CN101161652B - Quinolizine derivatives having antibacterial activity - Google Patents
Quinolizine derivatives having antibacterial activity Download PDFInfo
- Publication number
- CN101161652B CN101161652B CN2006101358955A CN200610135895A CN101161652B CN 101161652 B CN101161652 B CN 101161652B CN 2006101358955 A CN2006101358955 A CN 2006101358955A CN 200610135895 A CN200610135895 A CN 200610135895A CN 101161652 B CN101161652 B CN 101161652B
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- Prior art keywords
- hydrogen
- methoxyl group
- dioxy
- chlorion
- methylene
- Prior art date
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Abstract
The present invention relates to novel quinolizidine derivatives with antibiotic activity, the preparation method thereof, and medicine combination containing the compounds, as well as the application of the compounds to the fields of treatment/prevention on contagious diseases. The present invention belongs to the medicine technology field. Based on research, the quinolizidine derivatives with antibiotic activity provided by the present invention has the advantages of antibiotic effect with extended spectrum, high efficiency and low risk of drug tolerance, thereby being excellent in clinical applicable value, and capable of being used widely in clinic.
Description
1, technical field
The present invention relates to new quinolizine derivatives and preparation method thereof and the pharmaceutical composition that contains these compounds with anti-microbial activity, and these compounds preparation be used for the treatment of and/or the medicine of prophylaxis against infection diseases in purposes, belong to medical technical field.
2, background technology
Infectious diseases (infectious diseases) is by caused diseases such as bacterium, virus, fungies, is one of clinical several big diseases, and serious harm human life with healthy.Microbiotic is by some microorganism synthetic, can suppresses or kill the chemical substance of some pathogenic agent.Microbiotic is a kind of secondary metabolite of microorganism, can play inhibition or killing action to another kind of microbial growth and metabolism when a small amount of lower concentration uses, and is widely used in caused infectious diseases such as bacterium, virus, fungi.Microbiotic be widely used in clinical after, because antibiotic use lack of standardization, created the chance that frequently contacts with microbiotic to bacterium, with antibiotic repeated trial of strength in, bacterium has been familiar with antibiotic characteristic gradually, thereby producer sudden change, cause bacterium to produce resistance, under antibiotic selection pressure, mutation rate can become hundred times of increases, and very easily develop into multidrug resistant, constitute a serious difficulty to clinical treatment.The speed that bacterial resistance produces is far away faster than the speed of our new drug development, if things go on like this, we may return to the state before the 1970s and 1980s, there is not microbiotic to use, the mankind will face the threat of a lot of infectious diseases again, and therefore the research and development of new drug-resistance bacteria medicine have become the focus of domestic and international concern.
3, summary of the invention
The present invention aims to provide a kind of new have good anti-microbial activity and the little compound of resistance.
Technical scheme of the present invention is as follows:
The invention provides the compound shown in (1) that has general formula:
Wherein: R
1And R
2Identical or different, and independently represent C
1-C
5Alkoxyl group or R
1-R
2Be methylene-dioxy (O-CH
2-O-);
R
3Be hydrogen, C
1-C
10Alkyl, C
1-C
5Alkoxyl group;
R
4Be hydrogen, C
1-C
10Alkyl;
R
5Be hydrogen, fluorine, chlorine, bromine, iodine;
R
6And R
7Identical or different, and represent C
1-C
5Alkoxyl group;
R
8Be hydrogen, C
1-C
10Alkyl, C
1-C
5Alkoxyl group;
R
3And R
4Be not hydrogen simultaneously; R
3, R
5, R
8Be not hydrogen simultaneously; R
4, R
5, R
8Be not hydrogen simultaneously;
A
-Represent organic acid ion, inorganic acid ion or halide-ions.
C mentioned above
1-C
5Alkoxyl group is meant C
1-C
5The alkoxyl group of straight or branched, for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, pentyloxy etc.
C mentioned above
1-C
10Alkyl is meant C
1-C
10The alkyl of straight or branched, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl, hexyl, heptyl, octyl group, nonyl, decyl etc.
Preferred compound is:
R
1And R
2Identical or different, and independently represent C
1-C
3Alkoxyl group or R
1-R
2Be methylene-dioxy (O-CH
2-O-);
R
3Be hydrogen, C
1-C
5Alkoxyl group;
R
4Be hydrogen, C
1-C
8Alkyl;
R
5Be hydrogen, chlorine, bromine;
R
6And R
7Identical or different, and represent C
1-C
3Alkoxyl group;
R
8Be hydrogen, C
1-C
8Alkyl, C
1-C
3Alkoxyl group;
R
3And R
4Be not hydrogen simultaneously; R
3, R
5, R
8Be not hydrogen simultaneously; R
4, R
5, R
8Be not hydrogen simultaneously;
A
-Represent organic acid ion, inorganic acid ion or halide-ions.
Compound mentioned above, wherein A-is selected from acetate moiety, methanesulfonate, tosylate, maleate, amber acid radical, tartrate anion, citrate, fumarate, Aspartic Acid root, salicylate, glycerine acid group, xitix root, fumaric acid radical, nitrate radical, sulfate radical, phosphate radical, chlorion, bromide anion or iodide ion.
