CN101780082A - Use of imidazole alkaloids as anti-Infective medicament synergists and medicinal composition containing anti-Infective medicament synergists - Google Patents
Use of imidazole alkaloids as anti-Infective medicament synergists and medicinal composition containing anti-Infective medicament synergists Download PDFInfo
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Abstract
The invention of the invention discloses the use of imidazole alkaloids of a general formula (I) and pharmaceutically acceptable salts thereof in the preparation of anti-Infective medicament synergists and medicinal compositions containing the synergists.
Description
Technical field
The present invention relates to the anti-infectives synergist, specifically, the present invention relates to bisbenzylisoquinoline alkaloid or its pharmaceutically acceptable salt purposes and pharmaceutical composition thereof as the anti-infectives synergist.
Background technology
Drug resistance is the relevant antagonism of pathogen enantiopathy substance medicine.It is natural rule that pathogen produces drug resistance, i.e. its generation is the inevitable outcome of drug resistant gene long-term evolution, is not just to occur after anti-infectives is asked the city.The pathogen drug resistance is divided into intrinsic resistance (natural resistance), obtains drug resistance (acquired resistance), multidrug resistance (multi-drug resistance, MDR) and cross resistance (cross resistance).Intrinsic resistance also claims endogenous drug resistance (intrinsicresistance), the antimicrobial spectrum of its decision anti-infectives.Drug resistant gene one is by the chromosome coding mediation, due to promptly DNA or RNA suddenly change.Another is by plasmid (plasmid claims the R-plasmid again) mediation, and characteristics are mode many (conversion, transduction, combination and transpositions), and the incidence rate height shows generation fermentoid or modification enzyme and drug resistance usually.After acquired resistance is meant sensitive pathogens contact anti-infectives, because the drug resistance that the change of genetic variation, the metabolic pathway of surviving produces.Multidrug resistance means the drug resistance that simultaneously multiple anti-infectives commonly used is taken place, and main mechanism is the efflux pump gene mutation, secondly is infiltrative change of adventitia and the super wide spectrum enzyme of generation.Cross resistance is meant that the drug resistance between medicine transmits mutually, mainly occurs between the antibacterials of structural similarity.
Find and application anti-infectives synergist, both can reduce drug resistance, increase pathogen, can delay the application cycle of anti-infectives again the sensitivity of medicine, the clinical efficacy of increase anti-infectives.
The research of anti-infectives synergist is being carried out recently in decades always.The trimethoprim of Shi Yonging (TMP) is the synergist of antibacterium medicines such as sulfonamides clinically.China national patent " berberine is as the purposes of antifungal medicine synergist " (number of patent application 200410052989.7), " baicalin is as the purposes of antifungal medicine synergist " (number of patent application 200710041688.8), " reverse the medicinal plants synergist of azole drug antifungal activity multidrug resistance " (number of patent application 200610034165.6), " antifungal medicine synergist and its production and application " (number of patent application 00121370.9) discloses some can be as the structure or the material of antifungal medicine synergist.
Bisbenzylisoquinoline alkaloid has multiple biological activity (He Liwen etc.The pharmacy progress, 1996; 20:193.), comprise antibiotic, antitumor, analgesia, blood pressure lowering etc.; Find that also bisbenzylisoquinoline alkaloid has the activity of reversal of multidrug resistance of tumor cells (Ono M et al.CancerChemother Pharmacol, 1994; 35:10.).The tetrandrine that Gao Aili, Zhang Hong etc. have reported Dibenzylisoquinolinealkaloids to the anti-Candida albicans of fluconazol have synergistic activity (Chinese journal of dermatology .2008,41:31.).But do not see in addition bisbenzylisoquinoline alkaloid as yet as the report of anti-infectives synergist.
