CN107513040A - Substitute the preparation of benzo pyridine compound and the application of molecular targeted anti-tumor medicine - Google Patents
Substitute the preparation of benzo pyridine compound and the application of molecular targeted anti-tumor medicine Download PDFInfo
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- CN107513040A CN107513040A CN201710650870.7A CN201710650870A CN107513040A CN 107513040 A CN107513040 A CN 107513040A CN 201710650870 A CN201710650870 A CN 201710650870A CN 107513040 A CN107513040 A CN 107513040A
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- 0 COc1cc2c([N+]c3ccccc3)ncnc2cc1OCCCCN* Chemical compound COc1cc2c([N+]c3ccccc3)ncnc2cc1OCCCCN* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
Abstract
The invention belongs to technical field of medicine synthesis in pharmaceutical chemistry, the present disclosure provides one kind to be related to the benzo pyridine compound shown in formula (I), its officinal salt, solvate, the pharmaceutical composition containing the compound or pharmaceutically acceptable salt thereof, its preparation method, and its purposes in terms of molecular targeted antineoplaston medicine is prepared.R shown in Formula (I)1And R2There is any implication defined in description of the invention respectively.Benzo pyridine compound of the present invention has high-affinity to EGFR TK, can carry out regulating cell propagation by effectively suppressing EGFR TK activity, so as to reach the purpose for the treatment of malignant tumour, can be used as antineoplaston medicine or its lead compound.
Description
Technical field
The invention belongs to technical field of medicine synthesis in organic chemistry and pharmaceutical chemistry, be related to it is a kind of it is new have it is antitumor
The small molecule EGFR-TK inhibitor of bioactivity, and in particular to phonetic in the benzo that 7- positions are substituted by carboxylic acid group or its carboxylate group
Pyridine class compound or pharmaceutically acceptable salt thereof, the pharmaceutical composition containing the compound or pharmaceutically acceptable salt thereof, solvate, its preparation side
Method, and its purposes in terms of molecular targeted antineoplaston medicine is prepared.Pharmacological activity experiment shows that such compound is to more
Kind solid tumor cell has preferable proliferation inhibition activity, has broad-spectrum anti-tumor activity, can be used as molecular targeted antitumor
Medicine or its lead compound.
Background technology
Cancer (cancer) is currently to endanger one of major disease of human life and health, and its incidence of disease and the death rate occupy height
Under not, total death toll is also in the trend of rising year by year.Cancer is living organism under the effect of various carcinogenic factors, local organization
Cell lost on gene level the normal regulation that it grows is caused paraplasm with differentiation and formed neoformation.Cancer is thin
The characteristics of born of the same parents is：Unrestrictedly hyperplasia, endotrophic material are largely consumed；Cancer cell discharges a variety of toxin, produces body
Raw a series of symptoms；Cancer cell can be transferred to whole body growth and breeding everywhere, cause human body to be become thin, be powerless, anaemia, poor appetite,
Heating and serious organ function are impaired etc., and patient is dead finally due to organ failure.Surgical operation therapy, radiotherapy
It is the conventional conventional method of current treating cancer with chemotherapy, over the course for the treatment of, these methods are respectively provided with the effect of certain, but
It is that its side effect is larger, it is larger to sufferer injury, its life quality is declined to a great extent.The research and development of cancer therapy drug have turned into raw at present
Life science and medical domain are rich in challenge and significant Task.In recent years, with oncomolecularbiology not
Disconnected development, people have to the pathogenesis of cancer deeper into understanding, research finds that it occurs, developed and various carcinogens
Caused by gene mutation it is relevant.Signal transduction pathway after gene mutation in living organism gets muddled, and makes uncontrolled cellular proliferation,
Disdifferentiation and apoptosis regulation are not normal, so as to form malignant tumour.
At present, the research of tumor cells targeted therapy has obtained breakthrough, tyrosine protein kinase inhibitor into
For the research and development focus of molecular targeted therapy.It is known that the incidence of disease of solid tumor accounts for the overwhelming majority in malignant tumour, its
Occurrence and development and invasion and attack are closely related with EGFR expression with shifting.Using EGFR as action target spot, malignant tumour is carried out
Molecular targeted therapy, the specific and selective of clinical treatment is improved, be acknowledged as treating the hope place of malignant tumour.