Wherein, it is as shown in table 1 to enumerate part of compounds:
Table 1 part of compounds of the present invention
The present invention also provides the preparation method of the above-mentioned preferred compound of part, but is not limited only to following preparation method, also can make by additive method:
1, compound 1 (R
1-R
2Be methylene-dioxy (O-CH
2-O-), R
3Be methoxyl group, R
4Be hydrogen, R
5Be bromine, R
8Be methyl, R
6, R
7Be methoxyl group, A
-Be chlorion, i.e. 1-methoxyl group-8-methyl isophthalic acid 2-bromo-Berberine muriate) preparation
Reactions steps: with berberine hydrochloride, anhydrous tetrahydro furan adds in the exsiccant reaction flask (1), and heating up is stirred to backflow, drip the anhydrous tetrahydrofuran solution of methyl iodide, finish the back back flow reaction, reaction solution concentrates, and the silica gel chromatography purifying gets 8-methyl Berberine iodide.
(2) 8-methyl Berberine iodide are dissolved in the frozen water, after the stirring and dissolving,, drip and finish in 20 ℃ of dropping bromines, stirring reaction, reaction solution concentrates, and adds the nitric acid and the vitriol oil in the residuum, in 40 ℃ of stirrings.Reaction is finished, reaction mixture is poured in an amount of frozen water with cold 30% sodium hydroxide solution adjusting pH, ethyl acetate extraction for several times, merge organic layer, washing, anhydrous magnesium sulfate drying, filtrate decompression get 1-nitro-8-methyl isophthalic acid 2-bromo-Berberine iodide (being directly used in the next step) after reclaiming solvent.
(3) in the exsiccant reaction flask, add 1-nitro-8-methyl isophthalic acid 2-bromo-Berberine iodide, anhydrous methanol, sodium methylate is in 50 ℃ of stirrings.Reaction is finished, and reclaims solvent, and it is an amount of to add entry in residuum, and ethyl acetate extraction merges organic layer, anhydrous magnesium sulfate drying for several times.Filter, filtrate decompression reclaims solvent, gets 1-methoxyl group-8-methyl isophthalic acid 2-bromo-Berberine iodide.
(4) above-mentioned iodide are added entry, 10% sodium chloride solution stirs two hours postcooling crystallizatioies, filters, and gets 1-methoxyl group-8-methyl isophthalic acid 2-bromo-Berberine muriate (being compound 1).
2, compound 7 (R
1-R
2Be methylene-dioxy (O-CH
2-O-), R
3Be methoxyl group, R
4Be methyl, R
5Be bromine, R
8Be n-hexyl, R
6, R
7Be methoxyl group, A
-Be chlorion, i.e. 1-methoxyl group-8-n-hexyl-12-bromo-Berberine muriate) preparation
Reactions steps: (1) is in the dry reaction bottle, add the magnesium powder, anhydrous tetrahydro furan is in stirring down, add a little iodine, anhydrous tetrahydro furan number droplet to the iodine that drips 1-bromo normal hexane fades fully, drips the anhydrous tetrahydrofuran solution of 1-bromo normal hexane with the speed that keeps reaction solution slowly to reflux, and finishes the back back flow reaction, add berberine hydrochloride, and then back flow reaction, reaction solution concentrates, and the silica gel chromatography purifying gets 8-n-hexyl Berberine bromide.
(2) will go up step gained 8-n-hexyl Berberine bromide and be dissolved in the frozen water, and after the stirring and dissolving,, drip and finish in 20 ℃ of dropping bromines, stirring reaction, reaction solution concentrates, and adds the nitric acid and the vitriol oil in the residuum, in 40 ℃ of stirrings.Reaction is finished, reaction mixture is poured in an amount of frozen water with cold 30% sodium hydroxide solution adjusting pH, ethyl acetate extraction for several times, merge organic layer, washing, anhydrous magnesium sulfate drying, filtrate decompression get 1-nitro-8-n-hexyl-12-bromo-Berberine bromide (being directly used in the next step) after reclaiming solvent.
(3) in the exsiccant reaction flask, add 1-nitro-8-n-hexyl-12-bromo-Berberine bromide, anhydrous methanol, sodium methylate stirs 12h in 50 ℃.Reaction is finished, and reclaims solvent, and it is an amount of to add entry in residuum, and ethyl acetate extraction merges organic layer, anhydrous magnesium sulfate drying for several times.Filter, filtrate decompression reclaims solvent, gets 1-methoxyl group-8-n-hexyl-12-bromo-Berberine bromide.
(4) above-mentioned bromide is added entry, 10% sodium chloride solution stirs two hours postcooling crystallizatioies, filters, and gets 1-methoxyl group-8-n-hexyl-12-bromo-Berberine muriate (being compound 7).
3, compound 21 (R
1-R
2Be methylene-dioxy (O-CH
2-O-), R
3Be hydrogen, R
4Be methyl, R
5Be hydrogen, R
8Be methyl, R
6, R
7Be methoxyl group, A
-Be chlorion, promptly 8,13-dimethyl Berberine muriate) preparation
Reactions steps: with berberine hydrochloride, 20% aqueous acetone solution adds in the reaction flask (1), and after the stirring and dissolving, the aqueous sodium hydroxide solution of slow Dropwise 5 0% finishes then, and vigorous stirring 1h separates out a large amount of orange/yellow solid.Filter washing with acetone with 20%.With the dissolving of dry acetonitrile, add the 1-methyl iodide behind the filtration cakes torrefaction, the mixed-liquor return reaction concentrates, 13-methyl Berberine iodide, needn't purifying, directly carry out the next step.
(2) in the dry reaction bottle, anhydrous tetrahydro furan, step gained 13-methyl Berberine is stirred to backflow in the adding, drip the anhydrous tetrahydrofuran solution of methyl iodide, finish the back back flow reaction, reaction solution concentrates, the silica gel chromatography purifying gets 8,13-dimethyl Berberine iodide.
(3) above-mentioned iodide are added entry, 10% sodium chloride solution stirs two hours postcooling crystallizatioies, filters, and gets 8,13-dimethyl Berberine muriate (being compound 21).
