CN109846840B - Solid dosage form of vascular endothelial growth factor inhibitor and preparation method thereof - Google Patents
Solid dosage form of vascular endothelial growth factor inhibitor and preparation method thereof Download PDFInfo
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Abstract
The invention relates to the field of medicinal chemistry, and discloses a solid dosage form of a vascular endothelial growth factor inhibitor and a preparation method thereof. The solid dosage form of the vascular endothelial growth factor inhibitor contains a pharmaceutical active component, a filler, a disintegrant and a lubricant, wherein the content of the pharmaceutical active component is 20-80 wt%, the content of the filler is 10-70 wt%, the content of the disintegrant is 0.5-5 wt%, and the content of the lubricant is 0.5-5 wt%, based on the total weight of the solid dosage form, wherein the pharmaceutical active component is a 1, 4-diaminonaphthalene derivative and pharmaceutically acceptable salts and solvates thereof. The solid dosage form of the vascular endothelial growth factor inhibitor can inhibit vascular endothelial growth factor, can be used for treating and/or preventing diseases related to epidermal growth factor receptor tyrosine kinase in mammals, and can also be used for treating tumor diseases.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a solid dosage form of a vascular endothelial growth factor inhibitor and a preparation method thereof.
Background
Recent clinical and basic medical research results have demonstrated that tumor development and metastasis are dependent on the formation of new blood vessels. Tumor angiogenesis is the result of the interaction of tumor cells, vascular endothelial cells, vascular extracellular matrix, and the like. Among them, the biological function of vascular endothelial growth factor VEFG (vascular endothelial growth factor) is crucial in angiogenesis.
Most cell growth factor receptors contain the peptide chain sequence of tyrosine kinases, and overexpression or activation of different tyrosine kinase receptors is seen in many tumors. These receptors are further divided into several families according to the similarity of peptide chain sequences and their structural features: 1. the epidermal growth factor receptor family, including EGFR, HER-2, HER-3, HER-4, etc., the high expression of which is common in epithelial cell tumors; 2. the insulin receptor family, including insulin receptor, insulin-like growth factor receptor (IGF-R), and insulin-related receptor (IRR), among others, is commonly high expressed in blood cancers; 3. platelet derived growth factor receptor family (PDGFR) including PDGFR-alpha, PDEFR-beta, CSF-1R, c-Kit, etc., which are commonly highly expressed in brain tumors, blood cancers; 4. fibroblast Growth Factor Receptors (FGFR), including FGFR-1, FGFR-2, FGFR-3, FGFR-4, and the like, which have important roles in angiogenesis; 5. vascular Endothelial Growth Factor Receptors (VEGFRs), including VEGFR-1, VEGFR-2, and VEGFR-3, are important positive regulators of angiogenesis.
Vascular Endothelial Growth Factor (VEGF) is a growth factor that acts mainly on vascular endothelial cells, and has various functions of promoting endothelial cell proliferation, increasing microvascular permeability, inducing angiogenesis, and the like. The formation and development of tumors can be largely divided into two phases, namely the clonal proliferation phase of tumor cells and the subsequent phase in which angiogenesis promotes the continued growth of tumors. VEGF acts on the endothelial cells of the vascular network itself, and differentiates them to form new blood vessels. The new blood vessels not only provide a foundation for the material exchange of the tumor cells, but also can paracrine some cytokines to promote the proliferation of the tumor cells; meanwhile, as the wall structure of the new blood vessel is lack of integrity, the connection between endothelial cells is loose, the basement membrane has different thickness and is broken or damaged, and tumor cells are easy to enter the lumen of the blood vessel to cause blood invasion and metastasis. VEGF is therefore closely associated with tumor growth and metastasis. VEGF is detected in most tissues of healthy humans, but is expressed in very small amounts, and is highly expressed in many tumors (especially solid tumors), for example: liver cancer, brain tumor, breast cancer and kidney cancer tissues. Because of the dependence of growth and metastasis of solid tumors on new blood vessels, VEGF is a desirable target site for blocking the vascularization of solid tumors. VEGFR is a diffusible vascular endothelial specific mitogen and angiogenic growth factor receptor, plays a key role in physiological and pathological angiogenesis processes, and can inhibit endothelial cell apoptosis. The family includes VEGFR-1, VEGFR-2, VEGFR-3. It is currently believed that binding of VEGF to VEGFR-2, which causes VEGFR-2 to form a dimer, induces tyrosine kinase mediated phosphorylation and further activates the associated downstream signaling pathways.
