CN109758422A - A kind of small molecular protein kinase inhibition remover liquid injection and preparation method thereof - Google Patents
A kind of small molecular protein kinase inhibition remover liquid injection and preparation method thereof Download PDFInfo
- Publication number
- CN109758422A CN109758422A CN201811553666.4A CN201811553666A CN109758422A CN 109758422 A CN109758422 A CN 109758422A CN 201811553666 A CN201811553666 A CN 201811553666A CN 109758422 A CN109758422 A CN 109758422A
- Authority
- CN
- China
- Prior art keywords
- injection
- substituted
- small molecular
- formula
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to field of medicinal chemistry, a kind of small molecular protein kinase inhibition remover liquid injection and preparation method thereof is disclosed.The injection contains medicine activity component, sodium chloride and water for injection, and the medicine activity component is Isosorbide-5-Nitrae-diamines naphthalene derivatives and its pharmaceutically acceptable salt, solvate shown in formula (I).The small molecular protein kinase inhibition remover liquid injection can inhibit small molecular protein kinases, can be used for treating and/or preventing in mammal in epidermal growth factor recipient tyrosine kinase related disease, it may also be used for treatment tumor disease.
Description
Technical field
The present invention relates to field of medicinal chemistry, and in particular to a kind of small molecular protein kinase inhibition remover liquid injection and its preparation
Method.
Background technique
Clinic and basic medical research in recent years is as a result, it was confirmed that the occurrence and development and transfer of tumour depend on new vessels
Formation.Tumor Angiongesis is the result of the interactions such as tumour cell, vascular endothelial cell, Vessel extracellular matrix.Its
The biological function of medium vascular endothelial growth factor VEFG (vascular endothelial growth factor) is raw in blood vessel
Key position is in.
Most cells growth factor receptors contain the peptide sequence of tyrosine kinase, visible different junket ammonia in many tumours
The overexpression or activation of acid kinase receptor.According to the feature in the similitude and its structure of peptide sequence, these receptors are divided again
At several families: 1, Epidermal Growth Factor Receptor Family, including EGFR, HER-2, HER-3, HER-4 etc., the high table of this receptoroid
Up to being common in epithelial cell tumour；2, Insulin Receptor Family, including insulin receptor, insulin-like growth factor receptor
(IGF-R) and insulin-related receptor (IRR) etc. the high expression of this receptoroid, is common in leukemia；3, platelet-derived life
Growth factor receptor body family (PDGFR), including PDGFR- α, PDEFR- β, CSF-1R, c-Kit etc., this receptoroid is in brain tumor, blood
Common high expression in cancer；4, fibroblast growth factor acceptor (FGFR), including FGFR-1, FGFR-2, FGFR-3, FGFR-4
Deng this receptoroid its important function in terms of angiogenesis；5, vascular endothelial growth factor receptor (VEGFR), including
VEGFR-1, VEGFR-2, VEGFR-3 are the important positivity regulatory factors of angiogenesis.
VEFG is the growth factor for mainly acting on vascular endothelial cell, has and promotes endothelial cell proliferation, increases micro- blood
The multiple functions such as pipe permeability, induction of vascular generation.The formation and development of tumour can substantially be divided into two stages, i.e. tumour cell
The clonal expansion stage and vascularization then promote stage of tumour continued propagation.VEGF acts on itself existing blood
Pipe network endothelial cell makes it break up and form new blood vessel.New blood vessel is not only that the mass exchange of tumour cell provides basis, also
Can some cell factors of paracrine promote the proliferation of tumour cells；Simultaneously because the structural pipe wall of new vessels lacks integrality,
It is connected between endothelial cell loosely, basilar memebrane thickness is different, be broken or defect, tumour cell easily enter lumen of vessels and blood occur
Row invasion and transfer.Thus the growth of VEGF and tumour and transfer relationship are close.VEGF can be in most tissues of healthy human body
Detection, but expression quantity is little, then occurs high expression in many tumours (especially solid tumor), such as: liver cancer, brain tumor, mammary gland
In cancer and renal carcinoma tissue.Since the growth and transfer of solid tumor are to the dependence of new vessels, VEGF is to block solid tumor
The more satisfactory target area of vascularization.VEGFR is that a kind of diffusible blood vessel endothelium specificity mitogen and blood vessel are raw
Growth factor receptor body plays a crucial role during physiological and pathological vascularization, can inhibit endothelial cell apoptosis.The family
Including VEGFR-1, VEGFR-2, VEGFR-3.VEGFR-2 is caused to form two after generally believing VEGF in conjunction with VEGFR-2 at present
Aggressiveness lures tyrosine kinase mediated phosphorylation into, and one-step activation associated downstream signal of going forward side by side goes to access.
In recent years, a variety of drug for targeting VEGFR such as Sunitinib, Sorafenib, Pazopanib etc. went through to use
In the treatment of various tumours.Although these angiogenesis inhibitors have a very big advantage, practical application there are still
Partial tumors are strong to the newborn dependence of blood vessel, drug resistance, adverse reaction caused by the compensatory of mutation and tumor signal transduction
And the problems such as toxicity.Therefore stronger, the active smaller small molecular protein kinase inhibition of higher and toxicity of selectivity is further developed
Agent is appointed so very necessary.