4, compound 30 (R
1-R
2Be methylene-dioxy (O-CH
2-O-), R
3Be hydrogen, R
4Be n-octyl, R
5Be hydrogen, R
8Be n-octyl, R
6, R
7Be methoxyl group, A
-Be chlorion, promptly 8,13-di-n-octyl Berberine muriate) preparation
Reactions steps: with berberine hydrochloride, the aqueous solution of 20% acetone adds in the reaction flask, after the stirring and dissolving, slowly drips 30% aqueous sodium hydroxide solution then, finishes (1), and vigorous stirring is separated out a large amount of orange/yellow solid.Filter washing with acetone with 20%.With the dissolving of dry acetonitrile, add 1-n-octane bromide (d=1.11) behind the filtration cakes torrefaction, sodium iodide, the mixed-liquor return reaction concentrates, 13-n-octyl Berberine bromide, needn't purifying, directly carry out the next step.
(2) in the dry reaction bottle, add the magnesium powder, anhydrous tetrahydro furan, in stirring down, add a little iodine, anhydrous tetrahydro furan number droplet to the iodine that drips the 1-n-octane bromide fades fully, drips the anhydrous tetrahydrofuran solution of 1-n-octane bromide then with the speed that keeps reaction solution slowly to reflux, finish the back back flow reaction, add again and go up step gained 13-n-octyl Berberine bromide, and then back flow reaction, reaction solution concentrates, the silica gel chromatography purifying gets 8,13-di-n-octyl Berberine bromide.
(3) above-mentioned bromide is added entry, 10% sodium chloride solution stirs two hours postcooling crystallizatioies, filters, and gets 8,13-di-n-octyl Berberine muriate (being compound 30).
The present invention is the claimed pharmaceutical composition that comprises arbitrary compound recited above and one or more other active pharmaceutical ingredientss and/or pharmaceutical carrier and/or thinner further, wherein contains the active ingredient by the described compound 10mg～500mg of formula (1).Aforementioned pharmaceutical compositions can be applied to the patient who needs treatment, preferred oral preparation or injection or external preparation in modes such as oral, administered parenterally or external applications.
When being used for administered parenterally, can be made into injection.Injection means the intravital solution of confession injection, emulsion or the suspension that medicine is made and supplies to face with preceding preparation or be diluted to solution or the sterile preparation of the powder of suspension or strong solution that injection can be divided into injection liquid, injectable sterile powder and concentrated solution for injection.Injection liquid means that the confession that medicine is made is injected into sterile solution type injection liquid, emulsion-type injection liquid or the suspension type injection liquid of using in the body, can be used for intramuscularly, intravenous injection, intravenous drip etc.; Its specification has 1ml, 2ml, 5ml, 10ml, 20ml, 50ml, 100ml, 200ml, 250ml, 500ml etc., and wherein large volume (generally the being not less than 100ml) injection liquid of using for intravenous drip also claims intravenous infusion.Injectable sterile powder means that confession that medicine is made is faced with the suitable sterile solution of preceding usefulness and is mixed with settled solution or the evenly sterilized powder or the aseptic block of suspension, available suitable solvent for injection preparation back injection, also available intravenous infusion preparation posterior vein instils; Sterilized powder makes with solvent crystallization, spray-drying process or freeze-drying etc.Concentrated solution for injection means that confession that medicine is made faces the aseptic strong solution of using for intravenous drip with preceding dilution.
When making injection, can adopt the ordinary method production in the existing pharmacy field, optional use solvent or non-aqueous solvent.The most frequently used aqueous solvent is a water for injection, also available 0.9% sodium chloride solution or other suitable aqueous solution; Non-aqueous solvent commonly used is a vegetables oil, is mainly the injection soybean oil, and other also have the aqueous solution of ethanol, propylene glycol, polyoxyethylene glycol etc.During the preparation injection, can add suitable additives according to the character of medicine, as osmotic pressure regulator, pH value conditioning agent, solubilizing agent, weighting agent, oxidation inhibitor, fungistat, emulsifying agent, suspending agent etc.Osmotic pressure regulator commonly used comprises sodium-chlor, glucose, Repone K, magnesium chloride, calcium chloride, sorbyl alcohol etc., preferred sodium-chlor or glucose; PH value conditioning agent commonly used comprises acetic acid-sodium-acetate, lactic acid, Citric Acid-Sodium Citrate, sodium bicarbonate-yellow soda ash etc.; Solubilizing agent commonly used comprises Polysorbate 80, propylene glycol, Yelkin TTS, polyoxyethylenated castor oil etc.; Weighting agent commonly used comprises lactose, N.F,USP MANNITOL, sorbyl alcohol, dextran etc.; Oxidation inhibitor commonly used has S-WAT, sodium bisulfite, Sodium Pyrosulfite etc.; Fungistat commonly used is phenol, cresols, trichloro-butyl alcohol etc.Injection container commonly used has glass ampoule, vial, plastic ampoule, Plastic Bottle etc.
Be used for when oral, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and the auxiliary materials and mixing compacting that suits form, based on oral ordinary tablet, other has lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coated tablet etc.Capsule means medicine or is added with the auxiliary material filling in Capsules or be sealed in solid preparation in the soft capsule material, according to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (capsule and pill), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means medicine and suitable auxiliary material uniform mixing, and the spherical or near-spherical solid preparation so that proper method is made comprises dripping pill, sugar-pill, piller etc.Granule means that medicine and suitable auxiliary material make the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as particle), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution makes for oral clarified liq preparation in suitable solvent.Oral suspensions means the insoluble solid pharmaceutical, is dispersed in the liquid medium, makes for oral suspension body preparation, also comprises dry suspensoid or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.
