Nitric oxide-releasing glucocorticosteroid

A technology of corticosteroids and nitric oxide, applied in the field of anti-inflammatory drugs and NO-donating glucocorticoids, which can solve the problems of general anti-inflammatory effects of glucocorticoids and insignificant side effects of glucocorticoids

Inactive Publication Date: 2009-04-01
TIANJIN PHARMA GROUP CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the stability ratio—NO 2 Donor glucocorticoids are good, but because hydrocortisone is a low-efficiency, low-side-effect glucocorticoid, the anti-inflammatory effect of the prepared NO-donating glucocorticoid is average, and the effect of reducing the side effects of glucocorticoid is not good. obvious

Method used

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  • Nitric oxide-releasing glucocorticosteroid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0100] Synthesis of Furazamethylprednisolone

[0101] 1) Synthesis of 4-(methylprednisolone-21-oxo-)-4-oxo-butyric acid (3.1)

[0102] Dissolve 5.62g (15mmol) of methylprednisolone in 80ml of pyridine, add 3g (30mmol) of succinic anhydride, heat and reflux for 10 hours to stop the reaction, pour it into 200ml of saturated ice brine after cooling, adjust the pH to 5 with hydrochloric acid, and let it stand A white solid was precipitated, filtered and washed with water to obtain 6.01 g of the product with a yield of 84.4%.

[0103] 2) 4-(methylprednisolone-21-oxo-)-4-oxo-butyric acid-2-[2-(3-benzenesulfonyl-1,2,5-oxadiazole-2-oxide- Synthesis of 4-oxygen-)ethoxy]ethyl ester (9.1)

[0104] Dissolve 0.6g (1mmol) of compound (3.1) in 20ml of anhydrous dichloromethane, add 1mmol of (8.1), 0.206g (1mmol) of DCC, and a few capsules of DMAP, and react at room temperature for 20h until white flocculents appear in the reaction solution. The product was formed, filtered and concentrate...

Embodiment 2

[0110] Furazan dexamethasone

[0111] 1) Synthesis of 2-(dexamethasone-21-oxo-)-2-oxo-acetic acid (3.2)

[0112] Dissolve 5.89g (15mmol) of dexamethasone in 80ml of pyridine, add 2.58g (30mmol) of oxalic anhydride, stop the reaction after heating back for 8 hours, pour it into 200ml of saturated ice-salt water after cooling, and adjust the pH to 5 with hydrochloric acid to stand still Precipitate a white solid, filter and wash with water to obtain 4.69g of product, yield 65.3% IR

[0113] 2) 2-(dexamethasone-21-oxo-)-2-oxo-acetic acid-2-[2-(3-benzenesulfonyl-1,2,5-oxadiazole-2-oxide-4 - Oxygen -) ethoxy] ethyl ester (9.2) synthesis

[0114] Dissolve 0.5g (1mmol) of compound (3.2) in 20ml of anhydrous dichloromethane, add 1mmol of (8.1), 0.206g (1mmol) of DCC, several capsules of DMAP, and react at room temperature for 20h until white flocculents appear in the reaction liquid The product was formed, filtered, and concentrated by column chromatography ethyl acetate:petroleum ...

Embodiment 3

[0121] Furazancisonide

[0122] 1) Synthesis of 4-(desisobutyryl ciclesonide-21-oxy)-4-oxo-butyric acid (3.3)

[0123] Dissolve 7.62g (15mmol) of deisobutyryl-ciclesonide in 80ml of pyridine, add 3g (30mmol) of succinic anhydride, heat and reflux for 10 hours to stop the reaction, pour it into 200ml of saturated ice-water brine after cooling, and wash with hydrochloric acid Adjust the pH to 5, and a white solid precipitates out after standing still. After filtering and washing with water, 5.5 g of the product is obtained with a yield of 55%.

[0124] 2) 4-(Deisobutyryl ciclesonide-21-oxygen)-4-oxo-butanoic acid [2-(3-benzenesulfonyl-1,2,5-oxadiazole-2-oxide-4 Synthesis of -oxygen-)ethoxy]ethyl ester (9.3)

[0125] Dissolve 0.7g (1mmol) of compound (3.3) in anhydrous dichloromethane, add (8.1) 1mmol, 0.206g (1mmol) of DCC, several capsules of DMAP, and react at room temperature for 20h until a white flocculent product is formed in the reaction solution , filtered, and concen...

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Abstract

The invention provides a nitric oxide-donating glucocorticoid, which is a compound (II) or the ester or the slat thereof of the following general formula: A-L-X, wherein, A is steroid hormones residue, a bridge group L can be linked with the hydroxyl group on R' th or 17th in a form of ester linkage, a bivalent bridge group L is selected from -(CO)Ob1 (C R'4R'5) na (CO)(R7)-, wherein, na is an integer from 0 to 4, b1 is an integer from 0 to 1, R4, R' 4or R'5 and R5 are equal or mutually different and are selected from H which has the saturated or unsaturated alkyl with 1-8 carbon atoms; the chain can be a straight chain, a branched chain or a ring, and the preference is that na is equal to 2, b1is 0, R4 is equal to R5 is equal to R' 4 is equal to R' 5 is equal to H. The invention further provides the application of the compound, or the physiologically acceptable slat, or the solvate thereof in producing the medicines for treating inflammatory, allergic or anaphylactic diseases.

Description

Technical field: [0001] The invention relates to the field of pharmaceutical compounds, in particular to NO donor glucocorticoids. The invention also discloses a preparation method of the derivative and its use as an anti-inflammatory drug. Background technique: [0002] Glucocorticoids are widely used clinically because of their powerful pharmacological effects, but long-term use can easily induce many adverse reactions such as hypertension, Cushing's syndrome, osteoporosis, diabetes, etc. For this reason, the international medical community has been working hard in recent years Pursue the development of new glucocorticoids with fewer side effects and better effects. [0003] Nitric oxide (NO) participates in the regulation of many physiological functions in the body, and is closely related to the cardiovascular system, nervous system, immune system, bone metabolism system, etc. It is a small molecule compound that has been studied in depth. In recent years, NO-donating dr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J43/00A61K31/58A61P29/00A61P37/00
Inventor 卢彦昌李静陈立营陈松
Owner TIANJIN PHARMA GROUP CORP
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