EGFR is a kind of transmembrane glycoprotein, belongs to receptor tyrosine kinases, closely related with cell signalling, influences cell
A series of activities such as growth, propagation and differentiation.Clinic shows that EGFR is expressed in kinds of tumor cells or high expression, including non-
ED-SCLC, breast cancer, incidence cancer, stomach cancer, colon cancer, the cancer of the esophagus, prostate cancer, carcinoma of urinary bladder, kidney, cancer of pancreas and ovum
Nest cancer etc..EGFR activation and the generation of tumour and growth it is closely related, including the propagation of cancer cell, Apoptosis suppression,
The generation of new vessels and the infiltration of cancer cell and transfer etc..The means for being presently used for attacking EGFR in malignant tumour mainly have
Two kinds, one be for the extracellular ligand binding region of acceptor, in and/or prevent the combination of part and acceptor, so as to prevent signal to
Endocellular transduction；One is the small molecule EGFR-TK inhibitor for acting on acceptor intracellular tyrosine kinase domain, is competed with ATP
The binding site of enzyme, the activity of inhibitory enzyme and the autophosphorylation of tyrosine, prevent the signal transduction in downstream.Such inhibitor has
High efficiency and specificity, preferably internal antitumous effect are that road has been paved in its clinical research.Researched and developed based on this receptor
Molecular targeted antineoplastic achieves significant effect in clinical studies, wherein using benzo pyrimidine as the small molecule of parent
The research of compound is the most prominent.
The content of the invention
Suppress it is an object of the invention to provide a kind of new substitution benzo pyridine compound as small molecule EGFR-TK
Agent, has broad spectrum activity, high efficiency and higher medical value, and preparation and clinic for molecular targeted antineoplaston medicine are ground
Study carefully application.
The invention discloses one kind to be related to the substitution benzo pyridine compound as shown in formula (I), its officinal salt, contains
The pharmaceutical composition of the compound or pharmaceutically acceptable salt thereof, solvate, its preparation method, and its it is molecular targeted antitumor preparing
Purposes in terms of medicine, the purposes particularly in terms of cancer treatment drug is prepared.
The purpose of the present invention is achieved through the following technical solutions：
One kind be related to benzo pyridine compound or pharmaceutically acceptable salt thereof as shown in formula (I), containing the compound or its can
The pharmaceutical composition of pharmaceutical salts, solvate
Wherein：Wherein R1It is expressed as cyano group or halogeno-group；Wherein R2It is expressed as carboxylic acid group or its carboxylate group.
R in the present invention1Can be more preferably cyano group, the respectively monosubstituted cyano group of 2-, 3- and 4- position.
R in the present invention2Can be more preferably caproyl or its carboxylate group, butyric acid base or its carboxylate group, its carboxylic
Hydrochlorate base is more preferably carboxylic acid sodium or potassium.
Compound shown in formula (I), it can select to form officinal salt with pharmaceutically acceptable acid.Wherein art
Language " officinal salt " includes but is not limited to the salt formed with inorganic acid, such as hydrochloride, sulfate, phosphate and its similar salt；
Simultaneously including the salt formed with organic acid, such as citrate, tosilate, stearate and its similar salt.Similarly, medicine
Acceptable cation includes but is not limited to potassium, sodium, calcium, magnesium, aluminium, lithium and ammonium ion on.
The present invention provides a kind of compound or pharmaceutically acceptable salt thereof included shown in any one of foregoing formula (I) and can medically connect
The one or more received come from filler, disintegrant, lubricant, glidant, effervescent agent, flavouring, preservative and coating material
Deng the pharmaceutical composition of formation.
The present invention provides a kind of compound or pharmaceutically acceptable salt thereof included shown in any one of foregoing formula (I) and is prepared into solvent conjunction
Thing, such as hydrate.
The present invention provide a kind of compound included shown in any one of foregoing formula (I) or its pharmaceutically officinal salt, contain
Use of the pharmaceutical composition, solvate of the compound or pharmaceutically acceptable salt thereof in terms of molecular targeted antineoplaston medicine is prepared
On the way, the purposes particularly in terms of cancer treatment drug is prepared.
The present invention provides a kind of preparation method for including the compound shown in any one of foregoing formula (I), it is characterised in that：Institute
Preparation method is stated to comprise the following steps：
The synthesis of compound (I)
Benzo pyridine compound (I) of the present invention and its officinal salt can be synthesized by following reaction.