When making oral preparations, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.Weighting agent commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, Microcrystalline Cellulose, lactose, pregelatinized Starch, N.F,USP MANNITOL etc.; Typical binders comprises Xylo-Mucine, PVP-K30, hydroxypropylcellulose, starch slurry, methylcellulose gum, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dry starch, polyvinylpolypyrrolidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises Magnesium Stearate, talcum powder, sodium lauryl sulphate, micropowder silica gel etc.
When being used for topical administration, can make ointment, ointment, lotion, liniment, paint, liniment, gelifying agent, powder, patch, etc.Ointment means that medicine and oil or water-soluble base are mixed and made into uniform semi-solid external preparation.Ointment means medicine dissolution or is scattered in and forms uniform semi-solid external preparation in the emulsion-type matrix.Lotion means solution, emulsion, the suspension that contains medicine, for cleaning or smear the preparation that no damaged skin is used.Liniment means solution, emulsion or the suspension that medicine is made with ethanol, oil or The suitable solvent, rubs the liquid preparation of wiping usefulness for no damaged skin.Paint means the water-based that contains medicine or oily solution, emulsion, suspension, for facing with the preceding liquid preparation of getting or be applied to skin or oral cavity and throat's mucous membrane that dips in gauze or cotton.Liniment means medicine dissolution in containing the film forming material organic solvent, is coated with to put film forming liquid preparation for external application behind the affected part on the skin.Gelifying agent means that medicine and the auxiliary material that can form gel make the glop or the semi-solid preparation of homogeneous, suspendible or emulsion-type.Powder means medicine or the dry powdered preparation of making through pulverizing, uniform mixing with suitable auxiliary material, is divided into oral powder and part powder.Patch means Pasting on skin, and medicine can produce a kind of laminar preparation of general or local action; Said preparation has back sheet, drug depot, the tamanori layer of (or nothing) release-controlled film arranged and faces the protective layer of removing with preceding need; Can be used for the intact skin surface, also can be used for having illness or incomplete skin surface.
When making external preparation, can add suitable matrix, additives or The suitable solvent as required.Ointment is made up of medicine and matrix, matrix is as the vehicle of ointment and the carrier of medicine, to the release of the quality of ointment and medicine, be absorbed with significant effects, matrix commonly used can be divided into grease type matrix, emulsion-type matrix and water-soluble base, and grease type matrix comprises lipid (mainly comprising: animal oil, vegetables oil, hydrogenated vegetable wet goods), lipoidis (mainly comprising: lanolin, beeswax, spermaceti, Insect Wax etc.), hydro carbons (mainly comprising: Vaseline, solid paraffin, Liquid Paraffin etc.), silicone; Emulsion-type matrix is commonly used soda soap, trolamine soap class, fatty alcohol sulphuric acid (ester) sodium class, polysorbate, lanolin, direactive glyceride, Fatty Alcohol(C12-C14 and C12-C18) etc.; Water-soluble base comprises polyoxyethylene glycol, glycogelatin etc.; Can add wetting Agent for Printing Inks, sanitas, oxidation inhibitor or transdermal enhancer in case of necessity; Liquid preparation for external application such as lotion, liniment, liniment, solvent commonly used has water, ethanol, glycerine, vegetables oil, Liquid Paraffin etc., film forming material commonly used that polyvinyl alcohol, polyvinylpyrrolidone, crylic acid resin etc. are arranged, softening agent has glycerine, propylene glycol, dibutyl phthalate etc., and it is suitable to skin or the non-stimulated additives of mucous membrane to add in case of necessity; The water-soluble base of gelifying agent generally has formations such as water, glycerine or propylene glycol and derivatived cellulose, carbomer and alginates, western yellow glue, gelatin, starch; Oil-base gel matrix has Liquid Paraffin and polyoxyethylene or fatty oil and colloid silicon or aluminium soap, zinc soap to constitute, and can add wetting Agent for Printing Inks, sanitas, oxidation inhibitor or transdermal enhancer in case of necessity.
The also further claimed The compounds of this invention of the present invention preparation be used for the treatment of and/or the medicine of prophylaxis against infection diseases in purposes; The compounds of this invention all has good antibacterial activity to gram positive organism, gram-negative bacteria and part fungies such as gold-coloured staphylococci, staphylococcus epidermidis, streptococcus pneumoniae, Salmonella typhi, escherichia coli, acrothesium floccosums; can be used for treating and/or preventing the various diseases that causes by pathogenic micro-organism of Mammals (comprising the people), can treat by infection such as the intestinal tract due to the sensitive organism, Otorhinolaryngologic Department and skin soft tissues.
New antimicrobial compounds of the present invention compared with prior art has the following advantages:
(1) provides a kind of first and be used for the treatment of and/or the new quinolizine derivatives of prophylaxis against infection diseases, enriched the clinical application kind with anti-microbial activity.
(2) the present invention has further carried out pharmacodynamic experiment to preferred compound, show that according to antibacterial experiment and anti-mouse skin tinea bacterium experiment in in-vitro antibacterial experiment, the body The compounds of this invention all has higher anti-microbial activity to gram positive organism, gram-negative bacteria and part fungies such as gold-coloured staphylococci, staphylococcus epidermidis, streptococcus pneumoniae, Salmonella typhi, escherichia coli, acrothesium floccosums, show that it has wide spectrum, anti-microbial effect efficiently.
(3) preparation technology of The compounds of this invention is simple, and medicine purity height, yield height, steady quality are easy to carry out large-scale commercial production.