Summary of the invention
On the one hand, the purpose of this invention is to provide the bisbenzylisoquinoline alkaloid shown in the general formula (I) or its pharmaceutically acceptable salt purposes aspect preparation anti-infectives synergist:
In the formula, R
1It is the straight or branched alkyl of 1-10 carbon atom;
R
2And R
3Be hydrogen, or R
2And R
3Be O together;
R
4And R
5Be hydrogen, methoxyl group, acetyl group, perhaps R
4And R
5Be O together;
X1, X2, X3, X4 can be identical or different, and are the straight or branched alkoxyl or the acyloxy of a halogen atom or 1-10 carbon atom independently of one another, and n is 0 to 3 integer.
We find to have the anti-infectives synergistic activity by bisbenzylisoquinoline alkaloid and the derivant thereof shown in the general formula (I) on the basis of a large amount of experiments, they can be used as the anti-infectives synergist as active component.Synergist of the present invention uses with anti-infectives, forms a kind of compositions, makes medicine, health product, cosmetics, medical apparatus and instruments, sterilizing article, hygienic article and sells, uses, thereby made things convenient for the crowd of some occasion.
Among the present invention, the anti-infectives synergist can be anti-fungal infection medicament synergistic agent, bacterial-infection resisting medicine synergist, viral infection resisting medicament synergistic agent, anti-actinomycotic infection medicament synergistic agent, anti-mycoplasma infection medicine synergist, anti-chlamydia infection medicament synergistic agent, anti-spirochaete infection medicament synergistic agent, rickettsicidal infection medicine synergist, protozoacide infection medicine synergist or anthelmintic infection medicine synergist.
Anti-infectives synergist of the present invention can be at the various pathogen that cause infection, comprise fungus, antibacterial, virus, actinomycetes, mycoplasma, chlamydia, spirillum, rickettsia, protozoon, the helminthic infection that can cause animal, plant constitutional or secondary infection, especially eukaryotic microorganisms fungus, prokaryotic micro-organisms antibacterial, actinomycetes, mycoplasma, chlamydia, spirillum, rickettsia.。Except the above-mentioned pathogen of enumerating, also comprise newfound other animal pathogen, phytopathogen.
Anti-infectives synergist of the present invention can be used as the synergist of following anti-infectives, as antibacterium, actinomycetes, mycoplasma, chlamydia, spirillum, rickettsial antibiotic and other infectious agents matter, including, but not limited to following anti-infectives, as long as this anti-infectives is subjected to the influence of anti-infectives synergist of the present invention and reduces: antibiotic such as beta-lactam, Macrolide, lincomycin class, polypeptide class, Tetracyclines, chloromycetin, quinolones, aminoglycosides; Sulfonamides and other antibacterials; Antifungal drug (nitrogen azole but do not contain fluconazol, propylene amine, Thiourea, antibiotics such as polyenoid class, lipopeptid class, glycolipid class, class lipopeptid, class glycolipid, nucleoside peptide class, amino acids, condensed ring aromatics, the morpholine class, fluorine miazines, sour jujube albomycin class, Nikemycin class); Antiviral drugs (ucleosides, non-nucleoside, nucleoside reverse transcriptase inhibitors); Anti-parasite medicine (antimalarial, antitrichomonal drug, anti-amebic, antischistosomal drug, antifilarial drug, vermifuge).But do not comprise the potentiation of tetrandrine, do not comprise the potentiation of tetrandrine the anti-particulate echinococcus of albendazole, the alveolar sphere larva of a tapeworm or the cercaria of a schistosome to the anti-Candida albicans of fluconazol.
Can adopt anti-infectives synergist associating anti-infectives of the present invention to treat, prevent the pathogenic infection of animal, plant,, reduce drug resistance to obtain better effect.
Under some concrete occasion, preferably, anti-infectives synergist of the present invention is selected from a kind of as in next group material or its pharmaceutically acceptable salt: tetrandrine, different tetrandrine, 5-bromine tetrandrine, 5-chlorine tetrandrine and 5,14-dibromo tetrandrine.
Under some specific occasion, can adopt 5-chlorine tetrandrine and 5,14-dibromo tetrandrine is as anti-infectives synergist of the present invention.
