Phosphoric acid/phosphonic acid derivatives and medical applications thereof

A technology of phosphonic acid derivatives and derivatives, which can be used in sugar derivatives, pharmaceutical formulations, medical preparations containing active ingredients, etc., and can solve problems such as carcinogenesis

Active Publication Date: 2014-11-19
北京双鹭生物技术有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0025] However, when Pradefovir, MB07811 and MB07133 enter the body, they will produce highly carcinogenic metabolic intermediates, which have carcinogenic effects

Method used

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  • Phosphoric acid/phosphonic acid derivatives and medical applications thereof
  • Phosphoric acid/phosphonic acid derivatives and medical applications thereof
  • Phosphoric acid/phosphonic acid derivatives and medical applications thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0060] Preparation of Thio-cytidine (Cf1109)

[0061]

[0062] Dissolve 2.1 g (0.01 mol) of phenol dichlorophosphate and 1.3 g (0.01 mol) of L-alanine methyl ester in 30 mL of anhydrous dichloromethane, and cool to -78°C. A solution of 2 ml of triethylamine dissolved in 20 mL of anhydrous dichloromethane was added dropwise with stirring, and the rate of addition was controlled to maintain the reaction temperature at -78°C. After the addition was complete, the reaction temperature was gradually raised to room temperature, and stirring was continued for 1 hour. The solvent was distilled off under reduced pressure, and 30 ml of anhydrous diethyl ether was added to the residue, and filtered. Evaporate the filtrate to dryness under reduced pressure to obtain a colorless oil, which is the phosphoramide intermediate V 1 , used directly in the next reaction.

[0063] Dissolve 0.21g of lamivudine in 50ml of THF, then add 7ml of pyridine, blow nitrogen, add 1ml of 1M THF solution ...

Embodiment 1

[0083] Example 1 9-[[[bis-((benzo[1,3]dioxol-4-yl)-oxyl)-phosphono]-methoxy]-ethyl]-adenine (I 1 ) preparation

[0084]

[0085] Add 13.7g 9-[(phosphono-methoxy)-ethyl]-adenine (PMEA) and 13.8g 4-hydroxybenzo[1,3]dioxane to 100ml N-methylpyrrolidone, heat Stir at 90°C, then add 10ml of triethylamine and 20g of dicyclohexylcarbodiimide in sequence, and heat and stir at 90°C for 15 hours. Natural cooling overnight, the solid was filtered off; the filtrate was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed successively with a saturated solution of sodium carbonate (2×200ml) and a saturated solution of sodium chloride (2×200ml), and the organic layer was washed with anhydrous sulfuric acid The sodium was dried overnight, the desiccant was filtered off, the filtrate was evaporated to dryness under reduced pressure, separated by silica gel column chromatography, and eluted with a mixed solvent of dichloromethane:methanol (20:1), the desir...

Embodiment 2

[0086] Example 2 9-[[[bis-((benzo[1,3]dioxol-5-yl)-oxyl)-phosphono]-methoxy]-ethyl]-adenine (I 2 ) preparation

[0087]

[0088] Referring to the method of Example 1, 5-hydroxybenzo[1,3]dioxane was used instead of 4-hydroxybenzo[1,3]dioxane, condensed with PMEA, treated and separated and purified by a similar method, Obtain target compound I 2 , yield 14%. Proton NMR spectrum δ (ppm, DMSO-d6): 8.15(s, 1H); 8.11(s, 1H); 7.32(b, 2H); 6.77-6.75(d, 2H); 6.68(s, 2H); 6.49-6.47 (d, 2H); 5.99 (s, 4H); 4.35-4.33 (t, 2H); 3.93-3.91 (t, 2H); 3.80-3.78 (d, 2H).

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PUM

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Abstract

The present invention relates to phosphoric acid / phosphonic acid derivatives shown by formula (I), wherein R1 and R2 represent the following structures: (Q1), or (Q2), or (Q3). Q1 represents ester derivatives of L-amino acids, wherein R3 is alkyl or cycloalkyl with 1-6 carbon atoms, and R4 is H or alkyl with 1-6 carbon atoms; Q2 represents hydroxyl substituted benzodioxane derivatives; Q3 represents hydroxyl substituted benzodioxolane derivatives; R1 and R2 are the same or different, but at least one of them is Q2 or Q3; D represents residues of pharmacologically active molecules containing a phosphoric acid / phosphonic acid group, i.e. formula (II) represents pharmacologically active molecules containing a phosphoric acid / phosphonic acid group; and when R1 and R2 are different, the configuration of the P atom connected to R1 and R2 is of R or S type.

Description

technical field [0001] The present invention relates to novel liver-targeting prodrug derivatives of pharmacologically active molecules containing phosphoric acid or phosphonic acid groups in the molecule and their non-toxic pharmaceutically acceptable salts, hydrates or solvates, and derivatives containing the prodrugs The pharmaceutical composition formed by prodrug derivatives and their non-toxic pharmaceutically acceptable salts, hydrates or solvates as active ingredients and suitable excipients, as well as the prodrug derivatives and their non-toxic pharmaceutically acceptable Salts, hydrates or solvates, pharmaceutical compositions containing the prodrug derivatives and non-toxic pharmaceutically acceptable salts, hydrates or solvates thereof as active ingredients are used in the preparation of therapeutic drugs for liver diseases or metabolic diseases the use of. Background technique [0002] The liver is the target organ of viral hepatitis, liver cirrhosis, and live...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561C07F9/655C07F9/6558C07H19/10C07H19/207A61K31/675A61K31/665A61K31/7072A61K31/7076A61P31/20A61P1/16A61P3/00A61P3/06A61P3/10
CPCC07H19/10C07H19/207C07F9/6524C07F9/65517C07F9/65586C07F9/6561C07F9/657181C07F9/65742C07F9/3808C07F9/4065C07F9/4087A61P1/16A61P3/00A61P31/12A61P31/14A61P31/20A61P3/06A61P3/10C07F9/65616
Inventor 王建明陈晓光陈军平樊珊
Owner 北京双鹭生物技术有限公司
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