Below routine by experiment beneficial effect of further setting forth compound of the present invention, these experimental examples comprise the pharmacodynamic experiment of compound of the present invention.Compound of the present invention has following beneficial effect, but this should be interpreted as that compound of the present invention only has following beneficial effect.
Used trial-product is all from following compounds in the following experimental example.
The antimicrobial spectrum and the anti-microbial activity of experimental example 1 The compounds of this invention
Trial-product; The compounds of this invention 1,2,6,7,9,11,17.
For trying bacterial classification: gold-coloured staphylococci ATCC25923, staphylococcus epidermidis ATCC12228, streptococcus pneumoniae ATCC49790, Salmonella typhi ATCC19430, escherichia coli ATCC25922, acrothesium floccosum ATCC10277.
The preparation of test liquid: compound 1,2,6,7,9,11,17 is made into the concentration of 800 μ g/ml respectively, and serial dilution is 400 μ g/ml, 200 μ g/ml, 100 μ g/ml, 50 μ g/ml, 25 μ g/ml, 12.5 μ g/ml, 6.25 μ g/ml, 3.125 μ g/ml, 1.56 μ g/ml.
The preparation of bacteria suspension: pick a small amount of lawn from fresh strain inclined plane, be seeded in and be fit to test on the substratum of all growths, cultivate reasonable time in specified temperature, cultivate the back as original bacteria liquid, carry out the dilution of 10 times of series with sterile saline, get the 0.1ml bacterium liquid of suitable concentration and measure viable count.
The mensuration of minimum inhibitory concentration (MIC): the preparation bacteria culture medium, accurately measure 8ml by every test tube, packing was in 120 ℃ of warm sterilizations 20 minutes.Accurately measure the test liquid 1ml of each concentration, inject sterilized substratum, each concentration of each bacterial classification repeats 3 times, and every is accurately injected the 0.1ml bacteria suspension.Other gets and does not a series ofly inoculate any culture of strains base as blank.Put in the corresponding incubator 37 ℃ respectively and cultivated 1 day, observe the growth phenomenon.With the OD value of 721 type spectrophotometric determination inoculums, nutrient solution OD value becomes positive correlation with the interior bacterial reproduction speed of nutrient solution.Culture after the cultivation and blank carry out colorimetric estimation on 721 spectrophotometers, do not have the minimum concentration of bacterial growth as minimum inhibitory concentration in, the substratum identical with the two absorption.
Experimental result and conclusion: experimental result sees Table 1.The MIC value of gram positive organisms such as 1,2,6,7,9,11,17 pairs of streptococcus aureuses of The compounds of this invention, staphylococcus epidermidis and gram-negative bacterias such as streptococcus pneumoniae, Salmonella typhi all is not less than 12.5 μ g/ml; MIC value to colon bacillus is not less than 50 μ g/ml; Fungies such as acrothesium floccosum are also had higher anti-microbial activity, and the MIC value is not less than 200 μ g/ml.Above-mentioned experimental result shows, The compounds of this invention has higher anti-microbial activity to gram positive organism and gram-negative bacteria and fungi, has the characteristics of broad-spectrum high efficacy.
The antimicrobial spectrum of table 1 The compounds of this invention and anti-microbial activity
The antimicrobial spectrum of experimental example 2 The compounds of this invention and anti-microbial activity (2)
Trial-product: The compounds of this invention 21,22,24,26,29,30,31.
For trying bacterial classification: gold-coloured staphylococci ATCC25923, staphylococcus epidermidis ATCC12228, streptococcus pneumoniae ATCC49790, Salmonella typhi ATCC19430, escherichia coli ATCC25922, acrothesium floccosum ATCC10277.
The preparation of test liquid: compound 21,22,24,26,29,30,31 is made into the concentration of 800 μ g/ml respectively, and serial dilution is 400 μ g/ml, 200 μ g/ml, 100 μ g/ml, 50 μ g/ml, 25 μ g/ml, 12.5 μ g/ml, 6.25 μ g/ml, 3.125 μ g/ml, 1.56 μ g/ml.
The preparation of bacteria suspension: pick a small amount of lawn from fresh strain inclined plane, be seeded in and be fit to test on the substratum of all growths, cultivate reasonable time in specified temperature, cultivate the back as original bacteria liquid, carry out the dilution of 10 times of series with sterile saline, get the 0.1ml bacterium liquid of suitable concentration and measure viable count.
The mensuration of minimum inhibitory concentration (MIC): the preparation bacteria culture medium, accurately measure 8ml by every test tube, packing was in 120 ℃ of warm sterilizations 20 minutes.Accurately measure the test liquid 1ml of each concentration, inject sterilized substratum, each concentration of each bacterial classification repeats 3 times, and every is accurately injected the 0.1ml bacteria suspension.Other gets and does not a series ofly inoculate any culture of strains base as blank.Put in the corresponding incubator 37 ℃ respectively and cultivated 1 day, observe the growth phenomenon.With the OD value of 721 type spectrophotometric determination inoculums, nutrient solution OD value becomes positive correlation with the interior bacterial reproduction speed of nutrient solution.Culture after the cultivation and blank carry out colorimetric estimation on 721 spectrophotometers, do not have the minimum concentration of bacterial growth as minimum inhibitory concentration in, the substratum identical with the two absorption.
Experimental result and conclusion: experimental result sees Table 2.21,22,24,26,29,30,31 pairs of streptococcus aureus MIC values of The compounds of this invention are not less than 3.125 μ g/ml; Staphylococcus epidermidis, pneumococcal MIC value all are not less than 6.25 μ g/ml; MIC value to Salmonella typhi is not less than 12.5 μ g/ml; MIC value to colon bacillus is not less than 50 μ g/ml; Fungies such as acrothesium floccosum are also had higher anti-microbial activity, and the MIC value is not less than 200 μ g/ml.Above-mentioned experimental result shows, the new compound of the present invention has higher anti-microbial activity to gram positive organism and gram-negative bacteria and fungi, has the characteristics of broad-spectrum high efficacy, for having the new compound of good clinical application potential.