Summary of the invention
The object of the present invention is to provide a kind of small molecular protein kinase inhibition remover liquid injections and preparation method thereof.
One aspect of the present invention provides a kind of small molecular protein kinase inhibition remover liquid injection, which contains pharmaceutical activity
Component, sodium chloride and water for injection, the medicine activity component are Isosorbide-5-Nitrae-diamines naphthalene derivatives and its medicine and pharmacology shown in formula (I)
Upper acceptable salt, solvate,
Wherein, L1And L2It each is selected from O, S and NH；
N is 0,1,2,3,4 or 5；
R1Selected from hydrogen, C1-C8Alkyl and C3-C7Naphthenic base；
R2Selected from hydrogen, C1-C8Alkyl, substituted C1-C8Alkyl, C3-C7Naphthenic base, substituted C3-C7Naphthenic base, virtue
Base, substituted aryl, heteroaryl and substituted heteroaryl；
R3Selected from hydrogen, C1-C8Alkyl and C3-C7Naphthenic base；
R4Selected from C3-C7Heterocyclylalkyl, substituted C3-C7Heterocyclylalkyl, aryl, substituted aryl, heteroaryl and by
Substituted heteroaryl.
Preferably, in formula (I), R1For hydrogen, R2Selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl
Base.
Preferably, in formula (I), L O, n 3, R3Selected from hydrogen, methyl and ethyl, R4Selected from morpholine, piperidines, pyrrolidines
And piperazine.
Preferably, the Isosorbide-5-Nitrae-diamines naphthalene derivatives structural formula are as follows:
Preferably, the concentration of the medicine activity component is 0.1-2mg/ml, more preferably 0.2-0.8mg/ml.
Preferably, sodium chloride 0.3-2g is contained in every 100ml injection.
The present invention also provides a kind of method for preparing above-mentioned small molecular protein kinase inhibition remover liquid injection, this method includes
Following steps:
(1) match liquid: the medicine activity component, sodium chloride and water for injection are stirred to being completely dissolved；
(2) aseptic filtration: refined filtration is carried out with the medical fluid that sterilizing filter prepares step (1)；
(3) encapsulating: by the medical fluid after aseptic filtration by labelled amount encapsulating in colourless low borosilicate ampoule；
(4) it sterilizes: using 110-130 DEG C of wet-hot steam sterilizing 10-20min.
Preferably, the sterilizing filter be 0.45um polytetrafluoroethylene (PTFE) filter core, 0.22um polytetrafluoroethylene (PTFE) filter core,
The sterilizing filter that 0.22um polytetrafluoroethylene (PTFE) filter core is sequentially connected in series.
It is 1,4- diamines naphthalene derivatives and its pharmaceutically acceptable salt included in injection of the present invention, molten
Object is closed in agent can be used as small molecular protein kinase inhibitor, can be used for treating and/or preventing in mammal in epidermal growth factor
Receptor tyrosine kinase related disease, it may also be used for treatment tumor disease.
Specific embodiment
Detailed description of the preferred embodiments below.It should be understood that described herein specific
Embodiment is merely to illustrate and explain the present invention, and is not intended to restrict the invention.
The endpoint of disclosed range and any value are not limited to the accurate range or value herein, these ranges or
Value should be understood as comprising the value close to these ranges or value.For numberical range, between the endpoint value of each range, respectively
It can be combined with each other between the endpoint value of a range and individual point value, and individually between point value and obtain one or more
New numberical range, these numberical ranges should be considered as specific open herein.
Small molecular protein kinase inhibition remover liquid injection of the present invention contains medicine activity component, sodium chloride and injection
Water, wherein the medicine activity component be Isosorbide-5-Nitrae-diamines naphthalene derivatives and its pharmaceutically acceptable salt shown in formula (I),
Solvate,
Wherein, L1And L2It each is selected from O, S and NH, preferably O；
N is 0,1,2,3,4 or 5；
R1Selected from hydrogen, C1-C8Alkyl and C3-C7Naphthenic base；
R2Selected from hydrogen, C1-C8Alkyl, substituted C1-C8Alkyl (such as halogenated alkyl), C3-C7Naphthenic base, substituted C3-
C7Naphthenic base (such as halogenated cycloalkyl), aryl, substituted aryl (such as halogenated aryl), heteroaryl and substituted heteroaryl
(such as haloheteroaryl)；
R3Selected from hydrogen, C1-C8Alkyl and C3-C7Naphthenic base；
R4Selected from C3-C7Heterocyclylalkyl, substituted C3-C7It is Heterocyclylalkyl (such as halogenated heterocycloalkyl), aryl, substituted
Aryl (such as halogenated aryl), heteroaryl and substituted heteroaryl (such as haloheteroaryl).
In a preferred embodiment, in formula (I), R1For hydrogen, R2Selected from aryl, substituted aryl, heteroaryl
With substituted heteroaryl.
