Bicyclic-fused heterogeneous ring compound, Preparation Method And The Use
Technical field
The invention belongs to medical art, be specifically related to a kind of Bicyclic-fused heterogeneous ring compound, its preparation method, pharmaceutical composition and the purposes for the preparation of antitumor drug thereof.
Background technology
Cancer has become a large chronic disease of serious harm human health at present.The people of annual suffers from cancer has 9,000,000 in the world according to statistics, and the patient dying from cancer is 6,000,000, almost just has a cancer death p.s..China's cancer year number of the infected, about 1,200,000, dies from the number of cancer up to more than 900,000, and patient to be treated more than 1,500,000, and has the trend risen year by year.Therefore cancer has now become the second largest killer being only second to cardiovascular disorder.Clinical treatment tumour, generally adopts operation, radiotherapy, the large therapy of chemotherapy three.Though embolic chemotherapy is comparatively quick, curative ratio is very low.The many cancer therapy drugs of clinical discovery exist significantly to damage and the toxic side effect of normal body simultaneously, such as mutagenesis and genetoxic.Therefore, to find effectively and the cancer therapy drug with less body injury and toxic side effect has become the focus of new drug research.
Summary of the invention
The object of this invention is to provide a kind of Bicyclic-fused heterogeneous ring compound or its pharmacy acceptable salt.
Another object of the present invention is to provide the preparation method of a kind of Bicyclic-fused heterogeneous ring compound or its pharmacy acceptable salt.
Another object of the present invention is to provide a kind of pharmaceutical composition, and it comprises Bicyclic-fused heterogeneous ring compound of the present invention or its pharmacy acceptable salt, and pharmaceutically acceptable carrier.
A further object of the invention is to provide Bicyclic-fused heterogeneous ring compound or its pharmacy acceptable salt is preparing the application in antitumor drug, and described tumour is small cell lung cancer, mammary cancer, liver cancer, colorectal carcinoma, glioblastoma, brain tumor, leukemia or carcinoma of the pancreas particularly.
The present invention relates to Bicyclic-fused heterogeneous ring compound or its pharmacy acceptable salt of general formula (I) structure:
Wherein:
R
1for halogen, cyano group, hydroxyl, nitro, amino, C
1-4alkyl, C
1-4thiazolinyl, C
1-4alkynyl or C
1-4alkoxyl group;
A and C is C independently
6-10aryl or C
3-8heteroaryl, optionally by halogen, cyano group, hydroxyl, C
1-4alkyl, amino, nitro, carboxyl or C
1-4alkoxyl group replaces;
B is C
3-8heterocyclylalkyl, optionally by halogen, cyano group, hydroxyl, amino, nitro, C
1-4alkoxyl group, C
1-4alkyl ,-CONHR or COOR replace; Wherein R is C
1-4alkyl.
in another preferred embodiment, halogen is preferably fluorine, chlorine or bromine;
in another preferred embodiment, C
1-4
alkyl is preferably methyl, ethyl, n-propyl, sec.-propyl or butyl;
in another preferred embodiment, C
6-10
aryl is preferably phenyl, naphthyl or tetralyl;
in another preferred embodiment, C
3-8
heteroaryl be preferably pyrryl, pyrazolyl, pyridyl, pyridazinyl, thiazolyl,
azoles base, different
azoles base, thiadiazolyl group, quinazolyl, benzothiazolyl, benzimidazolyl-, indolizinyl, indazolyl, indyl or quinolyl;
in another preferred embodiment, C
3-8
heterocyclylalkyl is preferably Pyrrolidine base, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, pyridazinyl, pyrazinyl, homopiperazine base or homopiperidinyl.
The present invention also comprises above-claimed cpd pharmacy acceptable salt.The pharmaceutical salts of suitable of the present invention Bicyclic-fused heterogeneous ring compound is the acid salt of the compounds of this invention that alkalescence is enough strong, such as, with mineral acid or organic acid list or two acid salt, described acid can be hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, trifluoroacetic acid, Citric Acid, toxilic acid, tartrate, fumaric acid, methylsulfonic acid or 4-toluenesulphonic acids etc.
