CN1513861A - Ibuprofen sugar conjugated product and its preparation method and application - Google Patents
Ibuprofen sugar conjugated product and its preparation method and application Download PDFInfo
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- CN1513861A CN1513861A CNA031391168A CN03139116A CN1513861A CN 1513861 A CN1513861 A CN 1513861A CN A031391168 A CNA031391168 A CN A031391168A CN 03139116 A CN03139116 A CN 03139116A CN 1513861 A CN1513861 A CN 1513861A
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- ibuprofen
- acetyl
- glucosamine
- deoxidation
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Abstract
A brufen saccharide conjugate C21H32N2O6 or 1-(2-deoxy-2-N-acetyl-glucose amine)-(+/-) brufen is prepared through converting N-acetylglocose in the supersaturated aqueous solution of ammonium dicarbonate to become N-acetylglucose amine, and coupling it with 2-(isobutylphenyl)-isopropylacylchlorine. It can be used to prepare the medicine for treating rheumatic or rheumatoid arthritis.
Description
Technical field
The present invention relates to a kind of Ibuprofen BP/EP glycoconjugate and simple and effective preparation method and application thereof.
Background technology
Ibuprofen BP/EP is a kind of NSAID (non-steroidal anti-inflammatory drug) (NSAIDs), be the active drug of treatment rheumatism, rheumatoid arthritis, but stomach and intestine are had stronger side effect, and drug half-life is short, and bioavailability is lower.For addressing these problems, people have carried out many-sided research, for example improvement of formulation, specificity NSAID (non-steroidal anti-inflammatory drug)--research of COX2 inhibitor and the research of NO-NSAIDs etc., but all can't thoroughly address the above problem.
Summary of the invention
The purpose of this invention is to provide a kind of Ibuprofen BP/EP glycoconjugate and its production and application, it can overcome the above-mentioned shortcoming of prior art.
A kind of Ibuprofen BP/EP glycoconjugate, the chemical name that it is characterized in that it are 1-(2-deoxidation-2-N-acetyl-glucosamine)-(±) Ibuprofen BP/EP, and molecular formula is C
21H
32N
2O
6, structural formula is
A kind of preparation method of Ibuprofen BP/EP glycoconjugate; it is characterized in that the N-acetyl glucosamine is dissolved in the unsaturated carbonate hydrogen aqueous ammonium; stirring reaction is 2～3 days under 40～45 ℃ of conditions; obtain the N-acetylglucosamine; then with the N-acetylglucosamine directly and 2-(isobutyl phenenyl)-different propionyl chloride carry out acylation reaction, obtain 1-(2-deoxidation-2-N-acetyl-glucosamine)-(±) Ibuprofen BP/EP through ethyl alcohol recrystallization.
The medicine that 1-(2-deoxidation-2-N-acetyl-glucosamine)-(±) Ibuprofen BP/EP is used to make treatment rheumatism, rheumatoid arthritis.
The present invention has overcome the drawback of traditional glycoconjugate preparation method complex steps, mainly refers to the protection-deprotection steps of glycosyl part.Prepare target compound by directly connecting mode with 2-(isobutyl phenenyl)-different propionyl chloride work in order to the key of amido linkage after the amination of unprotected acetamido glucose, simplified operation steps, making it suitability for industrialized production becomes possibility.1-of the present invention (2-deoxidation-2-N-acetyl-glucosamine)-(±) Ibuprofen BP/EP can be used for making the medicine of treatment rheumatism, rheumatoid arthritis.
Embodiment
1. the ratio of N-acetyl glucosamine in 1% (w/v) is dissolved in the unsaturated carbonate hydrogen aqueous ammonium, under 40-45 ℃ of condition stirring reaction 2-3 days, gradation is added solid ammonium bicarbonate to keep the state of saturation of solution in the reaction process, question response finishes, and is evaporated to half after adding a certain amount of distilled water diluting, and then mends and add water to original volume, reconcentration is to half, so repetitive operation is 5 times, last lyophilize, the quantitative N-acetylglucosamine crude product that obtains.