Anti-infectives can be (but being not limited to) more specifically: ketoconazole, miconazole, amphotericin B, bifonazole, terbinafine, ceftriaxone, erythromycin, ciprofloxacin, gentamycin, doxycycline and penicillin.
On the other hand, the invention provides a kind of anti-infective pharmaceutical composition, this pharmaceutical composition comprises:
(a) one or more the bisbenzylisoquinoline alkaloid shown in general formula (I) or its pharmaceutically acceptable salt:
In the formula, R
1It is the straight or branched alkyl of 1-10 carbon atom;
R
2And R
3Be hydrogen, or R
2And R
3Be O together;
R
4And R
5Be hydrogen, methoxyl group, acetyl group, perhaps R
4And R
5Be O together;
X
1, X
2, X
3, X
4Can be identical or different, and be the straight or branched alkoxyl or the acyloxy of a halogen atom or 1-10 carbon atom independently of one another, and n is 0 to 3 integer;
And
(b) one or more anti-infectives.
In above-mentioned pharmaceutical composition, anti-infectives and synergist of the present invention mix, formation is as the medicine of one, health product, cosmetics, medical apparatus and instruments, sterilizing article, hygienic article and sell, use, thereby made things convenient for patient or other crowds of some occasion.In the above-mentioned pharmaceutical composition, anti-infectives also can separate use successively with synergist of the present invention.
Preferably, in the pharmaceutical composition of the present invention, the anti-infectives synergist is to be selected from a kind of as in next group material or its pharmaceutically acceptable salt: tetrandrine, different tetrandrine, 5-bromine tetrandrine, 5-chlorine tetrandrine and 5,14-dibromo tetrandrine; Anti-infectives then is selected from the material as next group: Beta-lactam medicine, Macrocyclolactone lactone kind medicine, lincomycin class medicine, polypeptide drug, tetracycline medication, the chloromycetin medicine, quinolones, the aminoglycosides medicine, disulfonamide, the nitrogen azole drug that does not comprise fluconazol, the propylene amine drug, the thiourea medicine, antibiotics such as polyenoid class medicine, lipopeptid class medicine, glycolipid class medicine, class lipopeptid medicine, class glycolipid medicine, the nucleoside peptide medicament, amino acid drug, condensed ring aromatics medicine, morpholine class medicine, fluorine miazines medicine, sour jujube albomycin class medicine, Nikemycin class medicine, nucleoside medicine, the non-nucleoside medicine, nucleoside reverse transcriptase inhibitors, antimalarial, antitrichomonal drug, anti-amebic, antischistosomal drug, antifilarial drug and vermifuge.
Under some concrete occasion, above-mentioned anti-infectives can be selected from the material as next group: ketoconazole, miconazole, amphotericin B, bifonazole, terbinafine, ceftriaxone, erythromycin, ciprofloxacin, gentamycin, doxycycline and penicillin.
In the pharmaceutical composition of the present invention, the bisbenzylisoquinoline alkaloid shown in the general formula (I) or its pharmaceutically acceptable salt can be any stereoisomers of its C (1) and C (1 ').
Certainly, pharmaceutical composition of the present invention may further include acceptable excipient on one or more the pharmacology.Its used excipient does not have special restriction yet, the dosage form of being taked also is not particularly limited, can both be the exterior-applied formulation of topical therapeutic, preventive effect equally, as ointment, solution, gel, liniment, aerosol, lotion etc., perhaps be the dosage form of whole body therapeutic, preventive effect, as containing agent, tablet, capsule, pill, syrup, suspending agent, chew chewing gum, wafer, injection or other helps the dosage form that drug absorption is utilized.
The present invention will reverse the drug-fast synergist of anti-infectives and anti-infectives uses simultaneously, the pathogenic infection of treatment, prevention animal, plant, not only can increase the effective percentage of treatment, prevention, reduce case fatality rate, can also reduce simultaneously the using dosage of anti-infectives, alleviate its untoward reaction.
Synergist of the present invention can be used from the laboratory diagnosis instrument with anti-infectives one, as the anti-infectives sensitivity tests.