In recent years, various VEGFR-targeted drugs such as Sunitinib, Sorafenib, Pazopanib, etc. have been approved for the treatment of various tumors. Although these tumor angiogenesis inhibitors have great advantages, the practical application still has the problems of weak dependence of part of tumors on angiogenesis, drug resistance, adverse reaction and toxicity caused by mutation and compensation of tumor signal transduction. Therefore, it is necessary to develop a small molecule protein kinase inhibitor with stronger selectivity, higher activity and less toxicity.
Disclosure of Invention
The invention aims to provide a solid dosage form of a vascular endothelial growth factor inhibitor and a preparation method thereof.
The invention provides a solid dosage form of a vascular endothelial growth factor inhibitor, which contains a pharmaceutical active component, a filler, a disintegrant and a lubricant, wherein the content of the pharmaceutical active component is 20-80 wt%, the content of the filler is 10-70 wt%, the content of the disintegrant is 0.5-5 wt%, and the content of the lubricant is 0.5-5 wt%, based on the total weight of the solid dosage form, wherein the pharmaceutical active component is a 1, 4-diamine naphthalene derivative shown in a formula (I) and pharmaceutically acceptable salts and solvates thereof,
wherein L is1And L2Each selected from O, S and NH;
n is 0, 1, 2, 3, 4 or 5;
R1selected from hydrogen, C1-C8Alkyl and C3-C7A cycloalkyl group;
R2selected from hydrogen, C1-C8Alkyl radicalC substituted with1-C8Alkyl radical, C3-C7Cycloalkyl, substituted C3-C7Cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
R3selected from hydrogen, C1-C8Alkyl and C3-C7A cycloalkyl group;
R4is selected from C3-C7Heterocycloalkyl, substituted C3-C7Heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
Preferably, in formula (I), R1Is hydrogen, R2Selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl.
Preferably, in formula (I), L is O, n is 3, R3Selected from hydrogen, methyl and ethyl, R4Selected from morpholine, piperidine, pyrrolidine and piperazine.
Preferably, the 1, 4-diamine naphthalene derivative has the structural formula:
preferably, the active ingredient is present in an amount of 50 to 80 wt%, the filler is present in an amount of 16 to 46 wt%, the disintegrant is present in an amount of 0.5 to 2 wt%, and the lubricant is present in an amount of 0.5 to 2 wt%, based on the total weight of the solid dosage form.
Preferably, the filler is at least one of anhydrous lactose, lactose monohydrate, sucrose, starch, dextrin, microcrystalline cellulose, and pregelatinized starch.
Preferably, the disintegrant is at least one of croscarmellose sodium, pregelatinized starch, sodium carboxymethylcellulose, polyvinylpyrrolidone, and crospovidone.
Preferably, the lubricant is at least one of magnesium stearate, calcium stearate, zinc stearate, talc, silica and polyethylene glycol powder.
Preferably, the solid formulation is a tablet or capsule and comprises 20mg, 50mg, 100mg, 200mg or 400mg of the pharmaceutically active ingredient per tablet or per capsule.
The invention also provides a preparation method for preparing the solid dosage form, which comprises the following steps:
(1) weighing the active ingredients, the filler, the disintegrant and the lubricant according to the proportion, and sieving the active ingredients, the filler, the disintegrant and the lubricant by a sieve of 60-100 meshes;
(2) putting the sieved materials into a three-dimensional mixer for total mixing, wherein the rotating speed of the three-dimensional mixer is 5-20 rpm, and the time is 5-30 minutes;
(3) and (3) directly pressing the mixed material obtained in the step (2) into tablets or filling capsules.
The 1, 4-diamine naphthalene derivative contained in the solid dosage form and pharmaceutically acceptable salts and solvates thereof can be used as an inhibitor of vascular endothelial growth factor, can be used for treating and/or preventing diseases related to epidermal growth factor receptor tyrosine kinase in mammals, and can also be used for treating tumor diseases.
Detailed Description
The following describes in detail specific embodiments of the present invention. It should be understood that the detailed description and specific examples, while indicating the present invention, are given by way of illustration and explanation only, not limitation.