In another preferred embodiment, in formula (I), L O, n 3, R3Selected from hydrogen, methyl and ethyl, R4Choosing
From morpholine, piperidines, pyrrolidines and piperazine.
In a particular embodiment, the Isosorbide-5-Nitrae-diamines naphthalene derivatives structural formula are as follows:
The preparation method of 1,4- diamines naphthalene derivatives shown in formula (I) may comprise steps of:
(a) formula (1) compound represented carries out dealkylation, obtains formula (2) compound represented；
(b) formula (2) compound represented carries out nucleophilic substitution, obtains formula (3) compound represented；
(c) in the presence of the hydrogen peroxide tert-butyl alcohol and potassium hydroxide, hydroxyl is introduced in formula (3) compound represented,
Obtain formula (4) compound represented；
(d) substitution reaction occurs for formula (4) compound represented, obtains formula (5) compound represented；
(e) nucleophilic substitution reaction occurs for formula (5) compound represented and amino substituents, obtains changing shown in formula (6)
Close object；
(f) formula (6) compound represented carries out hydro-reduction reaction, obtains target compound；
Wherein, X is halogen, L1、L2、n、R1、R2、R3And R4Define it is identical as definition above.
In step (a), it is preferable that the dealkylation carries out in the presence of L-Methionine, and solvent used is
Methanesulfonic acid, reaction temperature are 85-95 DEG C.
In step (b), it is preferable that the nucleophilic substitution carries out under alkaline condition, reaction temperature 75-85
℃。
Preferably, the reaction of step (c) carries out in the presence of the hydrogen peroxide tert-butyl alcohol and potassium hydroxide, and reaction temperature is
0±5℃。
In a specific embodiment, the process route of Isosorbide-5-Nitrae-diamines naphthalene derivatives preparation method shown in formula (I)
It is as follows:
Specific preparation process includes: with 6,7- dimethoxy -1- nitronaphthalene for starting material, is existed in L-Methionine
Under, the demethylation in methylsulphur sour solvent, then Williamson reaction occurs under alkaline condition with 3- chloropropyl morpholine, obtains
Mesosome introduces a hydroxyl in the presence of hydrogen peroxide tert-butyl alcohol and potassium hydroxide, then substitution reaction occurs with phosphorus pentachloride, connects
Affine substitution occurs with various amino substituents again, then obtain target compound using hydro-reduction.
Term explanation
" alkyl " of the invention refers to linear or branched saturated hydrocarbon base, preferably C1-C6 alkyl, is further preferably
C1-C3 alkyl, suitable C1-C3 alkyl are methyl, ethyl, propyl, isopropyl.
" halogen " of the invention refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, most preferably chlorine.
" halogenated alkyl ", " halogenated cycloalkyl ", " halogenated aryl ", " haloheteroaryl " and " halogenated heterocyclic alkane of the invention
Base " refers respectively to the alkyl at least replaced by a halogen, naphthenic base, aryl, heteroaryl and Heterocyclylalkyl.The halogenated alkyl
It such as can be halogenated C1-C6 alkyl.
" solvate " of the invention refers to associate with solvent, the compound usually to be associated by solvolysis reaction
Form.Conventional solvent includes water, methanol, ethyl alcohol, acetic acid, DMSO, THF, ether etc..Suitable solvate includes pharmaceutically
Acceptable solvate and further include both stoichiometric solvates and non-chemical dose solvate.If it is
Water, then solvate is referred to as hydrate, such as monohydrate, dihydrate, trihydrate etc..
" pharmaceutically acceptable salt " of the invention refers to that those are suitable for and people in the range of reasonable medical judgment
The tissue of class and lower animal contact without unsuitable toxicity, irritation, allergic reaction etc. and with reasonable benefit/wind
The salt that danger ratio matches.
" tumor disease " of the invention includes but is not limited to acoustic neurinoma, gland cancer, adrenal, cancer of anus, angiosarcoma
(such as lymphangioendothelial sarcoma, lymphangioendothelial sarcoma, angiosarcoma), appendix cancer, benign monoclonal gammopathy, bile duct
Cancer, bladder cancer, breast cancer, the cancer of the brain, bronchiolar carcinoma, carcinoid tumor, cervical carcinoma, choriocarcinoma, chordoma, colorectal cancer, knot
Form tissue cancer, cancer of the esophagus, cancer eye, gastric cancer, head-neck carcinoma, carcinoma of mouth, throat cancer, hematopoietic system cancer (such as leukaemia: acute
Lymphocytic leukemia ALL, acute myelocytic leukemia AML, chronic granulocytic leukemia CML and chronic lymphatic
Cell leukemia CLL), lymthoma, kidney, liver cancer, lung cancer (Small Cell Lung Cancer SCLC, non-small cell lung cancer NSCLC), marrow
Hyperplasia abnormal syndrome (MDS), myeloproliferative illness (MPD) (chronic granulocytic leukemia CML, chronic neutrophil leucocyte
Leukaemia CNL, eosinophilia syndrome HES), osteosarcoma, oophoroma, cancer of pancreas, prostate cancer, thyroid cancer,
Carcinoma of vagina etc..