Described Bicyclic-fused heterogeneous ring compound is:
General formula of the present invention (I) compound is synthesized by following steps:
Wherein, R
1, A, B, C definition with mentioned above.
Be the medicine preventing and/or treating tumour prepared by effective constituent with the compound shown in general formula (I) or its pharmacy acceptable salt, also belong to protection scope of the present invention.
The described tumour medicine that prevents and/or treats imports body as muscle, intracutaneous, subcutaneous, vein, mucosal tissue by the method that injection, injection, collunarium, eye drip, infiltration, absorption, physics or chemistry mediate; Or to be mixed by other materials or to import body after wrapping up.
When needing, one or more pharmaceutically acceptable carriers can also be added in said medicine.Described carrier comprises the thinner, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier, lubricant etc. of pharmaceutical field routine.
That prepares with general formula (I) compound or its pharmacy acceptable salt prevents and/or treats tumour medicine and can make the various ways such as injection liquid, tablet, pulvis, granule, capsule, oral liquid, paste, creme.The medicine of above-mentioned various formulation all can be prepared according to the ordinary method of pharmaceutical field.
Embodiment
embodiment 1:the synthesis of compound 1
The synthesis of compound 1a:
By 18.4g(100mmol) the chloro-5-methyl of 7--[1,2,4] triazole [4,3-c] pyrimidine-3-amine is dissolved in 300mL ethanol, and add the hydrazine hydrate of 10mL85%, under room temperature, vigorous stirring reacts 14 hours.Filter to obtain white solid, obtain compound as white solid 1a18.4g, yield 95% with dry after washing with alcohol.
MS(m/z):180.10[M+H]
+
The synthesis of compound 1b:
By 17.6g(100mmol) benzene sulfonyl chloride is dissolved in 20mL methylene dichloride, is cooled to 0 DEG C, is slowly added dropwise to 10mL pyridine and obtains clarified colorless liquid; To 14.4g(40mmol be dissolved with again) the 200mL dichloromethane solution of compound 1a slowly joins in reaction system, at room temperature stirs and spend the night.Decompression and solvent recovery, column chromatography for separation obtains compound as white solid 1b5.8g, yield 46%.
MS(m/z):320.09[M+H]
+
The synthesis of compound 1c:
By compound 1b3.2g(10mmol) be dissolved in 20ml methylene dichloride under nitrogen protection; drip CDI1.8g(11mmol) methylene dichloride (10ml) solution; after reacting 16h under normal temperature; drip 1-methyl piperidine-4-amine 1.1g(10mmol) methylene dichloride (10ml) solution; continue to stir 18h, adularescent precipitation generates.Suction filtration, filter cake washed with dichloromethane 2 × 10ml.Vacuum-drying, obtains product.Use tetrahydrofuran (THF) recrystallization.Obtain compound as white solid 1c4.3g, yield 94%.
MS(m/z):460.18[M+H]
+
The synthesis of compound 1:
By 2.3g(5mmol) dry compound 1c and 3.2g phenyl aldehyde mixed dissolution be in 20ml glacial acetic acid, add the sodium acetate of catalytic amount, 130 DEG C of back flow reaction 8 hours, decompression remove portion acetic acid, be cooled to 0-5 DEG C, suction filtration, solid is with after 15ml washed with diethylether twice, drying, obtains white powdery solids.Thick product methyl alcohol/chloroform (volume ratio 1/50 to 1/10) by purification by silica gel column chromatography, obtains compound as white solid 1,2.4g, yield 89% as eluent.
MS(m/z):548.21[M+H]
+
Ultimate analysis: theoretical value/measured value, C (57.02/57.08), H (5.34/5.28), N (23.02/23.10), O (5.86/5.80), S (5.86/5.84).
1HNMR(400MHz,CDCl
3)δ9.99(s,1H),7.86-7.33(m,10H),6.98(d,2H),6.27(s,1H),6.0(s,1H),4.0(s,1H),3.60(m,1H),2.50(t,4H),2.26(s,3H),2.0(s,1H),1.85(m,4H)。
embodiment 2:the synthesis of compound 2
Method, with embodiment 1, replaces phenyl aldehyde unlike with 1-naphthaldehyde, obtains light yellow solid.Yield: 72%.