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
The solid dosage form of the vascular endothelial growth factor inhibitor contains a pharmaceutical active component, a filling agent, a disintegrating agent and a lubricating agent.
In the solid dosage form of the vascular endothelial growth factor inhibitor, the content of the pharmaceutically active ingredient is 20 to 80 wt%, preferably 50 to 80 wt%, based on the total weight of the solid dosage form; the content of the filler is 10 to 70 weight percent, preferably 16 to 46 weight percent; the content of the disintegrant is 0.5-5 wt%, preferably 0.5-2 wt%; the content of the lubricant is 0.5 to 5% by weight, preferably 0.5 to 2% by weight.
In the invention, the active component of the medicine is 1, 4-diamine naphthalene derivative shown in formula (I) and pharmaceutically acceptable salt and solvate thereof,
wherein L is1And L2Each selected from O, S and NH, preferably O;
n is 0, 1, 2, 3, 4 or 5;
R1selected from hydrogen, C1-C8Alkyl and C3-C7A cycloalkyl group;
R2selected from hydrogen, C1-C8Alkyl, substituted C1-C8Alkyl (e.g. haloalkyl), C3-C7Cycloalkyl, substituted C3-C7Cycloalkyl (e.g., halocycloalkyl), aryl, substituted aryl (e.g., haloaryl), heteroaryl, and substituted heteroaryl (e.g., haloheteroaryl);
R3selected from hydrogen, C1-C8Alkyl and C3-C7A cycloalkyl group;
R4is selected from C3-C7Heterocycloalkyl, substituted C3-C7Heterocycloalkyl (e.g., haloheterocycloalkyl), aryl, substituted aryl (e.g., haloaryl), heteroaryl, and substituted heteroaryl (e.g., haloheteroaryl).
In a preferred embodiment, in formula (I), R1Is hydrogen，R2Selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl.
In another preferred embodiment, in formula (I), L is O, n is 3, and R is3Selected from hydrogen, methyl and ethyl, R4Selected from morpholine, piperidine, pyrrolidine and piperazine.
In a specific embodiment, the 1, 4-diaminonaphthalene derivative has the structural formula:
the method for preparing the 1, 4-diaminonaphthalene derivative represented by the formula (I) may include the steps of:
(a) dealkylation of the compound represented by the formula (1) to obtain a compound represented by the formula (2);
(b) subjecting a compound represented by formula (2) to a nucleophilic substitution reaction to obtain a compound represented by formula (3);
(c) introducing a hydroxyl group into the compound represented by the formula (3) in the presence of tert-butyl hydroperoxide and potassium hydroxide to obtain a compound represented by the formula (4);
(d) subjecting a compound represented by formula (4) to a substitution reaction to obtain a compound represented by formula (5);
(e) subjecting the compound represented by the formula (5) to an affinity substitution reaction with an amino substituent to obtain a compound represented by the formula (6);
(f) subjecting a compound represented by formula (6) to a hydrogenation reduction reaction to obtain a target compound;
wherein X is halogen, L1、L2、n、R1、R2、R3And R4Are as defined above.
In step (a), preferably, the dealkylation is carried out in the presence of L-methionine, the solvent used is methanesulfonic acid, and the reaction temperature is 85-95 ℃.
In step (b), preferably, the nucleophilic substitution reaction is carried out under basic conditions at a reaction temperature of 75-85 ℃.
Preferably, the reaction of step (c) is carried out in the presence of t-butanol hydroperoxide and potassium hydroxide at a reaction temperature of 0 ± 5 ℃.
In one embodiment, the process route for the preparation of the 1, 4-diaminonaphthalene derivatives of formula (I) is as follows:
the specific preparation process comprises the following steps: taking 6, 7-dimethoxy-1-nitronaphthalene as a starting material, demethylating in a methanesulfonic acid solvent in the presence of L-methionine, carrying out Williamson reaction with 3-chloropropyl morpholine under an alkaline condition, introducing a hydroxyl group into an obtained intermediate in the presence of tert-butyl hydroperoxide and potassium hydroxide, carrying out substitution reaction with phosphorus pentachloride, carrying out affinity substitution with various amino substitutes, and carrying out hydrogenation reduction to obtain a target compound.