In injection of the present invention, the concentration of the medicine activity component can be 0.1-2mg/ml, preferably
0.2-0.8mg/ml。
In injection of the present invention, it is preferable that contain sodium chloride 0.3-2g in every 100ml injection, more preferably
For 0.5-1.2g.
The present invention also provides the preparation method for preparing above-mentioned small molecular protein kinase inhibition remover liquid injection, this method includes
Following steps:
(1) match liquid: the medicine activity component, sodium chloride and water for injection are stirred to being completely dissolved；
(2) aseptic filtration: refined filtration is carried out with the medical fluid that sterilizing filter prepares step (1)；
(3) encapsulating: by the medical fluid after aseptic filtration by labelled amount encapsulating in colourless low borosilicate ampoule；
(4) it sterilizes: using 110-130 DEG C of wet-hot steam sterilizing 10-20min.
In a particular embodiment, the sterilizing filter is 0.45um polytetrafluoroethylene (PTFE) filter core, 0.22um polytetrafluoro
The sterilizing filter that ethylene filter core, 0.22um polytetrafluoroethylene (PTFE) filter core are sequentially connected in series.
The present invention will be described in detail by way of examples below, but scope of protection of the present invention is not limited thereto.
Preparation example 1
(1) 3- methoxyl group -5- nitro-beta naphthal is prepared
6,7- dimethoxy -1- nitronaphthalene (4.66g, 20mmol) and L-Methionine (2.98g, 20mmol) are dissolved in
In the methane sulfonic acid (400mmol) of 38.4g, 90 DEG C of oil baths are stirred to react 8h under the conditions of being heated at reflux, and TLC detects fully reacting
Afterwards, it is emerged with saturated sodium bicarbonate solution neutralization reaction to bubble-free, pH test paper is detected as neutral or alkalescent, then with acetic acid second
Ester aqueous phase extracted 3 times, combined ethyl acetate phase, saturated sodium-chloride is washed three times, and anhydrous magnesium sulfate dries, filters, evaporated under reduced pressure,
Column chromatography for separation obtains yellow powdery solid (1.18g, yield: 27%).
(2) 4- (3- ((3- methoxyl group -5- nitronaphthalene -2-) oxygen) propyl) morpholine is prepared
By 3- methoxyl group -5- nitro-beta naphthal (2.19g, 10mmol), Anhydrous potassium carbonate (1.80g, 13mmol) and anhydrous
Potassium iodide (0.166g, 1mmol) is dissolved in 25mlN, in dinethylformamide (DMF), after mixing evenly, is added into reaction solution
80 DEG C of oil baths of 3- chloropropyl morpholine (1.80g, 11mmol) are stirred to react 3h under the conditions of being heated at reflux, after TLC detects fully reacting,
It is cooled to room temperature, 150ml distilled water is added into reaction solution, then this water phase is extracted with ethyl acetate 3 times, combined ethyl acetate,
Three times, saturated sodium-chloride water solution is washed three times, and anhydrous magnesium sulfate dries, filters, and filtrate decompression is evaporated, and column chromatographs to obtain yellow for washing
Pulverulent solids (3.18g, yield: 92%).
(3) 6- methoxyl group -7- (3- morpholine propyl oxygroup) -4- nitro -1- naphthols is prepared
4- (3- ((3- methoxyl group -5- nitronaphthalene -2-) oxygen) propyl) morpholine (1.73g, 5mmol) is dissolved in 13ml dimethyl
In sulfoxide (DMSO), the potassium hydroxide (1.2g, 20mmol) of dissolution in 5 ml of water is added into this solution under the conditions of 0-5 DEG C,
Stirring after five minutes, the hydrogen peroxide tert-butyl alcohol (0.54g, 6mmol) of 2mlDMSO is added into solution.After being stirred at room temperature 6 hours,
Reaction solution is poured slowly into 100ml water, methylene chloride aqueous phase extracted three times, merges methylene chloride phase, and saturated sodium-chloride is water-soluble
Liquid is washed three times, and anhydrous sodium sulfate dries, filters, and is evaporated, column chromatography for separation, obtains yellow powder (yield: 78%).
(4) 4- (3- (the chloro- 3- methoxyl group -5- nitronaphthalene -2- oxygen of 8-) propyl) morpholine is prepared
6- methoxyl group -7- (3- morpholine propyl oxygroup) -4- nitro -1- naphthols (5.79g, 16mmol) is dissolved in phosphorus oxychloride
In (45ml, 490mmol), it is heated to reflux stirring 3h.Cooling, the sodium carbonate that reaction solution is slowly poured into 2mol/L under ice-water bath is molten
It in liquid (450ml), stirs, filters, filter cake is washed with warm water, is dried to obtain yellowish solid (yield: 65%).