Initiation material necessary to benzo pyridine compound (I) of the present invention and its chemical synthesis of officinal salt
It can be synthesized according to the organic chemistry program of standard, the synthetic method of these initiation materials is by described in example afterwards.Separately
Some required initiation materials can synthesize according to the similar step described in organic chemistry handbook and method.Centreization
Compound (III a-c) can be synthesized by compound (II) and the reaction of different cyano group substituted anilines.
The present invention carries out anti tumor activity in vitro measure by using mtt assay, and its result of the test shows：Shown in formula (I)
There is benzo pyridine compound preferable cell to breed to tumour cells such as HepG2, A549, DU145, MCF-7 and SH-SY5Y
Inhibitory activity.
The present invention carries out external EGFR-TK inhibitory activity by using ELISA method and determined, and its result of the test shows：Formula (I)
Shown benzo pyridine Compound ira vitro has preferable inhibitory activity to EGFR-TK.
The present invention relates to a kind of novel chemical synthetic drug of structure, its pharmacodynamics test shows：It can specifically make
For EGFR-TK, and preferably suppress its activity and its autophosphorylation, to suppress tumor cell proliferation, so as to suppress tumour
Growth, reach the purpose of oncotherapy.Compared to traditional cancer treatment method, chemotherapy of the present invention has
The advantages that targeting height, high specificity, small toxic side effect, molecular targeted chemotherapeutics that can be as treatment malignant tumour or its elder generation
Lead compound.
Brief description of the drawings
Fig. 1 formulas (I) illustrated embodiment compound and positive control medicine are surveyed to the external inhibitory activity of EGFR-TK
Test result
Embodiment
Here is the specific embodiment of the present invention.The invention will be further described for described embodiment, contributes to ability
The clearer understanding of field technique personnel and implementation, are not in any way restricted to the present invention, are only its illustration and representative.
Benzo pyridine compound of the present invention is a kind of powdered solid substance.
Embodiment 1
The synthesis of compound 4- (4- cyanophenylaminos) -6- methoxyl groups -7- (3- chlorine propoxyl group) quinazolines (III a)
The chloro- 6- methoxyl groups -7- of 4- (3- chlorine propoxyl group) quinazolines (II) (10.0g, 35mmol) are added to containing i-
In PrOH (200mL) 500mL eggplant-shape bottles, it is stirred at room temperature and is allowed to dissolve, adds 4- aminobenzenes cyanogen (5.0g, 43mmol), heating
To back flow reaction 2h.Reaction solution is cooled to room temperature, filters the solid of precipitation, and cold ethanol washing is dry that pale yellow powder shape is consolidated
Body, yield 93%.m.p.:126-128℃.1H NMR(400MHz,DMSO-d6):δ9.78(s,1H,NH),8.58(s,1H,
ArH),8.13(s,1H,ArH),8.11(s,1H,ArH),7.85-7.82(m,3H,ArH),7.27(s,1H,ArH),4.28(t,
J=8.0Hz, 2H ,-OCH2 CH2CH2Cl),3.99(s,3H,-OCH3), 3.82 (t, J=8.0Hz, 2H ,-OCH2CH2 CH2 Cl),
2.30-2.24(m,2H,-OCH2 CH2 CH2Cl).ESI-MS:m/z calcd found 370.13[M+H]+.
Embodiment 2
The synthesis of compound 4- (3- cyanophenylaminos) -6- methoxyl groups -7- (3- chlorine propoxyl group) quinazolines (III b)
Specific experiment operates the synthesis of same compound (III a), yield 90%.m.p.:124-126℃.1H NMR
(400MHz,DMSO-d6):δ 9.68 (s, 1H, NH), 8.55 (s, 1H, ArH), 8.37 (s, 1H, ArH), 8.13 (d, J=
8.1Hz, 1H, ArH), 7.84 (s, 1H, ArH), 7.55 (dd, J=21.1,7.8Hz, 2H, ArH), 7.24 (s, 1H, ArH),
4.27(s,2H,-OCH2 CH2CH2Cl),3.98(s,3H,-OCH3),3.82(s,2H,-OCH2CH2 CH2 Cl),2.26(m,2H,-
OCH2 CH2 CH2Cl).ESI-MS:m/z calcd found 370.15[M+H]+.
