oxygen] quinolyl-4] oxygen] benzene of compound 1
Base]-N'- (4- fluorophenyls) cyclopropane -1,1- diformamide) (632mg, 1mmol) is dissolved in tetrahydrofuran (10mL), ice-water bath
After to interior 0 DEG C of temperature, p-methyl benzenesulfonic acid (173mg, 1mmol) is added, 2h is reacted at room temperature, white solid is filtered to obtain after completion of the reaction
N- [the fluoro- 4- of 3- [[6- methoxyl groups -7- [[3- (morpholine -4- bases) propyl group] oxygen] quinolyl-4] oxygen] phenyl]-N'- (4- fluorobenzene
Base) cyclopropane -1,1- diformamide tosilate (compound 2) 650mg, yield 81%.
1H NMR(500MHz,DMSO-d6):δ 10.41 (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)。
The synthesis of the tyrosine kinase inhibitor glutamate compound of embodiment 2
(N- [the fluoro- 4- of 3- [[6- methoxyl groups -7- [[3- (morpholine -4- bases) propyl group] oxygen] quinolyl-4] oxygen] benzene of compound 1
Base]-N'- (4- fluorophenyls) cyclopropane -1,1- diformamides) (632mg, 1mmol) be dissolved in tetrahydrofuran/water (10mL, 1:1)
In, after ice-water bath to interior 0 DEG C of temperature, Pidolidone (147mg, 1mmol) is added, 8h is reacted at room temperature, is filtered after completion of the reaction
White solid N- [the fluoro- 4- of 3- [[6- methoxyl groups -7- [[3- (morpholine -4- bases) propyl group] oxygen] quinolyl-4] oxygen] phenyl]-N'-
(4- fluorophenyls) cyclopropane -1,1- diformamide glutamate (compound 3) 450mg, yield 58%.
LC-MS(ESI)m/z 633(M+H)。
The synthesis of the positive fourth phosphate compounds of the tyrosine kinase inhibitor of embodiment 3
(N- [the fluoro- 4- of 3- [[6- methoxyl groups -7- [[3- (morpholine -4- bases) propyl group] oxygen] quinolyl-4] oxygen] benzene of compound 1
Base]-N'- (4- fluorophenyls) cyclopropane -1,1- diformamide) (632mg, 1mmol) is dissolved in dichloromethane (10mL), ice-water bath
After to interior 0 DEG C of temperature, positive fourth phosphoric acid (154mg, 1mmol) is added, 4h is reacted at room temperature, white solid N- is filtered to obtain after completion of the reaction
[the fluoro- 4- of 3- [[6- methoxyl groups -7- [[3- (morpholine -4- bases) propyl group] oxygen] quinolyl-4] oxygen] phenyl]-N'- (4- fluorophenyls)
Positive fourth phosphate (compound 4) 650mg of cyclopropane -1,1- diformamide, yield 83%.
1H NMR(500MHz,DMSO-d6):δ 10.43 (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)。
The synthesis of the tyrosine kinase inhibitor malate compound of embodiment 4
(N- [the fluoro- 4- of 3- [[6- methoxyl groups -7- [[3- (morpholine -4- bases) propyl group] oxygen] quinolyl-4] oxygen] benzene of compound 1
Base]-N'- (4- fluorophenyls) cyclopropane -1,1- diformamide) (632mg, 1mmol) is dissolved in tetrahydrofuran (10mL), ice-water bath
After to interior 0 DEG C of temperature, malic acid (134mg, 1mmol) is added, 8h is reacted at room temperature, white solid N- is filtered to obtain after completion of the reaction
[the fluoro- 4- of 3- [[6- methoxyl groups -7- [[3- (morpholine -4- bases) propyl group] oxygen] quinolyl-4] oxygen] phenyl]-N'- (4- fluorophenyls)
Cyclopropane -1,1- diformamide malate (compound 5) 550mg, yield 72%.