(5) 4- fluorophenyl-(6- methoxyl group -7- (3- morpholine propoxyl group)) -4- nitro naphthalene -1- ammonia
By para-fluoroaniline (1.78g, 16mmol), 4- (3- (the chloro- 3- methoxyl group -5- nitronaphthalene -2- oxygen of 8-) propyl) morpholine
In (3.80g, 10mmol) and potassium carbonate (4.1g, 30mmol) solution 50mLDMF, 60 DEG C are heated with stirring to, 5h is reacted, is cooled to
Room temperature, filtering, solution refined with (DCM/MeOH=20:1), obtain yellow solid product 1.54g (yield: 61%), core
Magnetic hydrogen modal data is as follows.
1H-NMR(400MHz,DMSO-d6), 1.80-1.85 (m, 2H)；2.25-2.38 (t, 2H)；2.32-2.49 (t,
4H)；3.52-3.62 (t, 4H)；3.75 (s, 3H)；4.00 (s, 1H)；6.22-6.30 (dd, 1H)；6.32-6.39 (dd, 1H)；
6.42-6.49 (d, 2H)；6.75-6.89(d,2H)；6.98(s,2H).
(6) N ' -4- fluorophenyl-(6- methoxyl group -7- (3- morpholine propoxyl group)) -4- naphthalene -1,4- diamino
By 4- fluorophenyl-(6- methoxyl group -7- (3- morpholine propoxyl group)) -4- nitro naphthalene -1- ammonia (0.455g, 1mmol)
It is dissolved in 10ml methanol, 0.1g palladium carbon is added into solution at room temperature.The room temperature under the hydrogen atmosphere of ten atmospheric pressure
Stirring 12 hours, is filtered to remove palladium carbon with diatomite after having reacted, and washed three times with methanol, and column chromatography obtains compound 1,
White solid, yield 82%, nucleus magnetic hydrogen spectrum data are as follows.
1H-NMR(400MHz,DMSO-d6), 1.81-1.86 (m, 2H)；2.28-2.34 (t, 2H)；2.39-2.51 (t,
4H)；3.59-3.67 (t, 4H)；3.72 (s, 3H)；4.01 (s, 1H)；4.06 (s, 2H)；6.25-6.31 (dd, 1H)；6.35-
6.38 (dd, 1H)；6.45-6.48 (d, 2H)；6.74-6.86(d,2H)；6.83(s,2H).
According to method similar to Example 1, available compound 2-6, the structural formula and its nuclear-magnetism of these compounds
Hydrogen modal data is as shown in the table.
Test case 1
External target compound carries out the external activity experiment for inhibiting cancer cell multiplication.
The external activity experiment for inhibiting cancer cell multiplication is carried out to target compound, the results are shown in Table 1.
Material: MD-MBA-231 breast carcinoma cell strain, Methyl thiazoly tetrazolium assay MTT, 10% fetal calf serum, 96 orifice plates.
Method:
Cell culture: MD-MBA-231 breast carcinoma cell strain uses the RPMI1640 culture solution containing 10% fetal calf serum to blow and beat
Kind enter in culture bottle after uniformly, in 37 DEG C, 5%CO2It is incubated in saturated humidity cell incubator, grows to 70%- to cell density
With being passed on after 0.25% trypsin digestion when 90%.
Cell growth detection (mtt assay): MD-MBA-231 cell suspension is adjusted to 5 × 104/mL, is inoculated in 96 holes respectively
Plate (100 hole μ L/), 5000 cells/wells.After bed board 4h, the culture medium of 100 μ L compounds containing various concentration is added in every hole,
Final compound concentration in hole is set to be respectively as follows: 100,50,25,12.5,6.25 μ g/mL, each concentration sets four multiple holes, cell is not added
Hole reading when as blank control, the hole of compound is not added as negative control in refinement born of the same parents, and Sorafenib is positive as compound
Property control.In 37 DEG C, 5%CO2The MTT dyeing liquor of 10 μ L0.5% is added in middle incubation 48h, every hole, continues after being incubated for 4h,
2500rpm is centrifuged 12min, then abandons culture solution in plate hole, and DMSO solution, 100 holes μ L/ are added.In 570nm in microplate reader
Place measures the absorption value OD value in every hole, and inhibitory rate of cell growth is calculated as follows:
Each compound is obtained using Origin7.5 software matched curve according to the concentration of compound and corresponding inhibiting rate
IC50。
Table 1
It can be seen that the compound of the present invention to the IC of MD-MBA-231 breast cancer cell by the result of table 150It is drawn with rope
Fei Ni is substantially better than Sorafenib in the comparable order of magnitude, some compounds.
Embodiment 1
Every 100ml injection formula:
1 50mg of compound
Sodium chloride 900mg
Preparation process:
(1) water for injection of recipe quantity 80% is taken, water for injection temperature is controlled at 55 DEG C, compound described in recipe quantity is added
1 and sodium chloride, it stirs to being completely dissolved, then mends and add to the full amount of water for injection, be uniformly mixed；
(2) by the above-mentioned medical fluid for preparing with " 0.45um polytetrafluoroethylene (PTFE) filter core, 0.22um polytetrafluoroethylene (PTFE) filter core,
The sterilizing filter refined filtration that 0.22um polytetrafluoroethylene (PTFE) filter core " is sequentially connected in series；
(3) encapsulating: by the medical fluid after aseptic filtration by labelled amount encapsulating in colourless low borosilicate glass ampoule；
(4) it sterilizes: using 121 DEG C of wet-hot steams sterilizing 15min；
(5) lamp inspection, pack up to small molecular protein kinase inhibition remover liquid injection.