Embodiment 3
The synthesis of compound 4- (2- cyanophenylaminos) -6- methoxyl groups -7- (3- chlorine propoxyl group) quinazolines (III c)
The synthesis of the same compound of specific experiment operating procedure (III a), yield 91%.m.p.:123-125℃.1H NMR
(400MHz,DMSO-d6):δ 9.65 (s, 1H, NH), 8.48 (s, 1H, ArH), 8.13 (d, J=8.7Hz, 1H, ArH), 8.06
(d, J=8.04Hz, 1H, ArH), 7.62-7.58 (m, 2H, ArH), 7.26 (s, 1H, ArH), 7.20 (s, 1H, ArH), 4.17
(s,2H,-OCH2 CH2CH2Cl),3.92(s,3H,-OCH3),3.62(s,2H,-OCH2CH2 CH2 Cl),2.12(m,2H,-
OCH2 CH2 CH2Cl).ESI-MS:m/z calcd found 370.13[M+H]+.
Embodiment 4
Compound 6- (3- (4- ((4- cyano-phenyls) amino) -6- methoxyquinazoline hydrochloride base -7- propoxyl group) amino) caproic acid
The synthesis of (I a-1)
By 4- (4- cyanophenylaminos) -6- methoxyl groups -7- (3- chlorine propoxyl group) quinazoline (III a) (0.75g,
2.04mmol), DMF (10mL), 6-aminocaprolc acid (0.40g, 3.06mmol), is added separately in 50mL eggplant-shape bottles, in 80 DEG C
React 8~10h.Reaction solution is cooled to room temperature, pours into frozen water, ethyl acetate extraction, anhydrous Na2SO4 is dried, and vacuum rotary steam removes
Remove ethyl acetate, dry faint yellow solid, yield 85%.m.p.:270-272℃.1H NMR(400MHz,DMSO-d6):δ
9.78 (s, 1H, NH), 8.58 (s, 1H, ArH), 8.12 (d, J=8.5Hz, 2H, ArH), 8.04 (m, 3H, ArH), 7.27 (s,
1H,ArH),4.28(m,2H,-OCH2 CH2CH2N-),3.99(s,3H,-OCH3),2.71(m,4H,-CH2 NHCH2 CH2CH2O-),
2.46(m,2H,-CH2COO),1.98-1.42(m,8H,-OCH2 CH2 CH2N-,-CH2CH2CH2 -).ESI-MS:m/z calcd
found 464.21[M+H]+.
Embodiment 5
Compound 4- (3- (4- ((4- cyano-phenyls) amino) -6- methoxyquinazoline hydrochloride base -7- propoxyl group) amino) butyric acid
The synthesis of (I a-2)
By 4- (4- cyanophenylaminos) -6- methoxyl groups -7- (3- chlorine propoxyl group) quinazoline (III a) (0.75g,
2.04mmol), DMF (10mL), 4-Aminobutanoicacid (0.32g, 3.06mmol), is added separately in 50mL eggplant-shape bottles, in 80 DEG C
React 8~10h.Reaction solution is cooled to room temperature, pours into frozen water, ethyl acetate extraction, anhydrous Na2SO4 is dried, and vacuum rotary steam removes
Ethyl acetate is removed, drying is faint yellow to obtain solid, yield 83%.m.p.:274-276℃.1H NMR(400MHz,DMSO-d6):δ
9.77 (s, 1H, NH), 8.58 (s, 1H, ArH), 8.13 (d, J=8.5Hz, 2H, ArH), 8.05 (m, 3H, ArH), 7.29 (s,
1H,ArH),4.27(m,2H,-OCH2 CH2CH2N-),3.98(s,3H,-OCH3),2.58(m,4H,-CH2 NHCH2 CH2CH2O-),
2.48(m,2H,-CH2COO),2.06–1.93(m,4H,-OCH2 CH2 CH2N-,-CH2 CH2 CH2-).ESI-MS:m/z calcd
found 436.21[M+H]+.