The antimicrobial spectrum of table 2 The compounds of this invention and anti-microbial activity
The provide protection of experimental example 3 The compounds of this invention to infecting in the mouse body
Animal subject: healthy mice, 320, body weight 20～25g, the male and female dual-purpose is divided into 16 groups at random, 20 every group.
Trial-product: The compounds of this invention 1,2,7,21,22,30, physiological saline.
The configuration of test liquid: trial-product is configured to 0.1mg/ml with physiological saline respectively.
For trying bacterium liquid: with 5% gastric Mucin dilution streptococcus aureus, Salmonella typhi suspension, bacteria containing amount is 1010/ml.
Experimental technique: every mouse peritoneal injection bacterium liquid 0.5ml infects, and infects back 1h and presses table 3 gastric infusion, and the blank group gives physiological saline, infects back 24h and observes the animal survival number, judges the provide protection of trial-product.
The provide protection (n=10) of table 3 The compounds of this invention to infecting in the mouse body
Experimental result and conclusion: experimental result sees Table 3.Compare with the blank group, infect streptococcus aureus or Salmonella typhi in 1,2,6,21,22,24 pairs of mouse bodies of The compounds of this invention and have extremely significant provide protection, death toll reduces greatly.Show that The compounds of this invention has significant antibacterial activity in vivo, have good clinical value.
Experimental example 4 The compounds of this invention are to the provide protection of mouse skin trichophyton mentagrophytes infection
Animal subject: 240 of Wistar rats, be the national standard animal, mouse about body weight 400g, is male about 3 months ages.
Be subjected to the reagent thing:
The treatment group: The compounds of this invention 1,2,6,7,21,22,24,30, self-control after the DMSO dissolving, is made into the solution that mass concentration is 200 μ g/ml;
Miconazole group: commercial;
Control group: 5%DMSO;
The blank group: 0.9% sterile saline, to observe the natural growth and decline of fungi infestation.
Experimental technique: rat adaptability was fed after 1 week, with the left side of being tried the rat back side, middle side and right side is the infected area, the conventional alpha fungus that infects, and after fungus microscope examination, fungus culture and histopathology confirm, at above-mentioned three places each compound solution of difference external curing group, 5%DMSO solution and 0.9% sterile saline.2 times/d of every infection place coating, in continuous 8 weeks, every 3d carries out fungus microscope examination and skin to be decreased and observes.
Curative effect is judged: fully recover and disappear fully for skin decreases, mycology is checked negative; Produce effects be skin decrease disappear＞60%, mycology is checked negative; Transfer the skin damage well to and disappear 20%～60%, mycology is checked negative or positive; Invalidly disappear for skin decreases＜20%, mycology is checked positive; Recurrence skin occurs and decreases for after the clinical recovery in the original place, mycology is checked the positive.
The antimycotic experimentation on animals measurement result of table 4 The compounds of this invention
Experimental result and conclusion: the rat to the of back inoculation alpha fungus infected and forms in 6 days, confirmed through fungus microscope examination and fungus culture, and did pathology and dye through PAS, can see mycelia and spore in stratum corneum.After determining that fungi infestation forms, beginning externally applied agent treatment.From above-mentioned experimental result as can be seen each group of The compounds of this invention anti-microbial activity of alpha fungus all is higher than the miconazole group.Show that The compounds of this invention has beyond thought advantage aspect antimycotic.
4, embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.The auxiliary material of each formulation can be replaced with acceptable accessories in following examples, perhaps reduces, increases.
Represent R with compound 1
1-R
2Be methylene-dioxy (O-CH
2-O-), R
3Be methoxyl group, R
4Be hydrogen, R
5Be bromine, R
8Be methyl, R
6, R
7Be methoxyl group, A
-Be chlorion, i.e. 1-methoxyl group-8-methyl isophthalic acid 2-bromo-Berberine muriate.
Represent R with compound 7
1-R
2Be methylene-dioxy (O-CH
2-O-), R
3Be methoxyl group, R
4Be methyl, R
5Be bromine, R
8Be n-hexyl, R
6, R
7Be methoxyl group, A
-Be chlorion, i.e. 1-methoxyl group-8-n-hexyl-12-bromo-Berberine muriate.
With compound 21 represent R1-R2 be methylene-dioxy (O-CH2-O-), R3 is a hydrogen, and R4 is a methyl, and R5 is a hydrogen, and R8 is a methyl, and R6, R7 are methoxyl group, and A-is a chlorion, promptly 8,13-dimethyl Berberine muriate.
With compound 30 represent R1-R2 be methylene-dioxy (O-CH2-O-), R3 is a hydrogen, and R4 is a n-octyl, and R5 is a hydrogen, and R8 is a n-octyl, and R6, R7 are methoxyl group, and A-is a chlorion, promptly 8,13-di-n-octyl Berberine muriate.