Embodiment 2
Every 100ml injection formula:
2 40mg of compound
Sodium chloride 600mg
Preparation process:
(1) water for injection of recipe quantity 80% is taken, water for injection temperature is controlled at 55 DEG C, compound described in recipe quantity is added
2 and sodium chloride, it stirs to being completely dissolved, then mends and add to the full amount of water for injection, be uniformly mixed；
(2) by the above-mentioned medical fluid for preparing with " 0.45um polytetrafluoroethylene (PTFE) filter core, 0.22um polytetrafluoroethylene (PTFE) filter core,
The sterilizing filter refined filtration that 0.22um polytetrafluoroethylene (PTFE) filter core " is sequentially connected in series；
(3) encapsulating: by the medical fluid after aseptic filtration by labelled amount encapsulating in colourless low borosilicate glass ampoule；
(4) it sterilizes: using 115 DEG C of wet-hot steams sterilizing 18min；
(5) lamp inspection, pack up to small molecular protein kinase inhibition remover liquid injection.
Embodiment 3
Every 100ml injection formula:
3 30mg of compound
Sodium chloride 450mg
Preparation process:
(1) water for injection of recipe quantity 80% is taken, water for injection temperature is controlled at 55 DEG C, compound described in recipe quantity is added
3 and sodium chloride, it stirs to being completely dissolved, then mends and add to the full amount of water for injection, be uniformly mixed；
(2) by the above-mentioned medical fluid for preparing with " 0.45um polytetrafluoroethylene (PTFE) filter core, 0.22um polytetrafluoroethylene (PTFE) filter core,
The sterilizing filter refined filtration that 0.22um polytetrafluoroethylene (PTFE) filter core " is sequentially connected in series；
(3) encapsulating: by the medical fluid after aseptic filtration by labelled amount encapsulating in colourless low borosilicate glass ampoule；
(4) it sterilizes: using 112 DEG C of wet-hot steams sterilizing 20min；
(5) lamp inspection, pack up to small molecular protein kinase inhibition remover liquid injection.
Embodiment 4
Every 100ml injection formula:
4 60mg of compound
Sodium chloride 1000mg
Preparation process:
(1) water for injection of recipe quantity 80% is taken, water for injection temperature is controlled at 55 DEG C, compound described in recipe quantity is added
4 and sodium chloride, it stirs to being completely dissolved, then mends and add to the full amount of water for injection, be uniformly mixed；
(2) by the above-mentioned medical fluid for preparing with " 0.45um polytetrafluoroethylene (PTFE) filter core, 0.22um polytetrafluoroethylene (PTFE) filter core,
The sterilizing filter refined filtration that 0.22um polytetrafluoroethylene (PTFE) filter core " is sequentially connected in series；
(3) encapsulating: by the medical fluid after aseptic filtration by labelled amount encapsulating in colourless low borosilicate glass ampoule；
(4) it sterilizes: using 123 DEG C of wet-hot steams sterilizing 13min；
(5) lamp inspection, pack up to small molecular protein kinase inhibition remover liquid injection.
Embodiment 5
Every 100ml injection formula:
5 70mg of compound
Sodium chloride 1100mg
Preparation process:
(1) water for injection of recipe quantity 80% is taken, water for injection temperature is controlled at 55 DEG C, compound described in recipe quantity is added
5 and sodium chloride, it stirs to being completely dissolved, then mends and add to the full amount of water for injection, be uniformly mixed；
(2) by the above-mentioned medical fluid for preparing with " 0.45um polytetrafluoroethylene (PTFE) filter core, 0.22um polytetrafluoroethylene (PTFE) filter core,
The sterilizing filter refined filtration that 0.22um polytetrafluoroethylene (PTFE) filter core " is sequentially connected in series；
(3) encapsulating: by the medical fluid after aseptic filtration by labelled amount encapsulating in colourless low borosilicate glass ampoule；
(4) it sterilizes: using 125 DEG C of wet-hot steams sterilizing 12min；
(5) lamp inspection, pack up to small molecular protein kinase inhibition remover liquid injection.
