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Bong-seeking bisphosphonate rhein ester derivates and preparation method thereof

A technology of rhein ether and bisphosphonic acid, which can be used in the fields of medicinal chemistry and bone and joint disease treatment, and can solve problems such as reducing the quality of life of patients

Inactive Publication Date: 2010-06-16
上海慈瑞医药科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Pain and limited joint mobility are the most important problems in osteoarthritis, greatly reducing the patient's quality of life

Method used

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  • Bong-seeking bisphosphonate rhein ester derivates and preparation method thereof
  • Bong-seeking bisphosphonate rhein ester derivates and preparation method thereof
  • Bong-seeking bisphosphonate rhein ester derivates and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Example 1: 2-(1-Acetoxy-3-methoxycarbonyl-9,10-dihydro-9,10-diox-8-anthraquinone) oxyethyl-thio-ethyl bisphosphonic acid Synthesis of tetramethyl ester (compound 1):

[0061] Dissolve 1-acetoxyrhein methyl ester in tetrahydrofuran, add 2-hydroxyethyl-thio-ethyl bisphosphonate tetramethyl ester and triphenylphosphine, stir and add dropwise azo at -2°C Diethyl dicarboxylate, react with Mitrarobium at room temperature for 16 hours, evaporate the tetrahydrofuran in a water bath at 40°C under reduced pressure, add ethyl acetate to dissolve the residue, wash with water and saturated brine successively, and dry the organic layer with anhydrous sodium sulfate. Using petroleum ether: ethyl acetate=3:1 (V / V) as the eluent, column chromatography separates the light yellow product, which is the target compound.

[0062] Mass ratio of 1-acetoxyrhein methyl ester to tetrahydrofuran, 2-hydroxyethyl-thio-ethyl bisphosphonate tetramethyl, triphenylphosphine, diethyl azodicarboxylate and eth...

Embodiment 2

[0063] Example 2: 2-(1-Acetoxy-3-methoxycarbonyl-9,10-dihydro-9,10-diox-8-anthraquinone)oxyethyl-thio-ethyl bisphosphonic acid Synthesis of tetraethyl ester (compound 2):

[0064] Dissolve 1-acetoxyrhein methyl ester in tetrahydrofuran, add 2-hydroxyethyl-thio-ethyl bisphosphonate tetraethyl and triphenylphosphine, stir and drop at -5°C under ice salt bath Add diethyl azodicarboxylate, carry out Mitrarobium reaction at room temperature for 16 hours, evaporate tetrahydrofuran under reduced pressure in a water bath at 30°C, add ethyl acetate to dissolve the residue, wash with water and saturated brine successively, and use anhydrous sulfuric acid for the organic layer After drying with sodium, using petroleum ether:ethyl acetate=3:1 (V / V) as the eluent, column chromatography separates the light yellow product, which is the target compound.

[0065] Mass ratio of 1-acetoxyrhein methyl ester to tetrahydrofuran, 2-hydroxyethyl-thio-ethyl bisphosphonate tetraethyl, triphenylphosphine, d...

Embodiment 3

[0066] Example 3: 2-(1-Acetoxy-3-methoxycarbonyl-9,10-dihydro-9,10-diox-8-anthraquinone) oxyethyl-thio-ethyl bisphosphonic acid Synthesis of tetrabenzyl ester (compound 3):

[0067] Dissolve 1-acetoxyrhein methyl ester in tetrahydrofuran, add 2-hydroxyethyl-thio-ethyl bisphosphonate tetrabenzyl and triphenylphosphine, stir and add dropwise under ice salt bath at 0℃ Diethyl azodicarboxylate, react with Mitreirob at room temperature for 16 hours, evaporate tetrahydrofuran under reduced pressure at 45°C in a water bath, add ethyl acetate to dissolve the residue, wash with water and saturated brine successively, and use anhydrous sodium sulfate for the organic layer After drying, using petroleum ether:ethyl acetate=3:1 (V / V) as the eluent, column chromatography separates the light yellow product, which is the target compound.

[0068] Mass ratio of 1-acetoxyrhein methyl ester to tetrahydrofuran, 2-hydroxyethyl-thio-ethyl bisphosphonate tetrabenzyl, triphenylphosphine, diethyl azodicar...

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Abstract

The invention discloses bisphosphonate rhein ester derivate compounds of general formula (I). In the formula (I), R1 represents hydrogen, substituted or non-substituted C1 to C6 alkyl or benzyl; R2 represents hydrogen or acetyl; R3 represents hydrogen, methyl, ethyl or benzyl; and n is any integer of between 1 and 5. The invention also discloses a method for preparing the bisphosphonate rhein ester derivate compounds by a condensation reaction. Because of good bone-seeking property, the compounds of the invention can be used for curing osteoarthritis.

Description

Technical field [0001] The invention relates to a bisphosphonate rhein ether derivative with osteotaxis and a preparation method thereof, and belongs to the technical field of medicinal chemistry and bone and joint disease treatment. Background technique [0002] Osteoarthritis (OA) refers to a group of heterogeneous diseases related to joint symptoms and signs with impaired articular cartilage integrity, subchondral bone plate and joint marginal bone disease, that is, articular cartilage degeneration and subsequent A chronic arthropathy of primary bone hyperplasia, which is the result of degeneration due to abnormal biosynthesis of articular cartilage proteoglycan. Approximately 85% of the elderly in the United States over the age of 75 suffer from various degrees of arthritis. The incidence of osteoarthritis in my country is 9.6% in rural areas and 49% in urban retired people. This degenerative arthritis disease can invade the joints of the fingers, knees, hips, spine, etc. Th...

Claims

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Application Information

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IPC IPC(8): C07F9/40A61K31/662A61P29/00A61P19/02
Inventor 汤磊王建塔朱高峰
Owner 上海慈瑞医药科技股份有限公司