Embodiment 1 compound 1 (R
1
-R
2
Be methylene-dioxy (O-CH
2
-O-), R
3
Be methoxyl group, R
4
Be hydrogen, R
5
Be bromine, R
8
Be methyl, R
6
, R
7
Be methoxyl group, A
-
Be chlorion, i.e. 1-methoxyl group-8-methyl isophthalic acid 2-bromo-Berberine muriate)
Preparation
Reaction equation:
Reactions steps:
(1) with berberine hydrochloride 37.2g (100mmol), anhydrous tetrahydro furan 200ml (tetrahydrofuran (THF) moisture is less than 0.03%) adds in the dry reaction bottle, intensification is stirred to backflow, drip the anhydrous tetrahydrofuran solution of 15g methyl iodide, finish back back flow reaction 5h, reaction solution concentrates, and silica gel chromatography purifying (chloroform/ethyl acetate (15: 1) wash-out) gets 8-methyl Berberine iodide.
(2) 8-methyl Berberine iodide are dissolved in the 100ml frozen water, after the stirring and dissolving,, drip and finish in 20 ℃ of dropping bromine 16g (200mmol), stirring reaction 3 hours, reaction solution concentrates, and adds 20ml nitric acid and vitriol oil 20ml in the residuum, in 40 ℃ of stirring 18h.Reaction is finished, reaction mixture poured in an amount of frozen water into to regulate the pH value with 30% cold sodium hydroxide solution be 8, ethyl acetate extraction for several times, merge organic layer, washing, anhydrous magnesium sulfate drying, filtrate decompression get 1-nitro-8-methyl isophthalic acid 2-bromo-Berberine iodide (being directly used in the next step) after reclaiming solvent.
(3) in the exsiccant reaction flask, add 1-nitro-8-methyl isophthalic acid 2-bromo-Berberine iodide, anhydrous methanol 100ml, sodium methylate 5.4g stirs 12h in 50 ℃.Reaction is finished, and reclaims solvent, and it is an amount of to add entry in residuum, and ethyl acetate extraction merges organic layer, anhydrous magnesium sulfate drying for several times.Filter, filtrate decompression reclaims solvent, gets 1-methoxyl group-8-methyl isophthalic acid 2-bromo-Berberine iodide.
(4) above-mentioned iodide are added 100ml water, the sodium chloride solution of 100ml10% stirs two hours postcooling crystallizatioies, filters, and gets 19.8g1-methoxyl group-8-methyl isophthalic acid 2-bromo-Berberine muriate (being compound 1).Yield: 40%
Molecular formula: C
22H
21BrClNO
5
Molecular weight: 493.03
Results of elemental analyses:
Actual measurement: C:53.38%; H:4.34%; Br:16.17%; Cl:7.10%; N:2.78%
Theoretical: C:53.41%; H:4.28%; Br:16.15%; Cl:7.17%; N:2.83%
Embodiment 2 compounds 7 (R
1
-R
2
Be methylene-dioxy (O-CH
2
-O-), R
3
Be methoxyl group, R
4
Be methyl, R
5
Be bromine, R
8
Be n-hexyl, R
6
, R
7
Be methoxyl group, A
-
Be chlorion, i.e. 1-methoxyl group-8-n-hexyl-12-bromo-Berberine chlorine
The change thing) preparation
Reactions steps: (1) is in the dry reaction bottle, add magnesium powder 0.5 gram, anhydrous tetrahydro furan 50ml (tetrahydrofuran (THF) moisture is less than 0.03%), in stirring down, add a little iodine, anhydrous tetrahydro furan number droplet to the iodine that drips 1-bromo normal hexane fades fully, drip the anhydrous tetrahydrofuran solution of 3.3g1-bromo normal hexane (0.02mol) with the speed that keeps reaction solution slowly to reflux, finish back back flow reaction 1h, add berberine hydrochloride 7.5g (0.02mol), and then back flow reaction 2h, reaction solution concentrates, and silica gel chromatography purifying (chloroform/ethyl acetate (20: 1) wash-out) gets 8-n-hexyl Berberine bromide.
(2) will go up step gained 8-n-hexyl Berberine bromide and be dissolved in the 40ml frozen water, after the stirring and dissolving, drip bromine 3.2 grams (40mmol) in 20 ℃, drip and finish, stirring reaction 3 hours, reaction solution concentrates, add 4ml (0.48mol) nitric acid and vitriol oil 4ml in the residuum, stir 18h in 40 ℃.Reaction is finished, reaction mixture poured in an amount of frozen water into to regulate the pH value with 30% cold sodium hydroxide solution be 8, ethyl acetate extraction for several times, merge organic layer, washing, anhydrous magnesium sulfate drying, filtrate decompression get 1-nitro-8-n-hexyl-12-bromo-Berberine bromide (being directly used in the next step) after reclaiming solvent.
(3) in the exsiccant reaction flask, add 1-nitro-8-n-hexyl-12-bromo-Berberine bromide, anhydrous methanol 20ml, sodium methylate 1.1g stirs 12h in 50 ℃.Reaction is finished, and reclaims solvent, and it is an amount of to add entry in residuum, and ethyl acetate extraction merges organic layer, anhydrous magnesium sulfate drying for several times.Filter, filtrate decompression reclaims solvent, gets 1-methoxyl group-8-n-hexyl-12-bromo-Berberine bromide.