2. 1.22g (5.5mmol) N-acetylglucosamine crude product is dissolved in the 30mL methyl alcohol, add 1.0g (7.1mmol) triethylamine, treat that complete molten back drips 1.5g (6.8mmol) 2-(isobutyl phenenyl)-different propionyl chloride under condition of ice bath, continue reaction 1.5h with this understanding, add suitable quantity of water behind the stopped reaction and separate out a large amount of solids, filter, gained filter residue recrystallization in ethanol obtains target compound--1-(2-deoxidation-2-N-acetyl-glucosamine)-(±) Ibuprofen BP/EP, yield: 65.0%.Reaction formula is as follows:
Physico-chemical property: mp253～255 ℃, [α]
D 20+ 56 ° of (CH
3OH).
1H-NMR(DMSO)δ：8.17，8.15(d，1H，J＝9.1Hz，NHCOCH
3)，7.87，7.65(d，1H，J＝9.1Hz，NHCOCH)，7.20，7.15(d，2H，J＝8.0Hz，H-2′，H-6′)，7.06，7.03(d，2H，J＝8.3Hz，H-3′，H-5′)，5.00，4.98(d，1H，J＝5.2Hz，4-OH)，4.97，4.92(d，1H，J＝5.2Hz，3-OH)，4.76，4.72(t，1H，J＝9.6Hz，H-1，β)，4.58，4.53(t，1H，J＝6.0Hz，6-OH)，3.66，3.62(dd，1H，J＝12.1，5.4Hz，H-6a)，3.61(q，1H，J＝6.9Hz，COCHCH
3)，3.54(q，1H，J＝9.9Hz，H-2)，3.45～3.36(m，1H，H-6b)，3.31～3.28，3.24～3.20(m，1H，H-3)，3.10～3.03(m，2H，H-4，H-5)，2.39，2.38(d，2H，J＝7.1Hz，CH
2CH(CH
3)
2)，1.81～1.73(m，1H，CH
2CH(CH
3)
2)，1.45(s，3H，NHCOCH
3)，1.27(d，3H，J＝6.9Hz，COCHCH
3)，0.84(d，6H，J＝6.6Hz，CH
2CH(CH
3)
2).
13C-NMR(DMSO)δ：174.0(COCHCH
3)，170.0(NHCOCH
3)，139.5，139.3(C-4′)，139.0，138.7(C-1′)，128.8(C-2′，C-6′)，127.4，127.0(C-3′，C-5′)，79.3，79.0(C-1)，78.9，78.8(C-5)，74.5，74.3(C-3)，70.6，70.5(C-4)，60.8，61.0(C-6)，54.9，54.2(C-2)，44.9，44.5(NHCOCHCH
3)，44.3(CH
2CH(CH
3)
2)，29.8(CH
2CH(CH
3)
2)，22.5(NHCOCH
3)，22.3，22.2(CH
2CH(CH
3)
2)，17.7(COCHCH
3).IRυ
max：3294(NH)，1663，1545(CONH).HRMS：m/z?Calcd?for?C
21H
33NO
6[M+H]409.2329，found?409.2333.
3. 1-of the present invention (2-deoxidation-2-N-acetyl-glucosamine)-(±) Ibuprofen BP/EP has been carried out the inhibiting pharmacological evaluation of mouse ear Oleum Tiglii inflammation.The mouse random packet, is divided into trial-product group and control group, trial-product group subcutaneous injection trial target 50mgkg by 10 every group
-110mL
-1Physiological saline, control group injecting normal saline 10mLkg
-130min behind administration or the physiological saline, mouse left side ear is coated with 2% crotons fluid (V (Oleum Tiglii): V (ethanol): V (ether)=2: 20: 78) 50uL, 4h post-tensioning neck is put to death, cut ears, sweep away two auricles, weigh respectively with diameter 8mm stainless steel blunderbuss, with about two ear weight differences be the swelling degree, compare with control group, calculate ear swelling inhibiting rate (%), formula is as follows:
The pharmacological results finds that the ear swelling inhibiting rate of 1-of the present invention (2-deoxidation-2-N-acetyl-glucosamine)-(±) Ibuprofen BP/EP and Ibuprofen BP/EP is respectively 47.2%, 1.9%, illustrates that the anti-inflammatory activity of 1-(2-deoxidation-2-N-acetyl-glucosamine)-(±) Ibuprofen BP/EP obviously is better than Ibuprofen BP/EP.