Embodiment 6
Every 100ml injection formula:
6 70mg of compound
Sodium chloride 1200mg
Preparation process:
(1) water for injection of recipe quantity 80% is taken, water for injection temperature is controlled at 55 DEG C, compound described in recipe quantity is added
6 and sodium chloride, it stirs to being completely dissolved, then mends and add to the full amount of water for injection, be uniformly mixed；
(2) by the above-mentioned medical fluid for preparing with " 0.45um polytetrafluoroethylene (PTFE) filter core, 0.22um polytetrafluoroethylene (PTFE) filter core,
The sterilizing filter refined filtration that 0.22um polytetrafluoroethylene (PTFE) filter core " is sequentially connected in series；
(3) encapsulating: by the medical fluid after aseptic filtration by labelled amount encapsulating in colourless low borosilicate glass ampoule；
(4) it sterilizes: using 130 DEG C of wet-hot steams sterilizing 10min；
(5) lamp inspection, pack up to small molecular protein kinase inhibition remover liquid injection.
Test case
Influence factor test: 60 DEG C of high temperature examinations is carried out to the small molecular protein kinase inhibition remover liquid injection of embodiment preparation
It tests, 40 DEG C of high temperature tests, is tested under the conditions of illumination 4500lx ± 500lx, sampling in the 5th day and the 10th day carries out after setting-out
Product quality situation of change is investigated in detection.Test result see the table below 2-4.
Table 2: 60 DEG C of test results of high temperature
Table 3: 40 DEG C of test results of high temperature
Table 4: test result under the conditions of illumination 4500lx ± 500lx
It can be seen that the small molecular protein kinase inhibition prepared according to the method described in the present invention by the result of table 2-4
It is still colourless after remover liquid injection is placed 5 days, 10 days under the conditions of 60 DEG C of high temperature, 40 DEG C of high temperature, illumination 4500lx ± 500lx
Prescribed liquid, it is seen that foreign matter meets regulation, and stability is high.
The preferred embodiment of the present invention has been described above in detail, and still, the present invention is not limited thereto.In skill of the invention
In art conception range, can with various simple variants of the technical solution of the present invention are made, including each technical characteristic with it is any its
Its suitable method is combined, and it should also be regarded as the disclosure of the present invention for these simple variants and combination, is belonged to
Protection scope of the present invention.
Claims (9)
1. a kind of small molecular protein kinase inhibition remover liquid injection, the injection contain medicine activity component, sodium chloride and injection
Water, which is characterized in that the medicine activity component is Isosorbide-5-Nitrae-diamines naphthalene derivatives and its pharmaceutically acceptable shown in formula (I)
Salt, solvate,
Wherein, L1And L2It each is selected from O, S and NH；
N is 0,1,2,3,4 or 5；
R1Selected from hydrogen, C1-C8Alkyl and C3-C7Naphthenic base；
R2Selected from hydrogen, C1-C8Alkyl, substituted C1-C8Alkyl, C3-C7Naphthenic base, substituted C3-C7Naphthenic base, aryl, quilt
Substituted aryl, heteroaryl and substituted heteroaryl；
R3Selected from hydrogen, C1-C8Alkyl and C3-C7Naphthenic base；
R4Selected from C3-C7Heterocyclylalkyl, substituted C3-C7Heterocyclylalkyl, aryl, substituted aryl, heteroaryl and be substituted
Heteroaryl.
2. injection according to claim 1, which is characterized in that in formula (I), R1For hydrogen, R2Selected from aryl, it is substituted
Aryl, heteroaryl and substituted heteroaryl.
3. injection according to claim 1, which is characterized in that in formula (I), L O, n 3, R3Selected from hydrogen, methyl and
Ethyl, R4Selected from morpholine, piperidines, pyrrolidines and piperazine.
4. injection according to claim 1, which is characterized in that the Isosorbide-5-Nitrae-diamines naphthalene derivatives structural formula are as follows:
5. injection described in any one of -4 according to claim 1, which is characterized in that the concentration of the medicine activity component
For 0.1-2mg/ml.
6. injection according to claim 5, which is characterized in that the concentration of the medicine activity component is 0.2-0.8mg/
ml。
7. injection described in any one of -4 according to claim 1, which is characterized in that contain chlorine in every 100ml injection
Change sodium 0.3-2g.
8. a kind of preparation method of the small molecular protein kinase inhibition remover liquid injection as described in any one of claim 1-7,
Method includes the following steps:
(1) match liquid: the medicine activity component, sodium chloride and water for injection are stirred to being completely dissolved；
(2) aseptic filtration: refined filtration is carried out with the medical fluid that sterilizing filter prepares step (1)；
(3) encapsulating: by the medical fluid after aseptic filtration by labelled amount encapsulating in colourless low borosilicate ampoule；
(4) it sterilizes: using 110-130 DEG C of wet-hot steam sterilizing 10-20min.