Description of the terms
The "alkyl group" in the present invention means a straight or branched saturated hydrocarbon group, preferably a C1-C6 alkyl group, more preferably a C1-C3 alkyl group, and preferably a C1-C3 alkyl group is a methyl group, an ethyl group, a propyl group or an isopropyl group.
"halogen" in the context of the present invention means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, most preferably chlorine.
"haloalkyl", "halocycloalkyl", "haloaryl", "haloheteroaryl" and "haloheterocycloalkyl" in the context of the present invention refer to alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl, respectively, substituted with at least one halogen. The haloalkyl group may be, for example, a halogenated C1-C6 alkyl group.
"solvate" as used herein refers to a compound that is associated with a solvent, typically by a solvolysis reaction. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether, and the like. Suitable solvates include pharmaceutically acceptable solvates and also include both stoichiometric and non-stoichiometric solvates. If water, the solvate is referred to as a hydrate, e.g., a monohydrate, a dihydrate, a trihydrate, and the like.
The "pharmaceutically acceptable salts" of the present invention are those which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
"neoplastic disorders" of the invention include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangial sarcoma, angiosarcoma), appendiceal cancer, benign monoclonal gammopathy, cholangiocarcinoma, bladder cancer, breast cancer, brain cancer, bronchial cancer, carcinoid tumor, cervical cancer, choriocarcinoma, chordoma, colorectal cancer, connective tissue cancer, esophageal cancer, eye cancer, gastric cancer, head and neck cancer, oral cancer, throat cancer, hematopoietic cancer (e.g., leukemia: acute lymphocytic leukemia ALL, acute myelogenous leukemia AML, chronic myelogenous leukemia CML, and chronic lymphocytic leukemia CLL), lymphoma, renal cancer, liver cancer, lung cancer (small cell lung cancer SCLC, non-small cell lung cancer NSCLC), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD) (chronic myelogenous leukemia CML, MDS), Chronic neutrophilic leukemia CNL, hypereosinophilic syndrome HES), osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, vaginal cancer, and the like.
In the present invention, the filler may be a conventional choice in the art. In particular embodiments, the filler may include, but is not limited to, at least one of anhydrous lactose, lactose monohydrate, sucrose, starch, dextrin, microcrystalline cellulose, and pregelatinized starch.
In the present invention, the disintegrant may be a conventional choice in the art. In particular embodiments, the disintegrant may include, but is not limited to, at least one of croscarmellose sodium, pregelatinized starch, sodium carboxymethylcellulose, polyvinylpyrrolidone, and crospovidone.
In the present invention, the lubricant may be a conventional choice in the art. In particular embodiments, the lubricant may include, but is not limited to, at least one of magnesium stearate, calcium stearate, zinc stearate, talc, silica, and polyethylene glycol powder.
In a preferred embodiment, in the solid dosage form of the vegf inhibitor, the filler is a mixture of lactose monohydrate and microcrystalline cellulose, the disintegrant is sodium carboxymethyl cellulose, and the lubricant is magnesium stearate.
In the present invention, the solid formulation of the vascular endothelial growth factor inhibitor may be a tablet or a capsule. Preferably, each tablet or capsule contains 20mg, 50mg, 100mg, 200mg or 400mg of the pharmaceutically active component.
The invention also provides a method for preparing the solid preparation of the vascular endothelial growth factor inhibitor, which comprises the following steps:
(1) weighing the active components, the filler, the disintegrant and the lubricant according to the proportion, and sieving the active components with a 60-100 mesh sieve (preferably 100 mesh);
(2) putting the sieved materials into a three-dimensional mixer for total mixing, wherein the rotating speed of the three-dimensional mixer is 5-20 rpm (preferably 10rpm), and the time is 5-30 minutes (preferably 15 minutes);
(3) and (3) directly pressing the mixed material obtained in the step (2) into tablets or filling capsules.
The present invention will be described in detail by way of examples, but the scope of the present invention is not limited thereto.