Synergist of the present invention and anti-infectives one are used from the treatment and the prevention of pathogenic infection, but do not comprise the potentiation of tetrandrine, do not comprise the potentiation of tetrandrine the anti-particulate echinococcus of albendazole, the alveolar sphere larva of a tapeworm or the cercaria of a schistosome to the anti-Candida albicans of fluconazol.
Below, the specific embodiment in conjunction with pharmacological evaluation, zoopery, clinical trial and synergist of the present invention and anti-infective medicament composition, further describe the present invention, but these descriptions just are used to explain the present invention, rather than limit the invention to these modes.
The specific embodiment
The present inventor studies for a long period of time to the natural materials that contains general formula (I) with anti-infectives synergistic activity or synthesis of derivatives and clinical practice thereof, finds that they are at laboratory and all have the good drug-fast effect of reverse anti-infectives clinically.
Pharmacological evaluation
The present inventor finds that the natural plant extracts tetrandrine that contains general formula (I) can have potentiation to ketoconazole, miconazole, amphotericin B, the anti-Candida albicans of terbinafine when 2-30 μ g/ml, see Table 1.Tetrandrine can have potentiation to ketoconazole, bifonazole, the anti-trichophyton of terbinafine when 2-30 μ g/ml, see Table 2.Tetrandrine can have potentiation to ceftriaxone, the anti-staphylococcus aureus of erythromycin when 20-30 μ g/ml, see Table 3.Tetrandrine can have potentiation to ciprofloxacin, the anti-escherichia coli of gentamycin when 20-30 μ g/ml, see Table 4.Radix Stephaniae Tetrandrae first element can have potentiation to doxycycline, penicillin antigen nuclear microorganism Ureaplasma urealyticum, Actinomyces israelii, star-shaped nocardia when 20-30 μ g/ml, see Table 5.And after uniting use with tetrandrine, the MIC terminal point of anti-infectives is clear, and " conditions of streaking " disappears.
Table 1
MIC1 is the oidiomycetic MIC of antifungal drug dialogue; When MIC2 is antifungal drug associating tetrandrine (2 μ g/mL) to being tried the MIC of bacterium.CA-1～CA-16 is the Candida albicans strain number.
Table 2
MIC1 is the MIC of antifungal drug to trichophyton; When MIC2 is antifungal drug associating tetrandrine (2 μ g/mL) to being tried the MIC of bacterium.TR-1～TR-4 is a strain number.
Table 3
MIC1 is the MIC of anti-infectives to staphylococcus aureus; When MIC2 is anti-infectives associating tetrandrine (20 μ g/mL) to being tried the MIC of bacterium.STA-1～STA-4 is the Candida albicans strain number.
Table 4
MIC1 is the MIC of anti-infectives to escherichia coli; When MIC2 is anti-infectives associating tetrandrine (20 μ g/mL) to being tried the MIC of bacterium.ECO-1～ECO-4 is the escherichia coli strain number.
Table 5
MIC1 is the MIC of anti-infectives; When MIC2 is anti-infectives associating tetrandrine (20 μ g/mL) to being tried the MIC of bacterium.UU-1, UU-2 are Ureaplasma urealyticum, and A-1 is Actinomyces israelii, and N-4 is a star-shaped nocardia.
The present inventor also finds, the different tetrandrine, 5-bromine tetrandrine that contain general formula (I) can significantly strengthen the antibiotic or bactericidal action of anti-infectives to pathogen in experiment in vitro when 2-20 μ g/ml.Table 6 is part result of experiment.
Table 6
MIC1 is the MIC of anti-infectives to pathogen; MIC2 be anti-infectives when uniting different tetrandrine or 5-bromine tetrandrine to being tried the MIC of bacterium.CA-1, CA-2, CA-3, TR-1, STA-1, STA-2, ECO-1, ECO-2, UU-1, UU-2, A-1, N-4 are strain number.