4. 1-of the present invention (2-deoxidation-2-N-acetyl-glucosamine)-(±) Ibuprofen BP/EP has been carried out the pharmacological evaluation of mouse gastrointestinal damage.1-of the present invention (2-deoxidation-2-N-acetyl-glucosamine)-(±) Ibuprofen BP/EP and reference substance Ibuprofen BP/EP are made into the suspension of 12.5mg/ml respectively with 0.5%CMC-Na, press the 0.2ml/10g gastric infusion, behind the 45min, draw neck to put to death, dissect and take out stomach, inject fixedly 0.5h of 5% formalin.Cut off along the greater gastric curvature place then, wash away content, pave.The blutpunkte of visual inspection lining endothelium, point-like or streak ulcer are weighed degree of injury with this.Found that 1-of the present invention (2-deoxidation-2-N-acetyl-glucosamine)-(±) Ibuprofen BP/EP compares with Ibuprofen BP/EP, the gastrointestinal damage side effect significantly reduces.
Claims (3)
1. Ibuprofen BP/EP glycoconjugate, the chemical name that it is characterized in that it is 1-(2-deoxidation-2-N-acetyl-glucosamine)-(±) Ibuprofen BP/EP, molecular formula is C
21H
32N
2O
6, structural formula is
2. the preparation method of an Ibuprofen BP/EP glycoconjugate; it is characterized in that the N-acetyl glucosamine is dissolved in the unsaturated carbonate hydrogen aqueous ammonium; stirring reaction is 2～3 days under 40～45 ℃ of conditions; obtain the N-acetylglucosamine; then with the N-acetylglucosamine directly and 2-(isobutyl phenenyl)-different propionyl chloride carry out acylation reaction, obtain 1-(2-deoxidation-2-N-acetyl-glucosamine)-(±) Ibuprofen BP/EP through ethyl alcohol recrystallization.
3. 1-(2-deoxidation-2-N-acetyl-glucosamine)-(±) Ibuprofen BP/EP is used to make the medicine of treatment rheumatism, rheumatoid arthritis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03139116 CN1226300C (en) | 2003-08-15 | 2003-08-15 | Ibuprofen sugar conjugated product and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03139116 CN1226300C (en) | 2003-08-15 | 2003-08-15 | Ibuprofen sugar conjugated product and its preparation method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1513861A true CN1513861A (en) | 2004-07-21 |
| CN1226300C CN1226300C (en) | 2005-11-09 |
Family
ID=34240158
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 03139116 Expired - Fee Related CN1226300C (en) | 2003-08-15 | 2003-08-15 | Ibuprofen sugar conjugated product and its preparation method and application |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1300159C (en) * | 2005-02-24 | 2007-02-14 | 华东理工大学 | Ibuprofen sugar derivative and its preparing process and use |
| ITNA20080047A1 (en) * | 2008-07-29 | 2010-01-30 | Maria Grazia Rimoli | KETOROLAC GALACTOSILATE PROFARM FOR ANALGESIC AND ANTI-INFLAMMATORY USE WITH BETTER PHARMACOKINETIC CHARACTERISTICS AND TOXICOLOGICAL PROFILE OF THE STARTING DRUG |
-
2003
- 2003-08-15 CN CN 03139116 patent/CN1226300C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1300159C (en) * | 2005-02-24 | 2007-02-14 | 华东理工大学 | Ibuprofen sugar derivative and its preparing process and use |
| ITNA20080047A1 (en) * | 2008-07-29 | 2010-01-30 | Maria Grazia Rimoli | KETOROLAC GALACTOSILATE PROFARM FOR ANALGESIC AND ANTI-INFLAMMATORY USE WITH BETTER PHARMACOKINETIC CHARACTERISTICS AND TOXICOLOGICAL PROFILE OF THE STARTING DRUG |
| WO2010013279A2 (en) * | 2008-07-29 | 2010-02-04 | Stewart Italia Srl | Galactosylated pro-drugs of non-steroidal anti-inflammatories with improved pharmacokinetic characteristics and reduced toxicity of the starting drug |
| WO2010013279A3 (en) * | 2008-07-29 | 2010-05-06 | Stewart Italia Srl | Galactosylated pro-drugs of non-steroidal anti-inflammatories with improved pharmacokinetic characteristics and reduced toxicity of the starting drug |
| US8551958B2 (en) | 2008-07-29 | 2013-10-08 | Stewart Italia Srl | Galactosylated pro-drugs of non-steroidal anti-inflammatories with improved pharmacokinetic characteristics and reduced toxicity of the starting drug |
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| Publication number | Publication date |
|---|---|
| CN1226300C (en) | 2005-11-09 |
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