Embodiment 6
Compound 6- (3- (4- ((3- cyano-phenyls) amino) -6- methoxyquinazoline hydrochloride base -7- propoxyl group) amino) caproic acid
The synthesis of (I b-1)
By 4- (3- cyanophenylaminos) -6- methoxyl groups -7- (3- chlorine propoxyl group) quinazoline (III a) (0.75g,
2.04mmol), DMF (10mL), 6-aminocaprolc acid (0.40g, 3.06mmol), is added separately in 50mL eggplant-shape bottles, in 80 DEG C
React 8~10h.Reaction solution is cooled to room temperature, pours into frozen water, ethyl acetate extraction, anhydrous Na2SO4 is dried, and vacuum rotary steam removes
Remove ethyl acetate, dry faint yellow solid, yield 81%.m.p.:278-282℃.1H NMR(400MHz,DMSO-d6):δ
9.67 (s, 1H, NH), 8.54 (s, 1H, ArH), 8.38 (s, 1H, ArH), 8.15 (d, J=8.0Hz, 1H, ArH), 7.83 (s,
1H,ArH),7.65–7.54(m,2H,ArH),7.21(s,1H,ArH),4.28(m,2H,-OCH2 CH2CH2N-),3.99(s,
3H,-OCH3),2.71(m,4H,-CH2 NHCH2 CH2CH2O-),2.46(m,2H,-CH2COO),1.98-1.42(m,8H,-
OCH2 CH2 CH2N-,-CH2CH2CH2 -).ESI-MS:m/z calcd found 464.20[M+H]+.
Embodiment 7
Compound 4- (3- (4- ((3- cyano-phenyls) amino) -6- methoxyquinazoline hydrochloride base -7- propoxyl group) amino) butyric acid
The synthesis of (I b-2)
By 4- (3- cyanophenylaminos) -6- methoxyl groups -7- (3- chlorine propoxyl group) quinazoline (III a) (0.75g,
2.04mmol), DMF (10mL), 4-Aminobutanoicacid (0.32g, 3.06mmol), is added separately in 50mL eggplant-shape bottles, in 80 DEG C
React 8~10h.Reaction solution is cooled to room temperature, pours into frozen water, ethyl acetate extraction, anhydrous Na2SO4 is dried, and vacuum rotary steam removes
Remove ethyl acetate, dry faint yellow solid, yield 83%.m.p.:280-282℃.1H NMR(400MHz,DMSO-d6):δ
9.68 (s, 1H, NH), 8.54 (s, 1H, ArH), 8.38 (s, 1H, ArH), 8.15 (d, J=8.1Hz, 1H, ArH), 7.83 (s,
1H,ArH),7.67–7.44(m,2H,ArH),7.21(s,1H,ArH),4.19(t,2H,-OCH2 CH2CH2N-),3.98(s,
3H,-OCH3),2.58(m,4H,-CH2 NHCH2 CH2CH2O-),2.48(m,2H,-CH2COO),2.06–1.93(m,4H,-
OCH2 CH2 CH2N-,-CH2 CH2 CH2-).ESI-MS:m/z calcd found 436.22[M+H]+.
Embodiment 8
Compound 6- (3- (4- ((2- cyano-phenyls) amino) -6- methoxyquinazoline hydrochloride base -7- propoxyl group) amino) caproic acid
The synthesis of (I c-1)
By 4- (2- cyanophenylaminos) -6- methoxyl groups -7- (3- chlorine propoxyl group) quinazoline (III a) (0.75g,
2.04mmol), DMF (10mL), 6-aminocaprolc acid (0.40g, 3.06mmol), is added separately in 50mL eggplant-shape bottles, in 80 DEG C
React 8~10h.Reaction solution is cooled to room temperature, pours into frozen water, ethyl acetate extraction, anhydrous Na2SO4 is dried, and vacuum rotary steam removes
Remove ethyl acetate, dry solid, yield 81%.m.p.:270-272℃.1H NMR(400MHz,DMSO-d6):δ8.48(s,
1H, ArH), 8.13 (d, J=8.7Hz, 1H, ArH), 8.06 (d, J=8.0Hz, 1H, ArH), 7.91 (m, 1H, ArH), 7.62-
7.58(m,1H,ArH),7.25(s,1H,ArH),7.08(s,1H,ArH),4.03(m,2H,-OCH2 CH2CH2N-),3.87(s,
3H,-OCH3),2.69(m,4H,-CH2 NHCH2 CH2CH2O-),2.46(m,2H,-CH2COO),1.98-1.42(m,8H,-
OCH2 CH2 CH2N-,-CH2CH2CH2 -).ESI-MS:m/z calcd found 464.22[M+H]+.