The present inventor adopts flow cytometer and spectrofluorophotometer respectively, measure that 16 strains come from same parent but the Candida albicans different to fluconazol sensitivity, when no tetrandrine and tetrandrine 30 μ g/ml (non-cell toxicity dosage), accumulate/efflux experiment after, the variation of Rh123 fluorescence intensity in the variation of Rh123 positive cell rate and the cell.Extract the total RNA of this 16 strain Candida albicans then respectively, adopt RT-PCR relatively before the tetrandrine effect and behind the effect 24h, medicine efflux pump gene M DR1, FLU1, CDR1, the expression of CDR2 in fluconazol sensitivity/dose dependent sensitivity/persister.Found that when no tetrandrine and tetrandrine 30 μ g/ml, accumulate experiment back 16 strain Candida albicans Rh123 positive cell rate and be respectively 26.65% and 70.99%, the Rh123 average fluorescent strength is respectively 11.34,18.00 in the cell; Efflux its Rh123 positive cell rate of experiment back and be respectively 1.79% and 42.57%, the Rh123 average fluorescent strength is respectively 0.74,2.19 in the cell.When no tetrandrine, MDR1, FLU1, CDR1, the difference of CDR2 expression between fluconazol sensitivity/dose dependent sensitivity/persister all have statistical significance (P＜0.05); Compare with no tetrandrine person behind the tetrandrine 30 μ g/ml 24h, MDR1 in the fluconazol persister, FLU1 in fluconazol dose dependent sensitivity/persister, the difference of CDR1 and CDR2 expression in fluconazol sensitivity/dose dependent sensitivity/persister all has statistical significance (P＜0.05).The explanation of these materials, tetrandrine suppresses the heat-extraction system Candida albicans medicine outside external, reduces medicine and effluxes, and it is relevant with the expression of depressant thing efflux pump gene M DR1, FLU1, CDR1, CDR2 that it acts on link.These materials illustrate that also the potentiation of tetrandrine is not only relevant with the outer heat-extraction system of medicine, also has other mechanism of action.For example, we find, the mRNA level of the detected target enzyme of RT-PCR gene ERG11 is quantized relatively, and use SPSS 13.0 software kits and analyze, found that, the difference not statistically significant (P＞0.05) of expression between fluconazol sensitivity/dose dependent sensitivity/Resistant strain of Candida albicans ERG11 before the different tetrandrine effect, and behind different tetrandrine effect 24h, the expression difference of ERG11 has statistical significance (P＜0.05) in sensitivity/dose dependent sensitive strain, at this moment, the expression of ERG11 is on a declining curve.The potentiation that tetrandrine is described is not only relevant, also relevant with target enzyme gene with the outer heat-extraction system of medicine.
The present inventor finds again, when detecting with flow cytometer, produce the one-parameter histogram analysis according to 10000 cells that obtain in the FITC road, do not add and add the tetrandrine person, accumulate experiment back staphylococcus aureus Rh123 positive cell rate and be respectively 22.40% and 78.92% (x2=60432, P=0.000), therefore add tetrandrine after, the Rh123 savings significantly increases in the aureus cell.And do not add and when adding tetrandrine, efflux experiment back staphylococcus aureus Rh123 positive cell rate be respectively 3.12% and 63.50% (x2=77127, P=0.000), therefore add tetrandrine after, Rh123 effluxes remarkable minimizing.
Zoopery
Zoopery that the present inventor carries out finds, when using different tetrandrine 13mg/kg body weight, can strengthen the oidiomycotic effect of ketoconazole treatment mouse vagina, and the mycology cure rate reaches 98%, and does not have tangible local excitation, avirulence.Table 7 has provided the experimental result of different tetrandrine to the potentiation (mouse vagina candidiasis model) of ketoconazole.
