CN109549931A - A kind of freeze dried powder of anti-tumor drug and preparation method thereof - Google Patents
A kind of freeze dried powder of anti-tumor drug and preparation method thereof Download PDFInfo
- Publication number
- CN109549931A CN109549931A CN201811560877.0A CN201811560877A CN109549931A CN 109549931 A CN109549931 A CN 109549931A CN 201811560877 A CN201811560877 A CN 201811560877A CN 109549931 A CN109549931 A CN 109549931A
- Authority
- CN
- China
- Prior art keywords
- dried powder
- freeze dried
- excipient
- activity component
- substituted
- 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
Classifications
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
- A61K31/435—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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
-
- 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
- A61K31/535—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The present invention relates to field of medicinal chemistry, disclose a kind of freeze dried powder and preparation method thereof of anti-tumor drug.The freeze dried powder of the anti-tumor drug contains medicine activity component and excipient, the mass ratio of the medicine activity component and the excipient is 1:0.5-8, wherein, the medicine activity component is Isosorbide-5-Nitrae-diamines naphthalene derivatives and its pharmaceutically acceptable salt, solvate shown in formula (I).The freeze dried powder of the anti-tumor drug can inhibit VEGF, 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 freeze dried powder of anti-tumor drug and preparation method thereof.
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 freeze dried powders of a kind of anti-tumor drug and preparation method thereof.
The present invention provides a kind of freeze dried powders of anti-tumor drug, described containing medicine activity component and excipient
The mass ratio of medicine activity component and the excipient is 1:0.5-8, wherein the medicine activity component is shown in formula (I)
Isosorbide-5-Nitrae-diamines naphthalene derivatives and its pharmaceutically 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 mass ratio of the medicine activity component and the excipient is 1:0.8-2.
Preferably, the excipient is at least one of mannitol, glucose and lactose.
The present invention also provides a kind of preparation methods for preparing above-mentioned freeze dried powder, method includes the following steps:
(1) medicine activity component, excipient and water for injection are stirred to after being completely dissolved, obtains lyophilized stoste；
(2) by the lyophilized stoste, pre-freeze handles 1h~3h at -10 DEG C~-30 DEG C, after freezing, is evacuated to 5-
30Pa is warming up to -2 DEG C~-8 DEG C with 1 DEG C per hour~3 DEG C of speed, and lyophilization handles 5h~20h, again with per hour 5
DEG C~10 DEG C of speed is warming up to 5 DEG C~40 DEG C, parsing-desiccation handles 5h~10h.
Preferably, the total amount of the medicine activity component and the excipient and the volume ratio of the water for injection are 5-
20:100, more preferably 8-15:100.
It include 1,4- diamines naphthalene derivatives and its pharmaceutically acceptable salt, solvent in freeze dried powder of the present invention
Object is closed, can be used for treating tumor disease, it may also be used in EGF-R ELISA junket in treatment and/or prevention mammal
Histidine kinase related 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.
The freeze dried powder of anti-tumor drug of the present invention contains medicine activity component and excipient.
In the freeze dried powder of the anti-tumor drug, the mass ratio of the medicine activity component and the excipient can be with
For 1:0.5-8, preferably 1:0.8-2.
In the present invention, the medicine activity component is Isosorbide-5-Nitrae-diamines naphthalene derivatives and its pharmaceutically shown in formula (I)
Acceptable salt, 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 the present invention, the excipient can be the conventional selection of this field.In a particular embodiment, the tax
Shape agent is at least one of mannitol, glucose and lactose.
The present invention also provides a kind of methods of freeze dried powder for preparing above-mentioned anti-tumor drug, comprising the following steps:
(1) medicine activity component, excipient and water for injection are stirred to after being completely dissolved, obtains lyophilized stoste；
(2) by the lyophilized stoste, pre-freeze handles 1h~3h at -10 DEG C~-30 DEG C, after freezing, is evacuated to 5-
30Pa is warming up to -2 DEG C~-8 DEG C with 1 DEG C per hour~3 DEG C of speed, and lyophilization handles 5h~20h, again with per hour 5
DEG C~10 DEG C of speed is warming up to 5 DEG C~40 DEG C, parsing-desiccation handles 5h~10h.
