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RGD peptide-epimedium flavone combination, preparation method and application thereof

A technology of Huo flavonoid conjugates and epimedium, which is applied in the field of pharmaceutical compounds, can solve the problems of lack of theoretical guidance and unified standards, shortage, confusion of traditional Chinese medicine prescriptions, etc., and achieve the effects of high yield, easy product and fast synthesis speed

Inactive Publication Date: 2010-12-29
李毅林
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the chaotic prescription of traditional Chinese medicine, too much reliance on clinical experience, and the lack of modern pharmacological research make the traditional Chinese medicine treatment of osteoporosis lack of systematic theoretical guidance and unified standards, which greatly inhibits the development of traditional Chinese medicine treatment of osteoporosis.

Method used

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  • RGD peptide-epimedium flavone combination, preparation method and application thereof
  • RGD peptide-epimedium flavone combination, preparation method and application thereof
  • RGD peptide-epimedium flavone combination, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Synthesis of N-4-(7-O-Epimedium flavonoids) butyryl-RGD (n=3 in general formula II):

[0054] synthetic N G -Mesitylenesulfonyl-RGD dimethyl ester (Arg(Mts)-Gly-Asp(OMe) 2 ):

[0055] N G -Mesitylenesulfonyl-N-benzyloxycarbonyl-RGD dimethyl ester (Cbz-Arg(Mts)-Gly-Asp(OMe) 2 , Compound III) (5.0g, 7.2mmol) was dissolved in 400ml of methanol, 10% carbon-supported palladium catalyst (0.5g) was added, hydrogen was introduced and stirred at room temperature for 24h, the catalyst was removed by diatomaceous earth filtration, and the filtrate was evaporated under reduced pressure Solvent yielded 3.6 g of white solid N G -Mesitylenesulfonyl-RGD dimethyl ester (Arg(Mts)-Gly-Asp(OMe) 2 ), yield 89%;

[0056] Synthesis of N-(4-bromobutyryl)-N G -Mesitylenesulfonyl-RGD dimethyl ester (Br(Br(CH 2 ) 3 CO-Arg(Mts)-Gly-Asp(OMe) 2 ):

[0057] 4-Bromobutyric acid (1.1g, 6.5mmol) was dissolved in 200ml of dry dichloromethane, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide s...

Embodiment 2

[0063] Example 2 Synthesis of N-11-(7-O-Epimedium flavonoids)undecanoyl-RGD (n=10 in general formula II):

[0064] synthetic N G -Mesitylenesulfonyl-RGD dimethyl ester (Arg(Mts)-Gly-Asp(OMe) 2 ): with embodiment 1 step 1).

[0065] Synthesis of N-(11-bromoundecanoyl)-N G -Mesitylenesulfonyl-RGD dimethyl ester (Br(Br(CH 2 ) 10 CO-Arg(Mts)-Gly-Asp(OMe) 2 ):

[0066] 11-Bromoundecanoic acid (530 mg, 2.0 mmol) was dissolved in 100 ml of dry dichloromethane, and benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate (PyBOP ) (1.0g, 2.0mmol), 1-hydroxy-7-azobenzotriazole (HOAt) (50mg, 0.4mmol), N G -Mesitylenesulfonyl-RGD dimethyl ester (Arg(Mts)-Gly-Asp(OMe) 2 ) (1.1g, 2.0mmol), N, N-diisopropylethylamine (0.7ml, 4mmol), stirred at room temperature for 48 hours after adding, then added 100ml dichloromethane, and used 200ml 1mol / liter Wash twice with hydrochloric acid, then wash with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dr...

Embodiment 3

[0073] Example 3 Synthesis of N-21-(7-O-Epimedium flavonoids) eicosanoyl-RGD (n=20 in general formula II):

[0074] synthetic N G -Mesitylenesulfonyl-RGD dimethyl ester (Arg(Mts)-Gly-Asp(OMe) 2 ): with embodiment 1 step 1).

[0075] Synthesis of N-(21-bromoicocoyl)-N G -Mesitylenesulfonyl-RGD dimethyl ester (Br(Br(CH 2 ) 20 CO-Arg(Mts)-Gly-Asp(OMe) 2 ):

[0076] 21-Bromoeicosanoic acid (810mg, 2.0mmol) was dissolved in 100ml of dry dichloromethane, and benzotriazole-N,N,N',N'-tetramethylurea was added to the solution in sequence Hexafluorophosphate (HBTU) (1.1g, 3.0mmol), 6-chloro-1-hydroxybenzotriazole (Cl-HOBt) (140mg, 0.8mmol), N G -Mesitylenesulfonyl-RGD dimethyl ester (Arg(Mts)-Gly-Asp(OMe) 2 ) (1.1g, 2.0mmol), N, N-dimethylaminopyridine (DMAP) (600mg, 10mmol), stirred at room temperature for 24 hours after adding, then added 100ml dichloromethane, and used 200ml 1mol / liter Wash twice with hydrochloric acid, then wash with saturated aqueous sodium bicarbonate and...

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Abstract

The invention provides an RGD peptide-epimedium flavone combination synthesized by combining two structural units of RGD peptides and epimedium flavone which have pharmacological activities of different action mechanisms on osseous metabolic diseases, and also provides a synthesis method thereof. The compound of the invention has two receptor combining sites and simultaneously has the capability of combining estrogen receptors of icaritin and the capability of combining integrins alphaVbeta3 of RGD, and the capabilities of combining the two different receptors can produce a synergistic effect to greatly improve the curative activity of the medicament on osteoporosis and osseous metabolic diseases. The synthesis method has the advantages of high yield, high synthesis speed and easy purification of products.

Description

technical field [0001] The present invention relates to an RGD peptide (peptide containing arginine-glycine-aspartic acid)-Epimedium flavone conjugate, its preparation method and its application in the preparation of medicines for treating osteoporosis and bone metabolism diseases , belonging to the field of pharmaceutical compounds. Background technique [0002] In healthy individuals, the process of bone formation and degradation is in balance, and the activities of osteoblasts and osteoclasts are coordinated with each other. If this balance is broken, the activity of either osteoblast or osteoclast is high, regardless of tendency Both osteoclastosis and osteogenesis will lead to the degeneration of bone structure and function, as well as osteopenia and bone metabolic diseases. Osteoporosis (Osteoporosls, OP disease) caused by various reasons is a bone metabolic disease characterized by decreased bone mass, degeneration of bone tissue structure, decreased bone strength, i...

Claims

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Application Information

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IPC IPC(8): C07K5/09A61K31/352A61K47/48A61P19/08A61P19/10A61K47/64
Inventor 李毅林朱轶才张洁
Owner 李毅林
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