Preparation example 1
(1) Preparation of 3-methoxy-5-nitro-2-naphthol
Dissolving 6, 7-dimethoxy-1-nitronaphthalene (4.66g, 20mmol) and L-methionine (2.98g, 20mmol) in 38.4g of methanesulfonic acid (400mmol), stirring and reacting for 8h under the reflux heating condition of an oil bath at 90 ℃, after the TLC detection reaction is completed, neutralizing with a saturated sodium bicarbonate solution until no bubbles appear, detecting with a pH test paper to be neutral or weakly alkaline, extracting the aqueous phase for 3 times with ethyl acetate, combining the ethyl acetate phases, washing with saturated sodium chloride water for three times, drying with anhydrous magnesium sulfate, filtering, evaporating to dryness under reduced pressure, and performing column chromatography to obtain a yellow powdery solid (1.18g, yield: 27%).
(2) Preparation of 4- (3- ((3-methoxy-5-nitronaphthalene-2-) oxy) propyl) morpholine
Dissolving 3-methoxy-5-nitro-2-naphthol (2.19g, 10mmol), anhydrous potassium carbonate (1.80g, 13mmol) and anhydrous potassium iodide (0.166g, 1mmol) in 25ml of N, N-Dimethylformamide (DMF), stirring uniformly, adding 3-chloropropyl morpholine (1.80g, 11mmol) into the reaction solution, stirring under reflux and heating conditions for 3h, detecting by TLC after the reaction is complete, cooling to room temperature, adding 150ml of distilled water into the reaction solution, extracting the water phase 3 times with ethyl acetate, combining ethyl acetate, washing three times with water, washing three times with saturated sodium chloride aqueous solution, drying with anhydrous magnesium sulfate, filtering, drying the filtrate under reduced pressure, evaporating to dryness, and performing column chromatography to obtain yellow powdery solid (3.18g, yield: 92%).
(3) Preparation of 6-methoxy-7- (3-morpholinopropyloxy) -4-nitro-1-naphthol
4- (3- ((3-methoxy-5-nitronaphthalene-2-) oxy) propyl) morpholine (1.73g, 5mmol) was dissolved in 13ml of dimethyl sulfoxide (DMSO), to this solution was added potassium hydroxide (1.2g, 20mmol) dissolved in 5ml of water at 0-5 ℃ and after stirring for 5 minutes, 2ml of DMSO-t-butanol hydroperoxide (0.54g, 6mmol) was added to the solution. After stirring at room temperature for 6 hours, the reaction mixture was slowly poured into 100ml of water, the aqueous phase was extracted with dichloromethane three times, the dichloromethane phases were combined, washed with saturated aqueous sodium chloride solution three times, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and subjected to column chromatography to obtain a yellow powder (yield: 78%).
(4) Preparation of 4- (3- (8-chloro-3-methoxy-5-nitronaphthalene-2-oxy) propyl) morpholine
6-methoxy-7- (3-morpholinopropyloxy) -4-nitro-1-naphthol (5.79g, 16mmol) was dissolved in phosphorus oxychloride (45ml, 490mmol), and stirred under reflux for 3 h. After cooling, the reaction mixture was slowly poured into a 2mol/L sodium carbonate solution (450ml) in an ice-water bath, stirred, suction-filtered, the filter cake was washed with warm water, and dried to give a yellowish solid (yield: 65%).
(5) 4-fluorophenyl- (6-methoxy-7- (3-morpholinopropoxy)) -4-nitronaphthyl-1-amino
Para-fluoroaniline (1.78g, 16mmol), 4- (3- (8-chloro-3-methoxy-5-nitronaphthalene-2-oxy) propyl) morpholine (3.80g, 10mmol) and potassium carbonate (4.1g, 30mmol) in 50ml of dmf were stirred and heated to 60 ℃, reacted for 5h, cooled to room temperature, filtered, and the solution was purified with (DCM/MeOH ═ 20:1) to give 1.54g (yield: 61%) of a yellow solid product, which showed the following nuclear magnetic hydrogen spectrum data.
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-methoxy-7- (3-morpholinopropoxy)) -4-naphthyl-1, 4-diamine
4-fluorophenyl- (6-methoxy-7- (3-morpholinopropoxy)) -4-nitronaphthyl-1-ammonia (0.455g, 1mmol) was dissolved in 10ml of methanol, and 0.1g of palladium on carbon was added to the solution at room temperature. Stirring at room temperature for 12 hours under the condition of hydrogen gas with ten atmospheres, filtering by using kieselguhr to remove palladium carbon after the reaction is finished, washing by using methanol for three times, and carrying out column chromatography to obtain a compound 1 which is a white solid, has the yield of 82 percent and has the following nuclear magnetic hydrogen spectrum data.
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)。
In a similar manner to example 1, compounds 2 to 6 were obtained, and the structural formulae and nuclear magnetic hydrogen spectrum data thereof are shown in the following table.
Test example 1
In vitro target compounds were tested for activity in inhibiting cancer cell proliferation in vitro.
The results of in vitro activity experiments on the target compounds for inhibiting cancer cell proliferation are shown in table 1.
Materials: MD-MBA-231 breast cancer cell strain, tetramethyl azodicarbonamide MTT, 10% fetal calf serum and 96-pore plate.
The method comprises the following steps:
cell culture: the MD-MBA-231 breast cancer cell strain adopts RPMI1640 culture solution containing 10% fetal calf serumBlowing and beating uniformly, and then inoculating into a culture flask, and culturing at 37 ℃ with 5% CO2Incubating in a saturated humidity cell culture box, digesting by 0.25% trypsin when the cell density reaches 70% -90%, and then carrying out passage.
Cell growth assay (MTT method): the MD-MBA-231 cell suspension was adjusted to 5X 104/mL and seeded in 96-well plates (100. mu.L/well) at 5000 cells/well. After plating for 4h, 100 μ L of medium containing different concentrations of compounds was added to each well to give final concentrations of compounds in the wells: 100. and four duplicate wells are arranged at each concentration of 50, 25, 12.5 and 6.25 mu g/mL, the wells without cells are used as blank controls when reading, the wells without cells are used as negative controls, and sorafenib is used as a compound positive control. At 37 ℃ with 5% CO2After 48h incubation, 10. mu.L of 0.5% MTT staining solution was added to each well, and after further incubation for 4h, the plate wells were centrifuged at 2500rpm for 12min, and then the plate wells were discarded, and DMSO solution was added at 100. mu.L/well. Measuring the absorption value OD value of each hole at 570nm on a microplate reader, and calculating the cell growth inhibition rate according to the following formula:
according to the concentration of the compound and the corresponding inhibition rate, the IC of each compound is obtained by fitting a curve by using origin7.5 software50。
TABLE 1
| Compound (I) | IC50(μM) |
| Compound 1 | 16.05±0.68 |
| Compound 2 | 10.27±0.38 |
| Compound 3 | 20.18±0.20 |
| Compound 4 | 18.35±0.29 |
| Compound 5 | 8.11±0.17 |
| Compound 6 | 21.72±0.37 |
| Sorafenib | 13.96±0.62 |
As can be seen from the results in Table 1, the IC of the compound of the present invention on MD-MBA-231 breast cancer cells50The compound is equivalent to sorafenib in magnitude order, and some compounds are obviously superior to sorafenib.
Example 1
The compound 1, lactose monohydrate, microcrystalline cellulose, sodium carboxymethylcellulose and magnesium stearate were sieved through a 100 mesh sieve. And (4) putting the sieved materials into a three-dimensional mixer for total mixing, wherein the rotating speed of the three-dimensional mixer is 10rpm, and the time is 15 minutes. The mixed material was directly compressed into tablets or filled into capsules to prepare 10 ten thousand units, each unit containing 20mg of the compound 1.
Example 2
The compound 2, lactose monohydrate, microcrystalline cellulose, sodium carboxymethylcellulose and magnesium stearate were sieved through a 100 mesh sieve. And (4) putting the sieved materials into a three-dimensional mixer for total mixing, wherein the rotating speed of the three-dimensional mixer is 10rpm, and the time is 15 minutes. The mixed material is directly compressed into tablets or filled into capsules to prepare 10 ten thousand units, and each unit contains 50mg of the compound 2.
Example 3
The compound 3, lactose monohydrate, microcrystalline cellulose, sodium carboxymethylcellulose and magnesium stearate were sieved through a 100 mesh sieve. And (4) putting the sieved materials into a three-dimensional mixer for total mixing, wherein the rotating speed of the three-dimensional mixer is 10rpm, and the time is 15 minutes. The mixed materials are directly compressed into tablets or filled into capsules to prepare 10 ten thousand units, and each unit contains 100mg of the compound 3.