Embodiment 9
Compound 4- (3- (4- ((2- cyano-phenyls) amino) -6- methoxyquinazoline hydrochloride base -7- propoxyl group) amino) butyric acid
The synthesis of (I c-2)
4- (2- cyanophenylaminos) -6- methoxyl groups -7- (3- chlorine propoxyl group) quinazoline (III is added in 100mL eggplant-shape bottles
A) (0.75g, 2.04mmol), 4-Aminobutanoicacid (0.32g, 3.06mmol), 6~8h is reacted in 80 DEG C.Reaction solution is cooled to room
Temperature, pour into frozen water, ethyl acetate extraction, anhydrous Na2SO4 is dried, and vacuum rotary steam removes ethyl acetate, dry solid, receives
Rate 88%.m.p.:274-276℃.1H NMR(400MHz,DMSO-d6):δ 8.47 (s, 1H, ArH), 8.12 (d, J=8.7Hz,
1H, ArH), 8.04 (d, J=8.04Hz, 1H, ArH), 7.90 (m, 1H, ArH), 7.61-7.54 (m, 1H, ArH), 7.22 (s,
1H,ArH),7.09(s,1H,ArH),4.01(m,2H,-OCH2 CH2CH2N-),3.89(s,3H,-OCH3),2.58(m,4H,-CH2 NHCH2 CH2CH2O-),2.48(m,2H,-CH2COO),2.03–1.91(m,4H,-OCH2 CH2 CH2N-,-CH2 CH2 CH2-)
.ESI-MS:m/z calcd found 436.20[M+H]+.
Embodiment 10~11 is the part pharmacodynamic experiment of 4~9 compound of embodiment
Wherein：R1It is expressed as aligning cyano group, R2It is expressed as caproyl and butyric acid base.
Embodiment 10
In-vitro Inhibitory Effect of the compound to five kinds of tumor cell proliferations shown in formula (I).
Benzo pyridine compound involved in the present invention is the micromolecular inhibitor using EGFR-TK as action target spot, is adopted
Tumour cell increment suppression is detected with mtt assay：The tumor cell inoculation of exponential phase is entered in 96 well culture plates
Row is cultivated, and experimental group adds 0.1~100 μM of compound involved in the present invention after 24h, and each concentration sets 5 multiple holes, together
When blank control wells group (acellular) and negative control hole group is set, the complete medium of addition same volume in control wells group,
Using clinical medicine Gefitinib and Erlotinib as positive control medicine.After cultivating 72h, MTT (5mg/mL) 10 μ is added per hole
L, stand 4h at 37 DEG C, add 10%SDS solution 100 μ L, continue to place 10h at 37 DEG C, fully after dissolving, using 650nm as
Reference wavelength, its absorbance OD values are determined under 570nm, and calculate cell proliferation inhibition rate and its IC50Value, experimental result such as table
Shown in 1.
Embodiment 11
In-vitro Inhibitory Effect of the compound to EGFR-TK shown in formula (I).
Benzo pyridine compound of the present invention is the micromolecular inhibitor using EGFR-TK as action target spot, is used
ELISA method detects to EGFR-TK external inhibitory activity：Under optimal enzymatic reaction condition, to compound shown in formula (I)
The middle preferable I a-2 compounds of antitumor activity carry out the measure of the external inhibitory activity of EGFR-TK, while set marketed drug
Gefitinib is positive control medicine, calculates its inhibiting rate and its IC50Value.Experimental result is shown in Table shown in 2 and Fig. 1.
The suppression tumor cell proliferation of section Example compound and positive control medicine shown in the formula of table 1 (I) is lived
Property test result
a The IC50values are reported as means of at least three independent
experiments run in triplicate per concentration,and SD<10%.
The formula of table 2 (I) illustrated embodiment compound and positive control medicine are tested the external inhibitory activity of EGFR-TK
As a result
a Date are expressed as mean±SD of three independent experiments.Hig
hly significant differences vs the control were considered at**P<0.01。
Claims (8)
1. one kind has the substitution benzo pyridine compound or pharmaceutically acceptable salt thereof such as following formula (I), solvate, contains the chemical combination
The pharmaceutical composition of thing or its officinal salt, its architectural feature are：
Wherein：R1It is expressed as cyano group or halogeno-group；R2It is expressed as carboxylic acid group and its carboxylate group.
2. compound (I) according to claim 1 or its officinal salt, solvate, containing the compound or its can medicine
With the pharmaceutical composition of salt, its architectural feature is：Wherein R1The more preferably monosubstituted cyano group of 2-, 3- and 4- position；R2More preferably
For caproyl and its carboxylate group, butyric acid base and its carboxylate group, carboxylate group are more preferably carboxylic acid sodium or potassium.
