CN103709177A - Rifamycin and valnemulin hybrid antibiotic and preparation method thereof - Google Patents
Rifamycin and valnemulin hybrid antibiotic and preparation method thereof Download PDFInfo
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- CN103709177A CN103709177A CN201310710789.5A CN201310710789A CN103709177A CN 103709177 A CN103709177 A CN 103709177A CN 201310710789 A CN201310710789 A CN 201310710789A CN 103709177 A CN103709177 A CN 103709177A
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- valnemulin
- rifamycin
- rifomycin
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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
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Abstract
The invention discloses a rifamycin and valnemulin hybrid antibiotic compound and a preparation method thereof. The rifamycin and valnemulin hybrid antibiotic has a structure as shown in the formula (I). The preparation method comprises the following steps: (1) adding concentrated sulfuric acid into a DMF (Dimethyl Formamide) solution of rifamycin s and sodium salt to acidize for 0.5h, and then, dropwise adding dihydroxy-tert-butylamine to react to obtain an intermediate, i.e., oxazine rifamycin II; (2) mixing the intermediate, i.e., the oxazine rifamycin II and piperazine anhydrous in a protonic solvent, and reacting to obtain an intermediate, i.e., 3-formyl rifamycin III; and (3) mixing and dissolving the 3-formyl rifamycin III and valnemulin in a solvent, stirring at the temperature of 15-30 DEG C for 2h under the protection of nitrogen gas, and cooling to obtain the rifamycin and valnemulin hybrid antibiotic. Two drug molecules with different action mechanisms are connected together, the combination way of the rifamycin and valnemulin hybrid antibiotic compound is similar to that of a prodrug with dual functions, the linking group is stable, and the rifamycin and valnemulin hybrid antibiotic compound can take a very good treating effect.
Description
Technical field
The present invention relates to chemical synthetic drug field, particularly a kind of rifomycins valnemulin hybrid antibiotic compound and preparation method thereof.
Background technology
Rifomycin (rifamycins) is the mixture of the separation and Extraction from the meta-bolites of Mediterranean Sea streptomycete (Streptomyces mediterranoi) such as nineteen fifty-nine Sensi, then isolates again A, B, C, D, E etc.1962, rifamycin B was through being chemically converted to Rifamycin Sodium, and by first for clinical.Because its oral absorption is not good, therefore screen and obtain rifampicin, i.e. Rifampin again from a plurality of derivatives of 3-formyl Rifamycin Sodium.This product Orally-administrable, and good effect, but easily make bacterial strain produce resistance, working lipe is short, and lower to the Mycobacterium avium complex in AIDS complication (MAC) infection activity, toxicity is larger.The course of disease lungy and pathology are widely different, and long-term prescription may produce chronic toxicity to human body, and bacterium also can produce resistance to it.Along with the generation of human immunodeficiency virus (HIV) infection and Multidrug resistant bacteria, tuberculosis spreads once again.So, for a certain period, the novel derivative of rifomycin is competitively developed in countries in the world, try hard to obtain good effect, dosage is little, toxicity is low, the rifomycin new variety of antimicrobial agent and antiviral (comprising anti-AIDS), antitumor, anti-deep fungal infection etc., so semisynthetic antibiotics Rifordin, rifapentine (rifpentine), Li Fubu～y (rifabutin), sharp good fortune piperidines (FCE 1) etc. are come out one after another.Wherein Rifordin, rifapentine are all playing vital role in the diseases such as tuberculosis, leprosy and rifabutin aspect anti-drug resistance tubercle bacillus affection and treatment tubercule bacillus and acquired immune deficiency syndrome (AIDS) multiplicity of infection.In addition, rifaximin has also been widely used in clinical as unique rifamycinoid antibiotics for the treatment of enterobacterial infection.At present, to the research of rifamycinoid antibiotics still flourish.
Pleuromutilin is separated and carried out preliminary evaluation in nineteen fifty-one by Kavanagh etc. at first, it is by higher fungi the pick up the ears diterpene antibiotic of the class wide spectrum that bacterium produces of bacterium and Pa Shi of picking up the ears, can effectively suppress gram-positive microorganism, especially the most obvious with staphylococcus, suis, for mycoplasma infection, also there is therapeutic action simultaneously, bacteriostatic activity and the scope of its many derivatives are stronger than pleuromutilin, and antimicrobial spectrum is more extensive simultaneously.In recent years, along with G+ bacterium resistance, comprise the day by day serious of methicillin-resistant staphylococcus aureus, penicillin resistant parapneumonia coccus, vancomycin-resistant enterococcus, though Common Antibiotics linezolid, Quinupristin/dalfopristin and impersonating draws that fixed etc. microbial infection has certain curative effect to resistance in institute, because serious untoward reaction and lower bioavailability have limited its widespread use.Therefore, exploitation has novel antibacterial mechanism, compound that preferably bioavailability and being difficult for produces crossing drug resistant with traditional microbiotic becomes the primary approach of containing resistant organism.Pleuromutilin is a class tricyclic diterpene class microbiotic, its Main Function is in 50S ribosomal subunit, activity by inhibiting peptide based transferase is obstructed the protein synthesis of bacterium, there is unique anti-microbial activity, be difficult for producing the features such as crossing drug resistant with clinical traditional microbiotic used, so this analog derivative becomes the antibiotic main starting point of research novel human gradually.And such microbiotic mainly represents that medicine Tiamulin and valnemulin are widely used as microbiotic for animals, particularly in April, 2007, first pleuromutilin analog derivative people was ratified successfully listing with microbiotic Retapamulin (Retapamulin) by U.S. food drug surveilance office (FDA), realize this compounds and from microbiotic for animals to people, used antibiotic leap, started the tide of novel human pleuromutilin analog derivative research and development.Therefore select pleuromutilin derivative to carry out study on the synthesis no matter be all to there is good development prospect at veterinary drug or in people's medication.
These features for resistant organism, now many scientists shift to this theory of heterozygosis medicine by sight, on the basis of the single target spot compound of original exploitation, start the antibacterials of researching and developing many target spots compound and thering is dual function, nowadays, the R&D work of heterozygosis medicine has obtained significant progress, and there are many such medicament research and development successes in the whole world enter into clinical experimental stage.Roche Holding Ag is the company of whole world early start research and development heterozygosis antibacterials, the researchist of the said firm forms heterozygote by medicine that two kinds have been gone on the market or their derivative through chemosynthesis, with this expand medicine antimicrobial spectrum, strengthen the validity of resistant organism, improve pharmacokinetics and reduce side effect.Because quinolones easily operates aspect chemosynthesis, therefore become the choice drug of the synthetic heterozygosis medicine of researchist.The heterozygosis antibacterials that Roche Holding Ag develops are the earliest heterozygosis medicine ro-23-9424 that quinolones is combined with Beta-lactam medicine.Experiment in vitro shows, the antimicrobial spectrum of ro-23 – 9424 is wider, all effective to the resistant organism of quinolones and cephalosporins medicine, particularly Pseudomonas aeruginosa is had to stronger effect.But its weak point is that the transformation period is shorter, this may be not firmly reason of the ester bond that connects.At present, ro-23-9424 has entered the II clinical trial phase stage.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of rifomycins valnemulin heterozygosis compound usually to use as antibiosis for prior art deficiency.Another one object is to provide the preparation method of rifomycins valnemulin hybrid antibiotic.
For achieving the above object, adopt technical scheme as follows:
Rifomycins valnemulin hybrid antibiotic, has the structure of formula I:
The preparation method of above-mentioned rifomycins valnemulin hybrid antibiotic, includes following steps:
1) rifomycin s-sodium salt is dissolved and mixed in solvent DMF, good fortune mycin s-sodium salt: the vitriol oil=1.9～2:1 adds vitriol oil acidifying 0.5h in molar ratio, then drip dihydroxy tert-butyl amine, dihydroxy tert-butyl amine and rifomycin s-sodium salt mol ratio 1.5～1.9:1, be warming up to 35～50 ℃, insulation reaction 2 hours, add after cooling precipitation agent standing, filter, washing obtains intermediate oxazines rifomycin II;
2) in protic solvent, intermediate oxazines rifomycin II is mixed according to mol ratio 1:1.2～1.5 with Piperazine anhydrous, 45～60 ℃ are reacted 2 hours, by column chromatography, obtain intermediate 3-formyl rifomycin III;
3) get valnemulin hydrochloride and be added to the water completely and dissolve, with Fu's acid agent, regulate pH value to 8～9, filter, washing, the dry intermediate valnemulin IV that obtains;
4) by intermediate 3-formyl rifomycin III and intermediate valnemulin IV according to mol ratio 1:1.1～1.3 and in solvent mixed dissolution; nitrogen protection; at 15～30 ℃, stir and stir 2 hours for 2 hours, naturally cooling can obtain rifomycins valnemulin hybrid antibiotic.
The glacial acetic acid aqueous solution that in step 1), precipitation agent is pH6.5.
Step 2) described protic solvent is ethanol, methyl alcohol or acetone.
Fu's acid agent described in step 3) is ammoniacal liquor or saturated NaHCO
3solution.
Described in step 4), solvent is HTF or ethyl acetate.
Reaction process of the present invention is as follows:
Beneficial effect of the present invention:
The present invention couples together two kinds of different drug molecules of mechanism of action by LinK molecule, its combination is similar to the prodrug of dual function, and linking group is stable, and different two compounds of target combine, its antibacterial effect is also strengthened greatly, can play extraordinary result for the treatment of.
Embodiment
In order to understand better the present invention, below in conjunction with embodiment, further illustrate content of the present invention, but content of the present invention is not only confined to enforcement below.
The preparation process of rifomycins valnemulin hybrid antibiotic is as follows:
1) rifomycin s-sodium salt is dissolved and mixed in solvent DMF, good fortune mycin s-sodium salt: the vitriol oil=1.9～2:1 adds vitriol oil acidifying 0.5h in molar ratio, then drip dihydroxy tert-butyl amine, dihydroxy tert-butyl amine and rifomycin s-sodium salt mol ratio 1.5～1.9:1, be warming up to 35～50 ℃, insulation reaction 2 hours, add after cooling precipitation agent standing, filter, washing obtains intermediate oxazines rifomycin II;
2) in protic solvent, intermediate oxazines rifomycin II is mixed according to mol ratio 1:1.2～1.5 with Piperazine anhydrous, 45～60 ℃ are reacted 2 hours, by column chromatography, obtain intermediate 3-formyl rifomycin III;
3) get valnemulin hydrochloride and be added to the water completely and dissolve, with Fu's acid agent, regulate pH value to 8～9, filter, washing, the dry intermediate valnemulin IV that obtains;
4) by intermediate 3-formyl rifomycin III and intermediate valnemulin IV according to mol ratio 1:1.1～1.3 and in solvent mixed dissolution; nitrogen protection; at 15～30 ℃, stir 2 hours, naturally cooling can obtain rifomycins valnemulin hybrid antibiotic.
The glacial acetic acid aqueous solution that in step 1), precipitation agent is pH6.5.
Step 2) protic solvent is ethanol, methyl alcohol or acetone.
In step 3), Fu's acid agent is ammoniacal liquor or saturated NaHCO
3solution.
Step 4) solvent is HTF or ethyl acetate.
By LinK molecule, two kinds of different drug molecules of mechanism of action are coupled together, its combination is similar to the prodrug of dual function, and linking group is stable, and different two compounds of target combine, its antibacterial effect is also strengthened greatly, can play extraordinary result for the treatment of.
Embodiment 1
According to above-mentioned steps, determine that concrete technology and parameter are as follows:
In step 1), good fortune mycin s-sodium salt in molar ratio: the vitriol oil=1.9:1 acidifying; Mol ratio dihydroxy tert-butyl amine: rifomycin s-sodium salt=1.5:1 is reinforced; Wherein, the concentration of rifomycin s-sodium salt in solvent DMF is 0.02g/mL.
Step 2) in, intermediate oxazines rifomycin II: Piperazine anhydrous is reinforced according to mol ratio 1:1.2.Protic solvent is ethanol.
In step 3), saturated NaHCO is selected in Fu's acid agent
3solution.
In step 4), intermediate 3-formyl rifomycin III: intermediate valnemulin IV is reinforced according to mol ratio 1:1.1; Intermediate 3-formyl rifomycin III is dissolved in solvent HTF, and concentration is 0.025g/mL.
Can obtain target product I.Being dissolved in 1.2% aqueous ethanolic solution, being mixed with the solution of 0.5mg/L, is the filter paper of 6mm after high pressure steam sterilization diameter, drops into respectively in the solution and 1.2% aqueous ethanolic solution of above-mentioned order chemical compounds I, soaks 2min, dries after 2h standby.Compound concentration is that streptococcus aureus (Staphylococcus aureus ATCC9118) the bacterium liquid of 105cfu/mL is appropriate, getting this bacterium liquid of 20 μ L spreads upon in Luria-Bertani substratum equably, then above-mentioned processing filter paper be placed in respectively this substratum, in the electro-heating standing-temperature cultivator of 37 ℃, cultivate after 24 hours, the filter disc that soaks order chemical compounds I has produced obvious inhibition zone around
Embodiment 2
According to above-mentioned steps, determine that concrete technology and parameter are as follows:
In step 1), good fortune mycin s-sodium salt in molar ratio: the vitriol oil=2:1 acidifying; Mol ratio dihydroxy tert-butyl amine: rifomycin s-sodium salt=1.9:1 is reinforced; Wherein, the concentration of rifomycin s-sodium salt in solvent DMF is 0.05g/mL.
Step 2) in, intermediate oxazines rifomycin II: Piperazine anhydrous is reinforced according to mol ratio 1:1.2.Protic solvent is ethanol.
In step 3), saturated NaHCO is selected in Fu's acid agent
3solution.
In step 4), intermediate 3-formyl rifomycin III: intermediate valnemulin IV is reinforced according to mol ratio 1:1.1; Intermediate 3-formyl rifomycin III is dissolved in solvent HTF, and concentration is 0.0725g/mL.
Can obtain target product I.Being dissolved in 1.2% aqueous ethanolic solution, being mixed with the solution of 0.5mg/L, is the filter paper of 6mm after high pressure steam sterilization diameter, drops into respectively in the solution and 1.2% aqueous ethanolic solution of above-mentioned order chemical compounds I, soaks 2min, dries after 2h standby.Compound concentration is that streptococcus aureus (Staphylococcus aureus ATCC9118) the bacterium liquid of 105cfu/mL is appropriate, getting this bacterium liquid of 20 μ L spreads upon in Luria-Bertani substratum equably, then above-mentioned processing filter paper be placed in respectively this substratum, in the electro-heating standing-temperature cultivator of 37 ℃, cultivate after 24 hours, the filter disc that soaks order chemical compounds I has produced obvious inhibition zone around.
Embodiment 3
According to above-mentioned steps, determine that concrete technology and parameter are as follows:
In step 1), good fortune mycin s-sodium salt in molar ratio: the vitriol oil=1.9:1 acidifying; Mol ratio dihydroxy tert-butyl amine: rifomycin s-sodium salt=1.85:1 is reinforced; Wherein, the concentration of rifomycin s-sodium salt in solvent DMF is 0.0625g/mL.
Step 2) in, intermediate oxazines rifomycin II: Piperazine anhydrous is reinforced according to mol ratio 1:1.4.Protic solvent is ethanol.
In step 3), ammoniacal liquor is selected in Fu's acid agent.
In step 4), intermediate 3-formyl rifomycin III: intermediate valnemulin IV is reinforced according to mol ratio 1:1.15; Intermediate 3-formyl rifomycin III is dissolved in solvent HTF, and concentration is 0.125g/mL.
Can obtain target product I.Being dissolved in 1.2% aqueous ethanolic solution, being mixed with the solution of 0.5mg/L, is the filter paper of 6mm after high pressure steam sterilization diameter, drops into respectively in the solution and 1.2% aqueous ethanolic solution of above-mentioned order chemical compounds I, soaks 2min, dries after 2h standby.Compound concentration is that streptococcus aureus (Staphylococcus aureus ATCC9118) the bacterium liquid of 105cfu/mL is appropriate, getting this bacterium liquid of 20 μ L spreads upon in Luria-Bertani substratum equably, then above-mentioned processing filter paper be placed in respectively this substratum, in the electro-heating standing-temperature cultivator of 37 ℃, cultivate after 24 hours, the filter disc that soaks order chemical compounds I has produced obvious inhibition zone around.
Claims (6)
1. a rifomycins valnemulin hybrid antibiotic, is characterized in that having the structure of formula I:
2. the preparation method of rifomycins valnemulin hybrid antibiotic described in claim 1, is characterized in that including following steps:
1) rifomycin s-sodium salt is dissolved and mixed in solvent DMF, good fortune mycin s-sodium salt: the vitriol oil=1.9～2:1 adds vitriol oil acidifying 0.5h in molar ratio, then drip dihydroxy tert-butyl amine, dihydroxy tert-butyl amine and rifomycin s-sodium salt mol ratio 1.5～1.9:1, be warming up to 35～50 ℃, insulation reaction 2 hours, add after cooling precipitation agent standing, filter, washing obtains intermediate oxazines rifomycin II;
2) in protic solvent, intermediate oxazines rifomycin II is mixed according to mol ratio 1:1.2～1.5 with Piperazine anhydrous, 45～60 ℃ are reacted 2 hours, by column chromatography, obtain intermediate 3-formyl rifomycin III;
3) get valnemulin hydrochloride and be added to the water completely and dissolve, with Fu's acid agent, regulate pH value to 8～9, filter, washing, the dry intermediate valnemulin IV that obtains;
4) by intermediate 3-formyl rifomycin III and intermediate valnemulin IV according to mol ratio 1:1.1～1.3 and in solvent mixed dissolution; nitrogen protection; at 15～30 ℃, stir and stir 2 hours for 2 hours, naturally cooling can obtain rifomycins valnemulin hybrid antibiotic.
3. the preparation of rifomycins valnemulin hybrid antibiotic as claimed in claim 2, is characterized in that in step 1), precipitation agent is that pH value is 6.5 the glacial acetic acid aqueous solution.
4. the preparation of rifomycins valnemulin hybrid antibiotic as claimed in claim 2, is characterized in that step 2) described protic solvent is ethanol, methyl alcohol or acetone.
5. the preparation of rifomycins valnemulin hybrid antibiotic as claimed in claim 2, is characterized in that Fu's acid agent described in step 3) is ammoniacal liquor or saturated NaHCO3 solution.
6. the preparation of rifomycins valnemulin hybrid antibiotic as claimed in claim 2, is characterized in that described in step 4) that solvent is HTF or ethyl acetate.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107216343A (en) * | 2017-05-26 | 2017-09-29 | 武汉工程大学 | A kind of rifamycin isoniazid heterozygosis medicine and preparation method thereof |
| CN107261106A (en) * | 2017-05-27 | 2017-10-20 | 武汉工程大学 | Thymopeptide-5, chitosan inclusion compound of rifamycin isoniazid and preparation method thereof |
Citations (3)
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|---|---|---|---|---|
| CN101031572A (en) * | 2004-07-22 | 2007-09-05 | 坎布里制药公司 | (r/s) rifamycin derivatives, their preparation and pharmaceutical compositions |
| WO2010122436A1 (en) * | 2009-04-20 | 2010-10-28 | Alfa Wassermann S.P.A. | Rifamycin derivatives |
| CN102924350A (en) * | 2012-10-31 | 2013-02-13 | 中国农业科学院兰州畜牧与兽药研究所 | Pleuromutilin derivatives, and preparation method and application thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101031572A (en) * | 2004-07-22 | 2007-09-05 | 坎布里制药公司 | (r/s) rifamycin derivatives, their preparation and pharmaceutical compositions |
| WO2010122436A1 (en) * | 2009-04-20 | 2010-10-28 | Alfa Wassermann S.P.A. | Rifamycin derivatives |
| CN102924350A (en) * | 2012-10-31 | 2013-02-13 | 中国农业科学院兰州畜牧与兽药研究所 | Pleuromutilin derivatives, and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 邹懿，等: "截短侧耳素及其衍生物的研究进展", 《中国抗生素杂志》, vol. 34, no. 2, 28 February 2009 (2009-02-28), pages 65 - 69 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107216343A (en) * | 2017-05-26 | 2017-09-29 | 武汉工程大学 | A kind of rifamycin isoniazid heterozygosis medicine and preparation method thereof |
| CN107261106A (en) * | 2017-05-27 | 2017-10-20 | 武汉工程大学 | Thymopeptide-5, chitosan inclusion compound of rifamycin isoniazid and preparation method thereof |
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