CN101775027A - Novel derivative of Aspoxicillin and preparation method and medical application thereof - Google Patents
Novel derivative of Aspoxicillin and preparation method and medical application thereof Download PDFInfo
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- CN101775027A CN101775027A CN200910076144A CN200910076144A CN101775027A CN 101775027 A CN101775027 A CN 101775027A CN 200910076144 A CN200910076144 A CN 200910076144A CN 200910076144 A CN200910076144 A CN 200910076144A CN 101775027 A CN101775027 A CN 101775027A
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- aspoxicillin
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Abstract
The invention relates to a novel derivative of Aspoxicillin and a preparation method and medical application thereof. The novel derivative of Aspoxicillin has the chemical structure shown in formula I, wherein M represents cations such as Li+, Na+, K+ and the like. The compound I or pharmaceutically acceptable medical salts thereof or hydrate and solvate thereof can be prepared by directly neutralizing Aspoxicillin with metal hydroxide and freeze-drying.
Description
Technical field
The present invention relates to a kind of new derivatives of aspoxicillin and preparation method thereof, medicinal use, belong to medical technical field.
Background technology
The aspoxicillin is first injection amino acid pattern semi-synthetic penicillins medicine in the world at present, it introduces N4-methyl D-l-asparagine on the side chain of 6 of penicillin parent nucleus, greatly improved medicine distribution dynamic in vivo, prolong the medicine transformation period in vivo, had certain clinical meaning.
Aspoxicillin chemistry (2S by name, 5R, 6R)-6-[(2R)-2-[(2R)-2-amino-3-(N-methylamino-formyl) propionamido-]-2-(right-hydroxyphenyl) kharophen]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3,2,0]-and heptane-2-carboxylic acid trihydrate, structure is shown below:
Antibacterial activity in vitro studies show that, the aspoxicillin has broad spectrum antibiotic activity preferably, its antimicrobial spectrum is similar to piperacillin, has the strong antibiotic activity to comprising gram-positive microorganisms such as Staphylococcus, streptococcus, streptococcus pneumoniae and Gram-negative bacterias such as intestinal bacteria, hemophilus influenza and anerobe Bacteroides.Animal experiment shows: the anti-microbial activity of aspoxicillin is better than piperacillin etc., and this main and its transformation period of growing, higher Plasma Concentration are relevant with the better tissues characteristic distributions.The aspoxicillin produces powerful bacteriolysis by combining with the bacterium penicillin-binding protein, and this is itself and other other place of microbiotic phase region.Efficient to the septicemia that caused by Staphylococcus, streptococcus, Colibacter etc. and infective endocarditis is 61.5%; Efficient to the outer superinfection that injures surfaces such as art wound that is caused by Staphylococcus, streptococcus, Colibacter, Bacteroides etc. is 81.4%; To being 83.4% by the efficient of the respiratory tract infection due to Staphylococcus, streptococcus, streptococcus pneumoniae, faecalis, the hemophilus influenzae etc. (comprising pharyngitis, acute/chronic bronchitis, tonsillitis, bronchiectasis, chronic respiratory superinfection, pneumonia, pulmonary abscess etc.); Efficient to the cholecystitis, the cholangitis that are caused by streptococcus, faecalis, Colibacter etc. is 80%; Efficient to the peritonitis that is caused by streptococcus, faecalis, Colibacter, Bacteroides etc. is 90.0%.The aspoxicillin reaches 100% to infective enteritis, scarlet fever etc. are efficient in addition, and gynecological infection, ophthalmology infection, department of eye, Stomatological Department and meningitis etc. are all had curative effect preferably.Bacteriological evaluation shows: the aspoxicillin is 77.6% to the clearance rate of golden Portugal bacterium, is 80～90% to the clearance rate of streptococcus, streptococcus pneumoniae and enterococcus faecalis; To the clearance rate of negative bacterium such as intestinal bacteria and hemophilus influenzae more than 80%.
Documents and materials JP40686/1981 demonstration aspoxicillin does not have very easily moisture absorption of hydrate, neither be very stable to light; The JP226423/1986 result of study shows, can crystallization obtain the aspoxicillin trihydrate from the acidic aqueous solution of aspoxicillin, and this compound is stable and be difficult for static, the suitable pharmaceutical preparation of making, but its poorly water-soluble (2.8g/100ml).
Summary of the invention
The invention provides a kind of new derivatives of aspoxicillin, its chemical structure is suc as formula shown in the I:
Wherein M represents Li
+, Na
+, K
+Deng positively charged ion.
The present invention also comprises the pharmaceutically acceptable pharmaceutical salts of Compound I or its hydrate, solvate.
The invention still further relates to the preparation method of above-claimed cpd I or its pharmaceutically acceptable pharmaceutical salts or its hydrate, solvate, this compounds can by metal hydroxides directly in and the aspoxicillin, freeze-drying prepares then.