MS(M/Z):598.23[M+H]
+
Ultimate analysis: theoretical value/measured value, C (60.29/60.20), H (5.23/5.29), N (21.09/21.18), O (8.03/7.93), S (5.36/5.40).
embodiment 3:the synthesis of compound 3
Method, with embodiment 1, unlike replacing 4-methyl piperidine-1-amine with 4-methylpiperazine-1-amine, obtains white solid.Yield: 70%.
MS(M/Z):549.21[M+H]
+
Ultimate analysis: theoretical value/measured value, C (54.73/54.63), H (5.14/5.19), N (25.53/25.58), O (8.75/8.71), S (5.84/5.88).
embodiment 4:the synthesis of compound 4
Method, with embodiment 1, replaces benzene sulfonyl chloride unlike with Tosyl chloride, obtains white solid.Yield: 70%.
MS(M/Z):562.23[M+H]
+
Ultimate analysis: theoretical value/measured value, C (57.74/57.70), H (5.56/5.51), N (22.44/22.53), O (8.55/8.45), S (5.71/5.81).
embodiment 5-12:following compound 5-12 is synthesized according to similar approach
embodiment 13:anticancer experiment in vitro
Adopt classical cytotoxic activity vitro detection method mtt assay, test sample is to the cell proliferation toxicity of the human tumor cells of vitro culture.
During experiment, sample adds DMSO, is diluted to desired concn with RPMI1640 substratum, ultrasonic, is partly dissolved, and sample segment solution is suspension, with nutritive medium successively doubling dilution.
Cell strain: small cell lung cancer NCI-H446, glioblastoma U-251, colon cancer cell HCT116, HL-60 cells.
Experimental technique:
Experiment adopts conventional MTT detection method.Inoculating cell: cell in vegetative period of taking the logarithm, adds the RPMI-1640 nutrient solution containing 10% embryo bovine serum, cell dilution is become single cell suspension after the trysinization of 0.25%, and adjustment cell count, is inoculated in 96 orifice plates, every hole 100 μ L.Postvaccinal cell put 37 DEG C, cultivate 24 hours in 5% CO2gas incubator.Dosing: test medicine RPMI-1640 nutrient solution is carried out doubling dilution, configures 6 concentration altogether.In 96 orifice plates, add survey product liquid, 100 μ L/ holes, each sample concentration establishes 4 multiple holes, and control group establishes 5 multiple holes, and sample concentration is 1 × 10-4mol/L.The RPMI-1640 nutrient solution of control group containing 10% foetal calf serum supplies residual volume, makes reaction volume be 200 μ L/ holes.After application of sample, cell put 37 DEG C, continue cultivation 68 hours in 5% CO2gas incubator.Add MTT: abandon supernatant, add MTT5mg/ml, dissolve with PBS, every hole adds 10 μ L.Put 37 DEG C of continuation cultivations to take out after 4 hours.Survey OD value: the supernatant liquor in reject 96 orifice plate, every hole adds DMSO150 μ L.Measure OD value at microplate reader 570nm, calculate inhibitory rate of cell growth with following formula:
Inhibiting rate=[(1-medication group mean OD value/control group mean OD value)] × 100%
Experimental result:
To the restraining effect of the tumour cell of vitro culture
The power of the Tumor suppression activity of the compound in table 2 represents horizontally through " A ", " B ", " C ", " D ", wherein:
A represents that inhibiting rate is more than 70%;
B represents that inhibiting rate is more than 60 to being less than 70%;
C represents that inhibiting rate is more than 50 to being less than 60%;
D represents that inhibiting rate is more than 40 to being less than 50%.
embodiment 14:urogastron (EGFR)-Tyrosylprotein kinase experiment
Above test data shows, the Bicyclic-fused heterogeneous ring compound of the present invention has very high growth inhibitory activity to tumor cell, especially has significant inhibition to the growth of the tumour cell of EGFR high expression level.
Anti-tumor in vivo is tested, and toxicity test, the preliminary experiment of pharmacokinetics etc. shows, the compounds of this invention has excellent characteristic in above-mentioned.