Table 7
F: not medication; KCZ: ketoconazole; ITET: different tetrandrine.Under be designated as dosage (mg/kg)
The present inventor also finds, compares with ampicillin (AMP) with single, not exclusively stops up with 5-bromine tetrandrine (BrTET) associating ampicillin treatment Dou Kou to add the inductive rabbit chronic sinusitis of staphylococcus aureus model, can significantly improve curative effect.Inoculation back the 2nd day, each treated animal bacterial loads is 22.68 ± 1.63 * 10
4～23.12 ± 2.86 * 10
4CFU/ml
Group difference not statistically significant (P＞0.05).Inoculation back the 6th day, the AMP20+BrTET20 group is compared with the AMP20 group, AMP 10+BrTET20 group is compared with the AMP10 group, and bacterial loads difference has statistical significance (P is respectively 0.003,0.016).AMP 10+BrTET10 group is compared (P=0.646) with 10 groups of AMP, AMP 20+BrTET10 group is compared (P=0.834) bacterial loads difference not statistically significant with the AMP20 group.
Clinical experiment
The clinical trial that the present inventor carries out finds that tetrandrine can strengthen the antifungal activity of ketoconazole, terbinafine, reverses the drug resistance of ketoconazole, terbinafine antifungal activity, thereby improves the mycotic effect of treatment.Table 8 has provided tetrandrine and ketoconazole, terbinafine use the preliminary clinical test results for the treatment of people's fungal infection simultaneously.Specific practice is: according to the principle of simple random sampling, the patient who chooses equivalent amount is respectively as simple antifungal drug treatment group (A group), the antifungal drug+tetrandrine treatment group (B group) of using.Observe its mycology cure rate, clinical cure rate, total effective rate, relapse rate.
Table 5
The antifungal drug of using in this research is ketoconazole, terbinafine.Administering mode: 150mg, qw.The course of treatment: 3 weeks of vaginal candidiasis, 4 weeks of tinea pedis, tinea corporis and 2 weeks of tinea cruris, 16 weeks of tinea unguium.Observe the time of mycology cure rate, clinical cure rate, total effective rate: vaginal candidiasis, tinea pedis, tinea corporis, tinea cruris are after the drug withdrawal 14 days, and tinea unguium is 4 weeks after the drug withdrawal.Observe the time of relapse rate: vaginal candidiasis, tinea pedis, tinea corporis, tinea cruris are 12 weeks after the drug withdrawal, and tinea unguium is 24 weeks after the drug withdrawal.Tetrandrine is cream or suppository, is external.
The present inventor also finds,, unites 0.5% neomycin solution soak with 1% different tetrandrine and treats impetigo with 0.5% neomycin solution or compare with single, can significantly improve curative effect.After the medication the 6th day, two groups of patients' clinical recovery rate was respectively 8/13 (single with 0.5% neomycin solution) and 13/13 (1% different tetrandrine+0.5% neomycin solution), and latter's inflammation disappears more rapid.
Preparation embodiment
The following examples are for example understood prescription of the present invention and preparation scheme.
The suitable dose scope of chemical compound of the present invention or natural materials depends on used chemical compound and patient's disease, also depends on especially to absorb effectiveness and administration frequency and approach.
According to the route of administration difference, the natural or synthesis of derivatives synergist that contains general formula (I) can be by following prescription.For by any administration, can prepare The compounds of this invention or derivant, preferably be mixed with unit dosage forms, or human patients can be with the dosage form of single dose to self-administer.For the purpose of favourable, that The compounds of this invention or compositions are applicable to is oral, administration under parenteral route, part, rectum, intravenous, muscle, Intradermal, subcutaneous, the mucosa.Can design preparation is beneficial to active ingredient and slowly discharges.
1. local application:
(1) the natural or synthesis of derivatives that will contain general formula (I) is made into ointment with 0.01-5% ratio and fat-soluble medium (as vaseline) and is coated with affected part outward; Or with same ratio add an amount of emulsifying agent (as phospholipid, medicine: phospholipid=10-100: 1) be made into aqueous solution and be coated with or wash ill portion outward; Perhaps make other dosage form, as gel, liniment, spray, lotion, containing agent etc.
(2) contain the preparation of the natural or synthesis of derivatives ointment of general formula (I): choose the medicinal natural or synthesis of derivatives powder that contains general formula (I) of purification, (w: ratio w) is made ointment according to 1% with the vaseline of heating and melting.