9. according to the method described in claim 8, it is characterized in that, the sterilizing filter is the filter of 0.45um polytetrafluoroethylene (PTFE)
The sterilizing filter that core, 0.22um polytetrafluoroethylene (PTFE) filter core, 0.22um polytetrafluoroethylene (PTFE) filter core are sequentially connected in series.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811553666.4A CN109758422B (en) | 2018-12-18 | 2018-12-18 | Small molecule protein kinase inhibitor injection and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811553666.4A CN109758422B (en) | 2018-12-18 | 2018-12-18 | Small molecule protein kinase inhibitor injection and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109758422A true CN109758422A (en) | 2019-05-17 |
| CN109758422B CN109758422B (en) | 2021-07-06 |
Family
ID=66450241
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811553666.4A Active CN109758422B (en) | 2018-12-18 | 2018-12-18 | Small molecule protein kinase inhibitor injection and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109758422B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102731396A (en) * | 2011-10-31 | 2012-10-17 | 河北大学 | Polyamine naphthalimide compounds and application of same in preparation of pharmaceutical preparation |
| CN102766103A (en) * | 2012-07-24 | 2012-11-07 | 齐鲁制药有限公司 | 2-sulfo-4-amino-1-naphthol derivative and preparation method and application thereof |
| CN102977125A (en) * | 2011-09-06 | 2013-03-20 | 江苏先声药物研究有限公司 | 2,7-naphthyridine derivative, and preparation method and application thereof |
| CN106279147A (en) * | 2015-05-21 | 2017-01-04 | 中国科学院上海药物研究所 | A kind of pyrido nitrogen heterocyclic and its production and use |
-
2018
- 2018-12-18 CN CN201811553666.4A patent/CN109758422B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102977125A (en) * | 2011-09-06 | 2013-03-20 | 江苏先声药物研究有限公司 | 2,7-naphthyridine derivative, and preparation method and application thereof |
| CN102731396A (en) * | 2011-10-31 | 2012-10-17 | 河北大学 | Polyamine naphthalimide compounds and application of same in preparation of pharmaceutical preparation |
| CN102766103A (en) * | 2012-07-24 | 2012-11-07 | 齐鲁制药有限公司 | 2-sulfo-4-amino-1-naphthol derivative and preparation method and application thereof |
| CN106279147A (en) * | 2015-05-21 | 2017-01-04 | 中国科学院上海药物研究所 | A kind of pyrido nitrogen heterocyclic and its production and use |
Non-Patent Citations (2)
| Title |
|---|
| 耿海云等: "" VEGF/VEGFR信号通路抑制剂疗效预测的研究进展"", 《临床肿瘤学杂志》 * |
| 魏传梅等: ""以 VEGF/VEGFR 为靶点的抗肿瘤天然化合物研究进展"", 《中草药》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109758422B (en) | 2021-07-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105377835B (en) | Tyrosine protein kinase conditioning agent and its application process | |
| CN101687822A (en) | Di(arylamino)aryl compound | |
| EP2581371B1 (en) | Pyrrolyl substituted dihydroindol-2-one derivatives, preparation methods and uses thereof | |
| KR20090118601A (en) | Novel benzoxazole-pyridine derivatives or pharmaceutically acceptable salt thereof, preparation method thereof and pharmaceutical composition for the prevention and treatment of abnormal cell growth diseases containing the same as an active ingredient | |
| TW201236684A (en) | Pharmaceutically acceptable salts of (E)-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide, preparation process and pharmaceutical use there of | |
| CN104072480A (en) | Quinoline type compounds and preparing method and applications thereof | |
| CN102766103A (en) | 2-sulfo-4-amino-1-naphthol derivative and preparation method and application thereof | |
| CN106831824A (en) | Pyrrolopyridines and its application containing naphthyridones structure | |
| CN107383016A (en) | The preparation and application of the Pyrrolopyrimidine compounds of the structure containing heteroaryl amide | |
| CN112300082B (en) | Phenyl piperazine quinazoline compound or pharmaceutically acceptable salt thereof, preparation method and application | |
| CN107151233B (en) | Hydrazone-containing pyrimidine derivative and application thereof | |
| CN109879827A (en) | A kind of novel indazole analog derivative and its application | |
| CN101100466B (en) | Non-reversible protein tyrosine phosphorus acylase inhibitor and its preparation and application | |
| CN108676009A (en) | Pyrimidine derivatives as HER2 tyrosine kinase inhibitors and its application | |
| CN109846840A (en) | A kind of solid dosage forms of vascular endothelial growth factor receptor inhibitors and preparation method thereof | |
| CN109988110B (en) | 4-phenoxy quinoline sulfonylurea compound, intermediate for synthesizing the compound and its preparation method and use | |
| CN109758422A (en) | A kind of small molecular protein kinase inhibition remover liquid injection and preparation method thereof | |
| CN104926789A (en) | 4-phenoxyl substituted quinoline compound containing imidazolone and application thereof | |
| CN109651294A (en) | A kind of 1,4- diamines naphthalene derivatives and its preparation method and application | |
| CN106045971B (en) | Pirfenidone derivative and preparation method thereof | |
| CN109549931A (en) | A kind of freeze dried powder of anti-tumor drug and preparation method thereof | |
| CN105646448B (en) | Pyridine compounds and their and application thereof | |
| CN108689997A (en) | Cell cycle protein dependent kinase inhibitor 4- amino -2- pyrimidinecarboxylic acids derivative, it is prepared and purposes | |
| CN104059062A (en) | Benzothiazole and triazolediheterocycle-containing fused ring compound and application thereof | |
| WO2010083649A1 (en) | Bisarylurea derivatives and their use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |