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A solid dosage form of vascular endothelial growth factor inhibitor and its preparation method

A technology of solid dosage forms and growth factors, which can be applied in pill delivery, pharmaceutical formulations, medical preparations of non-active ingredients, etc., and can solve problems such as adverse reactions, mutant tumor signal transduction compensatory, drug resistance, etc.

Active Publication Date: 2021-08-10
江西润泽药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although these tumor angiogenesis inhibitors have great advantages, there are still some problems in practical application, such as the dependence of some tumors on angiogenesis, drug resistance, adverse reactions and toxicity caused by mutation and compensatory tumor signal transduction.

Method used

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  • A solid dosage form of vascular endothelial growth factor inhibitor and its preparation method
  • A solid dosage form of vascular endothelial growth factor inhibitor and its preparation method
  • A solid dosage form of vascular endothelial growth factor inhibitor and its preparation method

Examples

Experimental program
Comparison scheme
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preparation example Construction

[0046] The preparation method of the 1,4-diaminonaphthalene derivative shown in formula (I) can comprise the following steps:

[0047] (a) making the compound shown in formula (1) carry out dealkylation reaction, obtain the compound shown in formula (2);

[0048] (b) making the compound shown in formula (2) carry out nucleophilic substitution reaction, obtain the compound shown in formula (3);

[0049] (c) In the presence of tert-butanol hydroperoxide and potassium hydroxide, a hydroxyl group is introduced into the compound shown in formula (3) to obtain a compound shown in formula (4);

[0050] (d) Substituting the compound shown in formula (4) to obtain the compound shown in formula (5);

[0051] (e) making the compound shown in formula (5) undergo an affinity substitution reaction with an amino substituent to obtain a compound shown in formula (6);

[0052] (f) making the compound shown in formula (6) undergo a hydrogenation reduction reaction to obtain the target compoun...

preparation example 1

[0079] (1) Preparation of 3-methoxy-5-nitro-2-naphthol

[0080]

[0081] Dissolve 6,7-dimethoxy-1-nitronaphthalene (4.66g, 20mmol) and L-methionine (2.98g, 20mmol) in 38.4g of methanesulfonic acid (400mmol), and reflux the oil bath at 90°C Stir the reaction under heating conditions for 8 hours, after TLC detects that the reaction is complete, neutralize the reaction with a saturated sodium bicarbonate solution until no bubbles emerge, the pH test paper detects that it is neutral or weakly alkaline, and then extract the aqueous phase 3 times with ethyl acetate, The ethyl acetate phases were combined, washed three times with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, evaporated to dryness under reduced pressure, and separated by column chromatography to obtain a yellow powdery solid (1.18 g, yield: 27%).

[0082] (2) Preparation of 4-(3-((3-methoxy-5-nitronaphthalene-2-) oxygen) propyl) morpholine

[0083]

[0084] Dissolve 3-methoxy-5...

Embodiment 1

[0115]

[0116]

[0117] The compound 1, lactose monohydrate, microcrystalline cellulose, sodium carboxymethylcellulose and magnesium stearate were passed through a 100-mesh sieve. The sieved materials were placed in a three-dimensional mixer for total mixing, and the rotation speed of the three-dimensional mixer was 10 rpm for 15 minutes. The mixed materials were directly compressed into tablets or filled into capsules to prepare 100,000 units, each unit containing 20 mg of the compound 1.

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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 pharmaceutically active component, a filler, a disintegrating agent and a lubricant, wherein, based on the total weight of the solid dosage form, the content of the pharmaceutically active component is 20%. -80% by weight, the content of the filler is 10-70% by weight, the content of the disintegrant is 0.5-5% by weight, and the content of the lubricant is 0.5-5% by weight, wherein the drug The active components are 1,4-diaminenaphthalene derivatives and their pharmaceutically acceptable salts and solvates. The solid dosage form of the vascular endothelial growth factor inhibitor can inhibit vascular endothelial growth factor, can be used for the treatment and / or prevention of epidermal growth factor receptor tyrosine kinase-related diseases in mammals, and can also be used for the treatment of tumor diseases.

Description

technical field [0001] 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 technique [0002] The results of clinical and basic medical research in recent years have confirmed that the occurrence, development and metastasis of tumors depend on the formation of new blood vessels. Tumor angiogenesis is the result of the interaction between tumor cells, vascular endothelial cells, and vascular extracellular matrix. Among them, the biological function of vascular endothelial growth factor VEFG (vascular endothelial growth factor) plays a key role in angiogenesis. [0003] Most cell growth factor receptors contain peptide sequences of tyrosine kinases, and overexpression or activation of different tyrosine kinase receptors can be seen in many tumors. According to the similarity of the peptide chain sequence and its structural characteristics...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/20A61K9/48A61K47/38A61K31/40A61K31/4453A61K31/5375A61P35/00
Inventor 廖年生胡贤德胡庭国邓五生
Owner 江西润泽药业有限公司