(3) contain the preparation of the natural or synthesis of derivatives liniment of general formula (I): the medicinal natural or synthesis of derivatives powder that contains general formula (I) of choosing purification, with itself and phospholipid ratio mixing in 50: 1, add water and make aqueous solution, become liniment, be used for the local use of focus.
2. system's medication:
(1) will contain the natural of general formula (I) or synthesis of derivatives tabletting (containing coated tablet), or make capsule, pill, syrup, suspending agent, chew chewing gum, wafer, powder, solution, every content of dispersion is 50-500mg; Or make injection.
(2) contain the capsule preparation of the natural or synthesis of derivatives of general formula (I): choose the medicinal natural or synthesis of derivatives powder that contains general formula (I) of purification,, make capsule, in order to orally using with the ratio mixing of medicinal glucose powder according to 1: 10.
3. the medicinal preparation that contains the natural or synthesis of derivatives+anti-infectives of general formula (I):
(1) choose the medicinal natural or synthesis of derivatives powder and the anti-infectives powder that contains general formula (I) of purification respectively, (w: ratio w) is made ointment, is used for that focus is local to be used respectively according to 1% with the vaseline of heating and melting.Also can make aforesaid various local applications dosage form.
(2) choose the medicinal natural or synthesis of derivatives powder and the anti-infectives powder that contains general formula (I) of purification, the two with the ratio mixing of medicinal glucose powder according to 1: 10, makes capsule again by after 1: 10～1: 20 the mixed, in order to orally using.Also can make aforesaid various systems drug formulation.
Claims (10)
1. the bisbenzylisoquinoline alkaloid shown in the general formula (I) or its pharmaceutically acceptable salt purposes aspect preparation anti-infectives synergist:
In the formula, R
1It is the straight or branched alkyl of 1-10 carbon atom;
R
2And R
3Be hydrogen, or R
2And R
3Be O together;
R
4And R
5Be hydrogen, methoxyl group, acetyl group, perhaps R
4And R
5Be O together;
X
1, X
2, X
3, X
4Can be identical or different, and be the straight or branched alkoxyl or the acyloxy of a halogen atom or 1-10 carbon atom independently of one another, and n is 0 to 3 integer.
2. purposes as claimed in claim 1, it is characterized in that described anti-infectives synergist is anti-fungal infection medicament synergistic agent, bacterial-infection resisting medicine synergist, viral infection resisting medicament synergistic agent, anti-actinomycotic infection medicament synergistic agent, anti-mycoplasma infection medicine synergist, anti-chlamydia infection medicament synergistic agent, anti-spirochaete infection medicament synergistic agent, rickettsicidal infection medicine synergist, protozoacide infection medicine synergist or anthelmintic infection medicine synergist.
3. purposes as claimed in claim 1 or 2, it is characterized in that, described bisbenzylisoquinoline alkaloid or its pharmaceutically acceptable salt are selected from a kind of as in next group material or its pharmaceutically acceptable salt: tetrandrine, different tetrandrine, 5-bromine tetrandrine, 5-chlorine tetrandrine and 5,14-dibromo tetrandrine.
4. purposes as claimed in claim 3, it is characterized in that, described bisbenzylisoquinoline alkaloid or its pharmaceutically acceptable salt are selected from a kind of as in next group material or its pharmaceutically acceptable salt: 5-chlorine tetrandrine and 5,14-dibromo tetrandrine.
5. purposes as claimed in claim 1, it is characterized in that described bisbenzylisoquinoline alkaloid or its pharmaceutically acceptable salt are as the synergist as next group anti-infectives: Beta-lactam medicine, Macrocyclolactone lactone kind medicine, lincomycin class medicine, polypeptide drug, tetracycline medication, the chloromycetin medicine, quinolones, the aminoglycosides medicine, disulfonamide, the nitrogen azole drug that does not comprise fluconazol, the propylene amine drug, the thiourea medicine, antibiotics such as polyenoid class medicine, lipopeptid class medicine, glycolipid class medicine, class lipopeptid medicine, class glycolipid medicine, the nucleoside peptide medicament, amino acid drug, condensed ring aromatics medicine, morpholine class medicine, fluorine miazines medicine, sour jujube albomycin class medicine, Nikemycin class medicine, nucleoside medicine, the non-nucleoside medicine, nucleoside reverse transcriptase inhibitors, antimalarial, antitrichomonal drug, anti-amebic, antischistosomal drug, antifilarial drug and vermifuge.