Above-claimed cpd I of the present invention or its pharmaceutically acceptable pharmaceutical salts or its hydrate, solvate are mainly used in the treatment of various infectation of bacteria.
Aspoxicillin of the present invention new derivatives has well water-soluble, and is also non-hygroscopic, has well water-solublely, is very beneficial for preparation.
Embodiment
Can further describe the present invention by the following examples, yet invention of the present invention is not limited to the following examples, the scope that these embodiment do not limit the present invention in any way.Some change that those skilled in the art has done within the scope of the claims and adjust also should be thought and belongs to scope of the present invention.
Embodiment 1
10 gram aspoxicillin trihydrates are suspended in the 200ml water, and the ice-water bath cooling drips 1M sodium hydroxide solution 18.2ml, drips complete back and continues to stir 0.5h, and lyophilize obtains aspoxicillin sodium (I) 9.5g.
1H-NMR (water): 1.38 (S, 3H, CH3), 1.42 (S, 3H, CH3), 2.68 (S, 3H, CH3N), 2.82-2.93 (m, 2H, CH2CO), 4.12 (S, 1H, C3-H), 4.26 (m, 1H, CHNH2), 5.30～5.42 (m, 3H, C5-H, C6-H, CH-C6H5), 6.86 (d, 2H, Ar-H), 7.28 (d, 2H, Ar-H).
Embodiment 2
10 gram aspoxicillin trihydrates are suspended in the 200ml water, and the ice-water bath cooling drips 1M potassium hydroxide solution 18.2ml, drips complete back and continues to stir 0.5h, and lyophilize obtains aspoxicillin potassium (II) 9.9g.H-NMR (water): 1.35 (S, 3H, CH3), 1.40 (S, 3H, CH3), 2.65 (S, 3H, CH3N), 2.76-2.92 (m, 2H, CH2CO), 4.08 (S, 1H, C3-H), 4.23 (m, 1H, CHNH2), 5.22～5.38 (m, 3H, C5-H, C6-H, CH-C6H5), 6.80 (d, 2H, Ar-H), 7.24 (d, 2H, Ar-H).
Embodiment 3
The compound physical chemical property is investigated
| Compound | Water-soluble | Water absorbability | Mobile |
| ??Ⅰ | Yi Rong | Non-hygroscopic | Good |
| ??Ⅱ | Yi Rong | Non-hygroscopic | Good |
Embodiment 4
Compound stability is investigated
Claims (6)
1. the new derivatives of an aspoxicillin, its chemical structure is suc as formula shown in the I:
Wherein M represents Li
+, Na
+, K
+Deng positively charged ion.
2. the pharmaceutically acceptable pharmaceutical salts of the described Compound I of claim 1 or its hydrate, solvate.
3. the described compound of claim 1, preferred aspoxicillin sodium (I
1).
4. the described compound of claim 1, preferred aspoxicillin potassium (I
2).
5. the described compound of claim 1 can be by in the corresponding metal oxyhydroxide and aspoxicillin, and directly freeze-drying obtains.
6. the described compound of claim 1 is used for the treatment of various infectation of bacteria.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910076144A CN101775027A (en) | 2009-01-09 | 2009-01-09 | Novel derivative of Aspoxicillin and preparation method and medical application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910076144A CN101775027A (en) | 2009-01-09 | 2009-01-09 | Novel derivative of Aspoxicillin and preparation method and medical application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101775027A true CN101775027A (en) | 2010-07-14 |
Family
ID=42511630
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910076144A Pending CN101775027A (en) | 2009-01-09 | 2009-01-09 | Novel derivative of Aspoxicillin and preparation method and medical application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101775027A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102372727A (en) * | 2010-08-10 | 2012-03-14 | 海南美好西林生物制药有限公司 | Preparation method of Aspoxicillin sodium |
| CN103992337A (en) * | 2014-04-23 | 2014-08-20 | 南京优科生物医药研究有限公司 | Convenient method for preparing aspoxicillin sodium |
| CN113999251A (en) * | 2021-11-12 | 2022-02-01 | 海南海灵化学制药有限公司 | Synthetic method of aspoxicillin sodium |
-
2009
- 2009-01-09 CN CN200910076144A patent/CN101775027A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102372727A (en) * | 2010-08-10 | 2012-03-14 | 海南美好西林生物制药有限公司 | Preparation method of Aspoxicillin sodium |
| CN103992337A (en) * | 2014-04-23 | 2014-08-20 | 南京优科生物医药研究有限公司 | Convenient method for preparing aspoxicillin sodium |
| CN103992337B (en) * | 2014-04-23 | 2016-08-17 | 南京优科生物医药研究有限公司 | A kind of method preparing Aspoxicillin sodium easily |
| CN113999251A (en) * | 2021-11-12 | 2022-02-01 | 海南海灵化学制药有限公司 | Synthetic method of aspoxicillin sodium |
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Application publication date: 20100714 |