In method of the present invention, the total amount of the medicine activity component and the excipient and the water for injection
Volume ratio can be 5-20:100, preferably 8-15:100.
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
In an aseptic environment, 0.5g compound 1 and 0.5g mannitol are accurately weighed, is placed in clean in container, is added
Enter water for injection 4ml, stirs to after being completely dissolved, then inject water to 5ml, stir evenly, obtain lyophilized stoste.
It is partly jumped a queue in 10ml pipe-produced glass bottle by lyophilized stoste is filling, moves into freeze drier and carry out freezing processing, tool
Body lyophilized technique are as follows: lyophilized stoste is frozen into rapidly -25 DEG C, the duration 2 hours, is evacuated to 15Pa, with 2 DEG C per hour
Speed is warming up to -5 DEG C, and lyophilization is handled 12 hours, then is warming up to 20 DEG C with 8 DEG C per hour of speed, parsing-desiccation processing 8
Hour, Quan Jiasai rolls lid to get anti-tumor drug freeze dried powder A1.
Embodiment 2
In an aseptic environment, 0.3g compound 2 and 0.6g glucose are accurately weighed, is placed in clean in container, is added
Enter water for injection 4ml, stirs to after being completely dissolved, then inject water to 5ml, stir evenly, obtain lyophilized stoste.
It is partly jumped a queue in 10ml pipe-produced glass bottle by lyophilized stoste is filling, moves into freeze drier and carry out freezing processing, tool
Body lyophilized technique are as follows: lyophilized stoste is frozen into rapidly -30 DEG C, the duration 1.5 hours, is evacuated to 20Pa, with 1 DEG C per hour
Speed be warming up to -8 DEG C, lyophilization is handled 16 hours, then is warming up to 30 DEG C, at parsing-desiccation with 5 DEG C per hour of speed
Reason 5 hours, Quan Jiasai rolls lid to get anti-tumor drug freeze dried powder A2.
Embodiment 3
In an aseptic environment, 0.5g compound 3 and 0.4g lactose are accurately weighed, is placed in clean in container, is added
Water for injection 4ml is stirred to after being completely dissolved, then is injected water to 5ml, is stirred evenly, is obtained lyophilized stoste.
It is partly jumped a queue in 10ml pipe-produced glass bottle by lyophilized stoste is filling, moves into freeze drier and carry out freezing processing, tool
Body lyophilized technique are as follows: lyophilized stoste is frozen into rapidly -20 DEG C, the duration 3 hours, is evacuated to 10Pa, with 3 DEG C per hour
Speed is warming up to -3 DEG C, and lyophilization is handled 16 hours, then is warming up to 40 DEG C with 10 DEG C per hour of speed, parsing-desiccation processing
5 hours, Quan Jiasai, lid was rolled to get anti-tumor drug freeze dried powder A3.
Embodiment 4
In an aseptic environment, 0.4g compound 4 and 0.6g mannitol are accurately weighed, is placed in clean in container, is added
Enter water for injection 4ml, stirs to after being completely dissolved, then inject water to 5ml, stir evenly, obtain lyophilized stoste.
It is partly jumped a queue in 10ml pipe-produced glass bottle by lyophilized stoste is filling, moves into freeze drier and carry out freezing processing, tool
Body lyophilized technique are as follows: lyophilized stoste is frozen into rapidly -15 DEG C, the duration 3 hours, is evacuated to 5Pa, with 1 DEG C per hour
Speed is warming up to -8 DEG C, and lyophilization is handled 5 hours, then is warming up to 10 DEG C with 5 DEG C per hour of speed, parsing-desiccation processing 10
Hour, Quan Jiasai rolls lid to get anti-tumor drug freeze dried powder A4.
Embodiment 5
In an aseptic environment, 0.5g compound 5 and 0.7g mannitol are accurately weighed, is placed in clean in container, is added
Enter water for injection 4ml, stirs to after being completely dissolved, then inject water to 5ml, stir evenly, obtain lyophilized stoste.