3. compound (I) according to claims 1 to 2 or its officinal salt, solvate, containing the compound or its can
The pharmaceutical composition of pharmaceutical salts, wherein described compound preferably is selected from：
6- (3- (4- ((4- cyano-phenyls) amino) -6- methoxyquinazoline hydrochloride base -7- propoxyl group) amino) caproic acid
6- (3- (4- ((3- cyano-phenyls) amino) -6- methoxyquinazoline hydrochloride base -7- propoxyl group) amino) caproic acid
6- (3- (4- ((2- cyano-phenyls) amino) -6- methoxyquinazoline hydrochloride base -7- propoxyl group) amino) caproic acid
4- (3- (4- ((4- cyano-phenyls) amino) -6- methoxyquinazoline hydrochloride base -7- propoxyl group) amino) butyric acid
4- (3- (4- ((3- cyano-phenyls) amino) -6- methoxyquinazoline hydrochloride base -7- propoxyl group) amino) butyric acid
4- (3- (4- ((2- cyano-phenyls) amino) -6- methoxyquinazoline hydrochloride base -7- propoxyl group) amino) butyric acid.
4. compound (I) according to claim 1 or its officinal salt, solvate, containing the compound or its can medicine
With the pharmaceutical composition of salt, wherein described officinal salt is characterised by compound selection shown in formula (I) with pharmaceutically may be used
The acid of receiving forms officinal salt：Hydrochloride, sulfate, phosphate and its similar salt；It is citrate, tosilate, hard
Resin acid salt and its similar salt.
5. compound (I) according to claim 1 or its officinal salt, solvate, containing the compound or its can medicine
With the pharmaceutical composition of salt, wherein the pharmaceutical composition containing the compound or pharmaceutically acceptable salt thereof be characterised by containing
Compound and pharmaceutical carrier any one of the Claims 1 to 4 for the treatment of effective dose.
6. compound (I) according to claim 1 or its officinal salt, solvate, containing the compound or its can medicine
With the pharmaceutical composition of salt, its preparation method is characterised by, described method comprises the following steps：
The cyano-aniline that compound shown in formula (II) substitutes with diverse location is reacted, and obtains chemical combination shown in formula (III)
Thing；Compound shown in formula (III) is reacted from different amino substituted carboxylic acids under KI or sodium iodide catalytic condition, is obtained
To compound shown in formula (I)；Or reacted in the basic conditions, obtain the carboxylate of compound shown in formula (I).
7. compound (I) according to claim 1 or its officinal salt, solvate, containing the compound or its can medicine
With the pharmaceutical composition of salt, the application in terms of molecular targeted antineoplaston medicine is prepared.
8. compound (I) according to claim 1 or its officinal salt, solvate, containing the compound or its can medicine
With the pharmaceutical composition of salt, the application in terms of molecular targeted antineoplaston liver cancer and lung-cancer medicament is prepared.
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| CN201710650870.7A CN107513040A (en) | 2017-08-02 | 2017-08-02 | Substitute the preparation of benzo pyridine compound and the application of molecular targeted anti-tumor medicine |
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| CN201710650870.7A CN107513040A (en) | 2017-08-02 | 2017-08-02 | Substitute the preparation of benzo pyridine compound and the application of molecular targeted anti-tumor medicine |
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| CN108727285A (en) * | 2018-05-25 | 2018-11-02 | 北京师范大学 | Increase bioactivity and its application of cyano-aniline base substituted quinazoline class compound |
| WO2021164793A1 (en) * | 2020-02-19 | 2021-08-26 | 郑州同源康医药有限公司 | Compound used as kinase inhibitor and use thereof |
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| WO2008033748A2 (en) * | 2006-09-11 | 2008-03-20 | Curis, Inc. | Quinazoline based egfr inhibitors containing a zinc binding moiety |
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| CN1343201A (en) * | 1999-03-15 | 2002-04-03 | 贝林格尔英格海姆法玛公司 | Bicyclic heterocycles, pharmaceutical compositions containing these compounds, and processes for preparing them |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108727285A (en) * | 2018-05-25 | 2018-11-02 | 北京师范大学 | Increase bioactivity and its application of cyano-aniline base substituted quinazoline class compound |
| WO2021164793A1 (en) * | 2020-02-19 | 2021-08-26 | 郑州同源康医药有限公司 | Compound used as kinase inhibitor and use thereof |
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