LC-MS(ESI)m/z 633(M+H)。
The synthesis of the tyrosine kinase inhibitor alendronic acid salt compound of embodiment 5
(N- [the fluoro- 4- of 3- [[6- methoxyl groups -7- [[3- (morpholine -4- bases) propyl group] oxygen] quinolyl-4] oxygen] benzene of compound 1
Base]-N'- (4- fluorophenyls) cyclopropane -1,1- diformamides) (632mg, 1mmol) be dissolved in N,N-dimethylformamide (10mL)
In, after ice-water bath to interior 0 DEG C of temperature, alendronic acid (249mg, 1mmol) is added, 8h is reacted at room temperature, is filtered after completion of the reaction
White solid N- [the fluoro- 4- of 3- [[6- methoxyl groups -7- [[3- (morpholine -4- bases) propyl group] oxygen] quinolyl-4] oxygen] phenyl]-N'-
(4- fluorophenyls) cyclopropane -1,1- diformamide Alendronate (compound 6) 150mg, yield 17%.
LC-MS(ESI)m/z 633(M+H)。
The tyrosine-kinase enzyme inhibition activity of embodiment 6 is detected
The salt compounds of above-described embodiment are applied to the detection and screening to C-MET and KDR kinase inhibiting activities.
1. method
(1) added into 384 orifice plates 4 μ L preparation kinase buffer solution, or 4 μ L kinase solution (100% suppress pair
According to)；Xiang Kongzhong adds 2 μ L compound, or 2 μ L are free of the buffer (0%inhibition controls) of compound；Above institute
There are sample or control to be all provided with 2 multiple holes.
(2) 25 DEG C of incubation 5min；
(3) 2 μ L ATP/ substrates/MgCl is added into hole2/MnCl2/ SEB/DTT mixed liquors；
(4) 1000rpm centrifuges 1min, and 30 DEG C of concussions are incubated 30min；
(5) mixed liquor of 8 μ L XL-665/ antibody is added into hole；
(6) 25 DEG C of incubation 1h；
(7) PHERAstar FS instruments read 665nm and 620nm signals；
(8) according to kit specification analyze data, and with GraphPad Prism5 the Fitting Calculations IC50.
Ratio=665nm/620nm
2. experimental result
Each censorship compound and the testing result of reference compound are summarized as follows shown in Tables 1 and 2, wherein control compound
It is existing C-MET kinase inhibitors Foretinib (structural formula is as follows).For-Oxide, For-Methyl chemical structural formula
Also distinguish as follows.
Inhibitory activity of the compound 6 of table 1 to C-MET
Inhibitory activity of the compound 6 of table 2 to KDR
The inhibitory activity of the compound 2 of table 3 and 4 couples of C-Met/KDR
From table 1-3 data, the salt compounds of the above embodiment of the present invention have the tyrosine-kinases such as C-MET, KDR
The inhibitory activity of enzyme.
Embodiment 7 is tested Cytostatic to tumor cell
1. method
(1) cell culture：By tumour cell (such as human lung adenocarcinoma cell HCC78, people's Malignant glioma cells U87MG, people's stomach
Cancer cell MKN-45, Human umbilical vein endothelial cells HUVEC, human A549 cell lines etc.) cell culture medium culture is used, cultivate bar
Part is 37 DEG C, 5%CO2。
(2) cell is inoculated with：Take in exponential phase of growth, cell in good condition, add appropriate trypsin digestion cell, collect
Cell is centrifuged, and abandons supernatant.Be suspended cell again with the nutrient solution containing serum, is then counted and is taken cell suspension to be connect by 3000/ hole
Kind on 96 orifice plates, 90 μ L/ holes.Culture plate is transferred to constant temperature CO2In incubator, in 37 DEG C, 5%CO2And under the conditions of saturated humidity
Culture 24 hours.
(3) test-compound is added：10 μ L/ holes, are cultivated 72 hours, every group sets 3 parallel holes.
(4) result is determined：After compound effects 72 hours, the CCK8 in 10 μ L/ holes is added, is placed in incubator and is incubated suitably
Time, light absorption value is surveyed at 450nm.