It is partly jumped a queue in 10ml pipe-produced glass bottle by lyophilized stoste is filling, moves into freeze drier and carry out freezing processing, tool
Body lyophilized technique are as follows: lyophilized stoste is frozen into rapidly -10 DEG C, the duration 3 hours, is evacuated to 10Pa, with 1 DEG C per hour
Speed is warming up to -2 DEG C, and lyophilization is handled 20 hours, then is warming up to 40 DEG C with 5 DEG C per hour of speed, parsing-desiccation processing
10 hours, Quan Jiasai, lid was rolled to get anti-tumor drug freeze dried powder A5.
Embodiment 6
In an aseptic environment, 0.6g compound 6 and 0.5g mannitol are accurately weighed, is placed in clean in container, is added
Enter water for injection 4ml, stirs to after being completely dissolved, then inject water to 5ml, stir evenly, obtain lyophilized stoste.
It is partly jumped a queue in 10ml pipe-produced glass bottle by lyophilized stoste is filling, moves into freeze drier and carry out freezing processing, tool
Body lyophilized technique are as follows: lyophilized stoste is frozen into rapidly -18 DEG C, the duration 3 hours, is evacuated to 10Pa, with 1 DEG C per hour
Speed is warming up to -3 DEG C, and lyophilization is handled 18 hours, then is warming up to 30 DEG C with 5 DEG C per hour of speed, parsing-desiccation processing
10 hours, Quan Jiasai, lid was rolled to get anti-tumor drug freeze dried powder A6.
Test case
Following Detection of Stability is carried out to anti-tumor drug freeze dried powder obtained by above-described embodiment:
(1) high temperature detects
Each 45 bottles of embodiment finished product are randomly selected, is placed in testing chamber for medicine stability.It is placed 10 days under the conditions of 60 DEG C,
The the 0th, 5, the 10 day various indexs of sample detection are taken respectively, including investigate its appearance character, solubility and clarity.As a result it is detailed in
Table 2.
(2) high humidity detects
It randomly selects each 45 bottles of embodiment finished product, after every bottle of correct amount, is placed in testing chamber for medicine stability, Yu Wendu
25 DEG C, place 10 days under the conditions of relative humidity (RH) 90% ± 5%, in the 5th day and the 10th day sample detection and the 0th day sample into
Row compares；Investigate its appearance character, solubility and clarity.As a result see Table 3 for details.
(3) strong illumination detects
Each 45 bottles of embodiment finished product are randomly selected, is placed in the strong photo-stability testing case of drug, 4500 ± 500Lx of Yu Zhaodu
Under the conditions of place 10 days, respectively at the 0th, 5,10 day sample detection by comparing its appearance character, solubility and clarity etc. refer to
Mark investigates its photostability.As a result see Table 4 for details.
Table 2
Table 3
Table 4
The anti-tumor drug freeze dried powder prepared according to the method described in the present invention it can be seen from the result of upper table 2-4
With preferable high-temperature stability, high wet stability and strong illumination stability.
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 freeze dried powder of anti-tumor drug, contains medicine activity component and excipient, which is characterized in that the drug
The mass ratio of active component and the excipient is 1:0.5-8, wherein the medicine activity component is Isosorbide-5-Nitrae-shown in formula (I)
Diamines naphthalene derivatives and its pharmaceutically 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, 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. freeze dried powder according to claim 1, which is characterized in that in formula (I), R1For hydrogen, R2Selected from aryl, taken
Aryl, heteroaryl and the substituted heteroaryl in generation.
3. freeze dried powder 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. freeze dried powder according to claim 1, which is characterized in that the Isosorbide-5-Nitrae-diamines naphthalene derivatives structural formula are as follows:
5. freeze dried powder described in any one of -4 according to claim 1, which is characterized in that the medicine activity component and institute
The mass ratio for stating excipient is 1:0.8-2.
6. freeze dried powder described in any one of -4 according to claim 1, which is characterized in that the excipient be mannitol,
At least one of glucose and lactose.