6. purposes as claimed in claim 5, it is characterized in that described bisbenzylisoquinoline alkaloid or its pharmaceutically acceptable salt are as the synergist as next group anti-infectives: ketoconazole, miconazole, amphotericin B, bifonazole, terbinafine, ceftriaxone, erythromycin, ciprofloxacin, gentamycin, doxycycline and penicillin.
7. anti-infective pharmaceutical composition, this pharmaceutical composition comprises:
(a) one or more the bisbenzylisoquinoline alkaloid shown in general formula (I) or its pharmaceutically acceptable salt:
In the formula, R1 is the straight or branched alkyl of 1-10 carbon atom;
R2 and R3 are hydrogen, or R2 and R3 are O together;
R4 and R5 are hydrogen, methoxyl group, acetyl group, and perhaps R4 and R5 are O together;
X1, X2, X3, X4 can be identical or different, and are the straight or branched alkoxyl or the acyloxy of a halogen atom or 1-10 carbon atom independently of one another, and n is 0 to 3 integer;
And
(b) one or more anti-infectives.
8. anti-infective pharmaceutical composition as claimed in claim 7, it is characterized in that, described bisbenzylisoquinoline alkaloid or its pharmaceutically acceptable salt are selected from a kind of as in next group material or its pharmaceutically acceptable salt: tetrandrine, different tetrandrine, 5-bromine tetrandrine, 5-chlorine tetrandrine and 5,14-dibromo tetrandrine; 5-chlorine tetrandrine and 5 preferably, 14-dibromo tetrandrine.
9. as claim 7 or 8 described anti-infective pharmaceutical compositions, it is characterized in that described anti-infectives is selected from the material as next group: Beta-lactam medicine, Macrocyclolactone lactone kind medicine, lincomycin class medicine, polypeptide drug, tetracycline medication, the chloromycetin medicine, quinolones, the aminoglycosides medicine, disulfonamide, the nitrogen azole drug that does not comprise fluconazol, the propylene amine drug, the thiourea medicine, antibiotics such as polyenoid class medicine, lipopeptid class medicine, glycolipid class medicine, class lipopeptid medicine, class glycolipid medicine, the nucleoside peptide medicament, amino acid drug, condensed ring aromatics medicine, morpholine class medicine, fluorine miazines medicine, sour jujube albomycin class medicine, Nikemycin class medicine, nucleoside medicine, the non-nucleoside medicine, nucleoside reverse transcriptase inhibitors, antimalarial, antitrichomonal drug, anti-amebic, antischistosomal drug, antifilarial drug and vermifuge.
10. anti-infective pharmaceutical composition as claimed in claim 9, it is characterized in that described anti-infectives is selected from the material as next group: ketoconazole, miconazole, amphotericin B, bifonazole, terbinafine, ceftriaxone, erythromycin, ciprofloxacin, gentamycin, doxycycline and penicillin.
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| CN103910739A (en) * | 2014-03-26 | 2014-07-09 | 山东师范大学 | Bisbenzylisoquinoline glycine betaines as well as preparation method and application thereof in preparing anti-tumor medicines |
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| WO2013026383A1 (en) * | 2011-08-19 | 2013-02-28 | 杭州本生药业有限公司 | Tetrandrine derivatives with substituted 5-carbon, preparation method and use thereof |
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| CN114028453A (en) * | 2021-12-07 | 2022-02-11 | 北京中医药大学 | Broad-spectrum antiviral drug, and pharmaceutical composition and application thereof |
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