Example 4
Compound 4, lactose monohydrate, microcrystalline cellulose, sodium carboxymethylcellulose, and magnesium stearate were sieved through a 100 mesh sieve. And (4) putting the sieved materials into a three-dimensional mixer for total mixing, wherein the rotating speed of the three-dimensional mixer is 10rpm, and the time is 15 minutes. The mixed material is directly compressed into tablets or filled into capsules to prepare 10 ten thousand units, and each unit contains 200mg of the compound 4.
Example 5
Compound 5, lactose monohydrate, microcrystalline cellulose, sodium carboxymethylcellulose, and magnesium stearate were sieved through a 100 mesh sieve. And (4) putting the sieved materials into a three-dimensional mixer for total mixing, wherein the rotating speed of the three-dimensional mixer is 10rpm, and the time is 15 minutes. The mixed material is directly compressed into tablets or filled into capsules to prepare 10 ten thousand units, and each unit contains 400mg of the compound 5.
Example 6
The compound 6, lactose monohydrate, microcrystalline cellulose, sodium carboxymethylcellulose and magnesium stearate were sieved through a 100 mesh sieve. And (4) putting the sieved materials into a three-dimensional mixer for total mixing, wherein the rotating speed of the three-dimensional mixer is 10rpm, and the time is 15 minutes. The mixed material is directly compressed into tablets or filled into capsules to prepare 10 ten thousand units, and each unit contains 400mg of the compound 6.
Test example 2
10 tablets of the solid dosage forms prepared in examples 1 to 6 were taken, respectively, subjected to dissolution profile measurement in an aqueous medium, and the average values of the dissolution rates at different times were measured and calculated, and the results are shown in table 2 below.
TABLE 2
As can be seen from the data in table 2, the solid dosage forms prepared according to the process of the present invention have more than 90% of the pharmaceutically active compound dissolved in water within 10 minutes, meeting the dissolution criteria for the solid dosage form.
The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.
Claims (4)
1. A solid dosage form of a vascular endothelial growth factor inhibitor contains a pharmaceutical active component, a filler, a disintegrant and a lubricant, and is characterized in that the content of the pharmaceutical active component is 20-80 wt%, the content of the filler is 10-70 wt%, the content of the disintegrant is 0.5-5 wt%, and the content of the lubricant is 0.5-5 wt%, wherein the pharmaceutical active component is a 1, 4-diaminenaphthalene derivative shown as the following and pharmaceutically acceptable salts thereof,
wherein the filler is at least one of anhydrous lactose, lactose monohydrate, sucrose, starch, dextrin, microcrystalline cellulose and pregelatinized starch;
the disintegrant is at least one of croscarmellose sodium, pregelatinized starch, sodium carboxymethylcellulose, polyvinylpyrrolidone and crospovidone;
the lubricant is at least one of magnesium stearate, calcium stearate, zinc stearate, talcum powder, silicon dioxide and polyethylene glycol powder.
2. The solid dosage form of claim 1, wherein the active ingredient is present in an amount of 50 to 80 wt.%, the filler is present in an amount of 16 to 46 wt.%, the disintegrant is present in an amount of 0.5 to 2 wt.%, and the lubricant is present in an amount of 0.5 to 2 wt.%, based on the total weight of the solid dosage form.
3. The solid dosage form of any one of claims 1-2, wherein the solid dosage form is a tablet or capsule and comprises 20mg, 50mg, 100mg, 200mg or 400mg of the pharmaceutically active ingredient per tablet or per capsule.
4. A method of preparing a solid dosage form according to any of claims 1 to 3, comprising the steps of:
(1) weighing the active ingredients, the filler, the disintegrant and the lubricant according to the proportion, and sieving the active ingredients, the filler, the disintegrant and the lubricant by a sieve of 60-100 meshes;
(2) putting the sieved materials into a three-dimensional mixer for total mixing, wherein the rotating speed of the three-dimensional mixer is 5-20 rpm, and the time is 5-30 minutes;
(3) and (3) directly pressing the mixed material obtained in the step (2) into tablets or filling capsules.
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| CN101132792A (en) * | 2005-03-01 | 2008-02-27 | 诺瓦提斯公司 | Pharmaceutical composition comprising an indolylmaleimide derivative |
| 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 |
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| CN101132792A (en) * | 2005-03-01 | 2008-02-27 | 诺瓦提斯公司 | Pharmaceutical composition comprising an indolylmaleimide derivative |
| 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 |
| 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 |
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