7. the preparation method of freeze dried powder described in a kind of any one of claim 1-6, method includes the following steps:
(1) medicine activity component, excipient and water for injection are stirred to after being completely dissolved, obtains lyophilized stoste；
(2) by the lyophilized stoste, pre-freeze handles 1h~3h at -10 DEG C~-30 DEG C, after freezing, is evacuated to 5-30Pa, with
1 DEG C per hour~3 DEG C of speed is warming up to -2 DEG C~-8 DEG C, and lyophilization handles 5h~20h, again with per hour 5 DEG C~10
DEG C speed be warming up to 5 DEG C~40 DEG C, parsing-desiccation handles 5h~10h.
8. the method according to the description of claim 7 is characterized in that the total amount of the medicine activity component and the excipient with
The volume ratio of the water for injection is 5-20:100.
9. according to the method described in claim 8, it is characterized in that, the total amount of the medicine activity component and the excipient with
The volume ratio of the water for injection is 8-15:100.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811560877.0A CN109549931B (en) | 2018-12-18 | 2018-12-18 | Anti-tumor medicine freeze-dried powder and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811560877.0A CN109549931B (en) | 2018-12-18 | 2018-12-18 | Anti-tumor medicine freeze-dried powder and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109549931A true CN109549931A (en) | 2019-04-02 |
| CN109549931B CN109549931B (en) | 2021-09-24 |
Family
ID=65870655
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811560877.0A Active CN109549931B (en) | 2018-12-18 | 2018-12-18 | Anti-tumor medicine freeze-dried powder and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109549931B (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 CN201811560877.0A patent/CN109549931B/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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109549931B (en) | 2021-09-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2572848C2 (en) | Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{ 6-[4-(4-ethylpiperazin-1-yl)-phenylamino]-pyrimidin-4-yl} -1-methylurea and its fractions | |
| KR101034351B1 (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 | |
| EP2581371B1 (en) | Pyrrolyl substituted dihydroindol-2-one derivatives, preparation methods and uses thereof | |
| CN109415341A (en) | α derived from benzotriazole as TGF-β R1 inhibitor, β unsaturated acyl amine compound | |
| CN104053439A (en) | Meglumine salt formulations of 1-(5,6-dichloro-1h-benzo[D]imidazol-2-yl)-1H-pyrazole-4-carboxylic acid | |
| CN107383016A (en) | The preparation and application of the Pyrrolopyrimidine compounds of the structure containing heteroaryl amide | |
| CN102766103A (en) | 2-sulfo-4-amino-1-naphthol derivative and preparation method and application thereof | |
| CN108530426A (en) | 4- phenoxy groups substituted quinoline derivatives containing quinokysalines and its application | |
| CN106554347A (en) | Egfr kinase inhibitor and its preparation method and application | |
| CN112300082B (en) | Phenyl piperazine quinazoline compound or pharmaceutically acceptable salt thereof, preparation method and application | |
| CN103382182B (en) | Phenylurea coupling quinazoline compounds and preparation method thereof, pharmaceutical composition and medicinal usage | |
| CN107151233B (en) | Hydrazone-containing pyrimidine derivative and application thereof | |
| CN109879827A (en) | A kind of novel indazole analog derivative and its application | |
| CN109988110B (en) | 4-phenoxy quinoline sulfonylurea compound, intermediate for synthesizing the compound and its preparation method and use | |
| CN107474039A (en) | Ketone containing triazole and the 4- phenoxy groups substituted quinoline derivatives of imidazoles and its application | |
| CN114605391B (en) | Quinoxaline derivative, preparation method and application thereof | |
| CN109846840A (en) | A kind of solid dosage forms of vascular endothelial growth factor receptor inhibitors and preparation method thereof | |
| CN109549931A (en) | A kind of freeze dried powder of anti-tumor drug and preparation method thereof | |
| CN104926789A (en) | 4-phenoxyl substituted quinoline compound containing imidazolone and application thereof | |
| CN105541792B (en) | Polycyclic class PI3K inhibitor | |
| CN109651294A (en) | A kind of 1,4- diamines naphthalene derivatives and its preparation method and application | |
| CN109758422A (en) | A kind of small molecular protein kinase inhibition remover liquid injection and preparation method thereof | |
| WO2010083649A1 (en) | Bisarylurea derivatives and their use | |
| CN106045971A (en) | Pirfenidone derivative and preparation method thereof | |
| CN108947961A (en) | Indazole analog derivative and its preparation method and application |
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 |