2. experimental result
The testing result of each censorship compound is summarized as follows shown in table 4-6：
The compound 6 of table 4 is to human lung adenocarcinoma cell HCC78, people's Malignant glioma cells U87MG, Human umbilical vein endothelial cells
HUVEC, gastric carcinoma cells MKN-45 Proliferation Ability result (Fig. 1-3 is shown in corresponding matched curve)
The compound 2 of table 5 and 4 pairs of people's Malignant glioma cells U87MG, gastric carcinoma cells MKN-45, human lung adenocarcinoma cells
HCC78 Proliferation Ability result (Fig. 4-6 is shown in corresponding matched curve)
The compound 2 of table 6,4,6 pairs of Proliferation of Human Ovarian Cell SK-OV-3, human colon cancer cell HCT116, human lung adenocarcinoma cells
A549 Proliferation Ability result (Fig. 7-9 is shown in corresponding matched curve)
From above-mentioned table 4-6 data, salt compounds of the invention are by suppressing the EGFR-TKs such as C-MET, KDR
Activity, can effectively suppress human lung adenocarcinoma cell, gastric carcinoma cells, human colon cancer cell, Proliferation of Human Ovarian Cell, the pernicious glue of people
The propagation of the various cancer cells such as matter oncocyte, is particularly suitable for use in the treatment of cancer.
Embodiment described above only expresses embodiments of the present invention, and it describes more specific and detailed, but can not
Therefore it is interpreted as the limitation to the scope of the claims of the present invention.It should be pointed out that for the person of ordinary skill of the art,
Without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to the protection model of the present invention
Enclose.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.
Claims (9)
1. the salt compounds with logical formula (I),
Wherein,
R1 is selected from halogen, halogen anion, lower halogenated alkyl, lower alkyl alkyl, light alkene base, Lower alkyne base, taken
For saturation or unsaturation ring alkyl, substitution or not substituted aroma alkyl, substitution or not substituted aromatic base, substitution or not substituted heterocycle
Base, substitution or not substituted heterocycle alkyl or for sky；
Y is selected from C, O, N, S or is sky；
X be selected from carbonate, sulfate radical, inferior sulfate radical, bisulfate ion, phosphate radical, orthophosphite, hydrogen phosphate, dihydrogen phosphate,
Molybdate, chlorate anions are sky.
2. salt compounds according to claim 1, it is characterised in that the logical formula (I) compound includes：
3. a kind of pharmaceutical composition, it is characterised in that salt chemical combination described in claim 1 of the said composition comprising safe and effective amount
Thing and pharmaceutically acceptable carrier.
4. a kind of tyrosine kinase inhibitor, includes the salt compounds described in claim 1 or 2.
5. tyrosine kinase inhibitor according to claim 4, it is characterised in that the EGFR-TK include C-MET,
VEGFR, KDR, RON, KIT, PDGF, FGF, SRC kinases.
6. application of the salt compounds described in claim 1 or 2 in the medicine for preparing treating cancer.
7. application according to claim 6, it is characterised in that the cancer include lung cancer, stomach cancer, oophoroma, colon cancer,
Cancer of pancreas, adenocarcinoma of esophagus, glioblastoma.
8. application of claim 3 described pharmaceutical composition in the medicine for preparing treating cancer.
9. application of the salt compounds described in claim 1 or 2 in the medicine for preparing treatment inflammation.
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| CN103626700A (en) * | 2012-08-25 | 2014-03-12 | 上海壹志医药科技有限公司 | Salt of cyclopropane dicarboxamide derivative |
| US20140221372A1 (en) * | 2013-02-06 | 2014-08-07 | GlaxoSmithKline Intellectual Property (NO 2.) Limited | Method of administration and treatment |
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| JP5788527B2 (en) * | 2011-12-02 | 2015-09-30 | 味の素株式会社 | Side effects reducing agent of kinase inhibitor |
| CN102964308B (en) * | 2012-11-30 | 2015-03-18 | 中国药科大学 | Novel pyrimidine compound, preparation method thereof, pharmaceutical composition containing novel pyrimidine compound and application of novel pyrimidine compound |
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| WO2012044577A1 (en) * | 2010-09-27 | 2012-04-05 | Exelixis, Inc. | Dual inhibitors of met and vegf for the treatment of castration resistant prostate cancer and osteoblastic bone metastases |
| CN103626700A (en) * | 2012-08-25 | 2014-03-12 | 上海壹志医药科技有限公司 | Salt of cyclopropane dicarboxamide derivative |
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