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Statin-diphosphonic acid conjugates, preparation method and application thereof

A technology of a conjugate and bisphosphonate, applied in the field of statin-bisphosphonate conjugates, achieves the effects of good osteophilicity and a simple and feasible synthesis method

Inactive Publication Date: 2008-07-09
HUNAN NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no report on the synthesis method and application of bisphosphonates containing statin structure in the prior art

Method used

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  • Statin-diphosphonic acid conjugates, preparation method and application thereof
  • Statin-diphosphonic acid conjugates, preparation method and application thereof
  • Statin-diphosphonic acid conjugates, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] (1) Preparation of fluvastatin lactone

[0022] Take 1228mg (2.98mmol) of fluvastatin, 484mg of N,N'-carbonyldiimidazole, dissolve in 100ml of dichloromethane, stir at room temperature for 48h, evaporate the solvent under reduced pressure, and use ethyl acetate:n-hexane (1:1) column Chromatography, the column chromatography product was dissolved in 5ml of ethyl acetate, and 30ml of petroleum ether was added dropwise to obtain 0.415g of fluvastatin lactone crystals, with a yield of 35.2%

[0023] (2) Statin-bisphosphonic acid conjugate ((3S, 5R, E)-7-(3-(4-fluorophenyl)-1-isopropyl-1-hydrogen-2-indole)-3, Preparation of 5-dihydroxy-6-heptenamide) tetraethyl methine diphosphate:

[0024] Get 166mg (0.4mmol) fluvastatin lactone, dissolve in 3ml (mass ratio 1: 15) tetrahydrofuran, add 183mg aminomethine bisphosphonate tetraethyl ester (0.6mmol, molar ratio 1.2 times), the reaction mixture is in Stir and react at 50°C for 48 hours. After the reaction is complete, distill o...

Embodiment 2

[0032] (1) Preparation of atorvastatin lactone:

[0033] Get atorvastatin 0.5g (0.813mmol), be dissolved in 10ml toluene, heat to reflux for 4 hours, evaporate solvent under reduced pressure, ethyl acetate:n-hexane:methanol=4:4:1 column chromatography, obtain atorvastatin Vastatin lactone 327mg. Yield 74.4%.

[0034] (2) 3-((3R, 5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrole- Preparation of 1-yl)-3,5-dihydroxy-6-heptaneamide)propane-1,1-bisphosphonic acid tetraethyl ester

[0035] Take 327mg (0.605mmol) of atorvastatin lactone, 360mg (1.086mmol, molar ratio 1:3) of 3-aminopropane-1,1-bisphosphonate tetraethyl ester, dissolve in 20ml (mass ratio 1:53) Toluene, stirred at 70°C for 12 hours, after the reaction was complete, the solvent was distilled off under reduced pressure, and column chromatography of ethyl acetate:n-hexane:methanol (4:4:1) gave compound 5: 3-((3R,5R)-7- (2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1...

Embodiment 3

[0042] (1): 3-((3S,5R,E)-7-(3-(4-fluorophenyl)-1-isopropyl-1-hydrogen-2-indole)-3,5-dihydroxy Preparation of -6-heptenamide) propane-1,1-bisphosphate tetraethyl ester

[0043] Take 149mg (0.362mmol) of fluvastatin lactone, 240mg (0.706mmol, 2 times) of 3-aminopropane-1,1-bisphosphonate tetraethyl ester, dissolve in 7ml (mass ratio 1:41) benzene, 55°C Stirred for 20 hours, the reaction was complete, the solvent was distilled off under reduced pressure, and ethyl acetate:n-hexane:methanol (4:4:1) column chromatography gave compound 6,3-((3S,5R,E)-7-( 3-(4-Fluorophenyl)-1-isopropyl-1-hydrogen-2-indole)-3,5-dihydroxy-6-heptenamide)propane-1,1-bisphosphate tetraethyl Ester 0.211g, yield: 80.4% Compound NMR and phosphorus spectrum data are as follows:

[0044] 1 HNMR (CCl 3 D) 7.554-6.999 (m, 8H); 6.688 (d, 1H, J = 16.2); 5.709 (dd, 1H, J = 5.1, 15.6); 4.864 (t, 1H, J = 6.9); 4.480 (t, 1H, J=5.4); 4.230-4.119(m, 9H); 3.545-3.419(m, 2H); 2.462(tt, 1H, J=5.7, 24.6); 2.362-2.055(m...

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Abstract

The invention relates to a statin-double phosphonate coupling compound for curing osteoporosis and other bone calcium metabolic diseases and a preparation process and an application, in particular to an atorvastain or fluvastatin-coupling compound and a synthesis and an application. The invention comprises mixing fluvastatin lactone or atorvastain lactone and double phosphonate according to statin lactone: double phosphonate ester= 1:1-3, obtaining statin double phosphonate coupling compound, and then obtaining salt through the reaction of the 1:4-20:4-20 proportion of double phosphonate coupling compound: 2, 4, 6-trimethyl pyridine: trimethyl bromo-silicane in solution with below 5-10 DEG C of reaction temperature. The synthesis process of the invention is simple, which can synthesize eight new compounds, namely that four new intermediate compounds and four target compounds, and provides an effective medicament for preventing and curing osteoporosis and other bone calcium metabolic diseases.

Description

technical field [0001] The invention relates to a statin-bisphosphonic acid conjugate which can be used for treating osteoporosis and other bone-calcium metabolism diseases, its preparation method and application. Specifically, it is atorfastatin or fluvastatin-bisphosphonate or atorfastatin or fluvastatin-bisphosphonate and its synthesis method and application. Background technique [0002] Osteoporosis is a common bone metabolic disease. Bisphosphonic acid compounds have become effective drugs for the treatment of this disease because of their unique osteotropic properties and good chelation effects. However, these compounds can only inhibit bone resorption unilaterally. , does not promote bone formation. Because of its good bone affinity, it can be used as a carrier of bone formation-promoting drugs to deliver the bone-forming drugs to the target bone tissue, and at the same time, it can also inhibit bone resorption, thereby achieving dual curative effects. According to...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/572A61K31/663A61P19/10A61P3/14
Inventor 徐广宇左高磊
Owner HUNAN NORMAL UNIVERSITY
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