(4) above-mentioned bromide is added 25ml water, the sodium chloride solution of 30ml10% stirs two hours postcooling crystallizatioies, filters, and gets 4.2g1-methoxyl group-8-n-hexyl-12-bromo-Berberine muriate (being compound 7).Total recovery: 35.4%
Molecular formula: C
27H
31BrClNO
5
Molecular weight: 563.11
Results of elemental analyses:
Actual measurement: C:57.39%; H:5.58%; Br:14.19%; Cl:6.22%; N:2.45%
Theoretical: C:57.41%; H:5.53%; Br:14.14%; Cl:6.28%; N:2.48%
(R1-R2 is that (O-CH2-O-), R3 is a hydrogen to methylene-dioxy, and R4 is a methyl, R5 to embodiment 3 compounds 21 Be hydrogen, R8 is a methyl, and R6, R7 are methoxyl group, and A-is a chlorion, promptly 8,13-dimethyl Berberine muriate) preparationReaction equation:
Reactions steps:
(1) with berberine hydrochloride 15g (40mmol), 20% aqueous acetone solution 80ml adds in the reaction flask, after the stirring and dissolving, slowly drips the aqueous sodium hydroxide solution of 40ml50% then, finishes, and vigorous stirring 1h separates out a large amount of orange/yellow solid.Filter washing with acetone with 20%.With the dry acetonitrile dissolving of 100ml, add 15ml1-methyl iodide (d=2.29) behind the filtration cakes torrefaction, mixed-liquor return reaction 3 hours concentrates, 13-methyl Berberine iodide, needn't purifying, directly carry out the next step.
(2) in the dry reaction bottle, anhydrous tetrahydro furan 50ml, step gained 13-methyl Berberine is stirred to backflow in the adding, the anhydrous tetrahydrofuran solution of Dropwise 5 ml methyl iodide, finish back back flow reaction 5h, reaction solution concentrates, and silica gel chromatography purifying (chloroform/ethyl acetate (10: 1) wash-out) gets 8.5g8,13-dimethyl Berberine iodide.
(3) above-mentioned iodide are added 25ml water, the sodium chloride solution of 30ml10% stirs two hours postcooling crystallizatioies, filters, and gets 5.4g8,13 dimethyl Berberine muriates (being compound 21).Total recovery: 33.8%
Molecular formula: C
22H
22ClNO
4
Molecular weight: 399.12
Results of elemental analyses:
Measured value: C:66.02%; H:5.61%; Cl:8.83%; N:3.48%
Theoretical value: C:66.08%; H:5.55%; Cl:8.87%; N:3.50%
Embodiment 4 compounds 30 (R1-R2 be methylene-dioxy (O-CH2-O-), R3 is a hydrogen, and R4 is a n-octyl,
R5 is a hydrogen, and R8 is a n-octyl, and R6, R7 are methoxyl group, and A-is a chlorion, promptly 8, and 13-di-n-octyl Berberine muriate)
Preparation
Reaction equation:
Reactions steps:
(1) with berberine hydrochloride 7.5g (20mmol), the aqueous solution 40ml of 20% acetone adds in the reaction flask, after the stirring and dissolving, slowly drips the aqueous sodium hydroxide solution of 20ml30% then, finishes, and vigorous stirring 1h separates out a large amount of orange/yellow solid.Filter washing with acetone with 20%.With the dry acetonitrile dissolving of 50ml, add 20ml1-n-octane bromide (d=1.11) behind the filtration cakes torrefaction, the 1g sodium iodide, mixed-liquor return reaction 1.5h concentrates, 13-n-octyl Berberine bromide, needn't purifying, directly carry out the next step.
(2) in the dry reaction bottle, add magnesium powder 0.5g, anhydrous tetrahydro furan 50ml (tetrahydrofuran (THF) moisture is less than 0.03%), in stirring down, add a little iodine, anhydrous tetrahydro furan number droplet to the iodine that drips the 1-n-octane bromide fades fully, drip the anhydrous tetrahydrofuran solution of 1-n-octane bromide 3.9g (0.02mol) then with the speed that keeps reaction solution slowly to reflux, finish back back flow reaction 1h, add again and go up step gained 13-n-octyl Berberine bromide, and then back flow reaction 2h, reaction solution concentrates, silica gel chromatography purifying (chloroform/ethyl acetate (20: 1) wash-out) gets 4.3 grams 8,13-di-n-octyl Berberine bromide.
(3) above-mentioned bromide is added 25ml water, the sodium chloride solution of 30ml10% stirs two hours postcooling crystallizatioies, filters, and gets 3.1g8,13-di-n-octyl Berberine muriate (being compound 30).Total recovery: 26.1%
Molecular formula: C
36H
50ClNO
4
Molecular weight: 595.34
Results of elemental analyses:
Measured value: C:72.49%; H:8.51%; Cl:5.91%; N:2.32%
Theoretical value: C:72.52%; H:8.45%; Cl:5.95%; N:2.35%
The preparation of embodiment 5 The compounds of this invention injection liquids
1, prescription:
Compound 1 or 7 or 21 or 30 10～500mg
Polysorbate is an amount of
Water for injection 2000ml
Prepare 1000 altogether
2, preparation technology:
1) will produce with the ampoule dosing with vessel, plant and instrument etc. clear up, degerming, depyrogenation.
2) take by weighing raw material and auxiliary material by prescription.
3) get the water for injection that polysorbate adds dosing amount 80%, stirring and dissolving; The needle-use activated carbon that adds dosing amount 0.05% stirs 15min, filters, and takes off charcoal.
4) in solution, add compound 1 (or compound 7 or compound 21 or compound 30), stirring and dissolving;
5) the pH value of survey solution, adjust pH in case of necessity.
6) benefit adds to the full amount of water for injection constant volume.
7) soup is checked clarity through the smart filter of the millipore filtration of 0.22 μ m.
8) inspection of semifinished product.
9) soup is loaded in the ampoule.
10) 100 ℃ of flowing steam sterilization 30min.
11) leak detection, the lamp inspection.
12) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 6 The compounds of this invention tablets
1, prescription:
Compound 1 or 7 or 21 or 30 10～500mg
Pregelatinized Starch is an amount of
Low-substituted hydroxypropyl cellulose is an amount of
Microcrystalline Cellulose is an amount of
The 2%HPMC aqueous solution is an amount of
Micropowder silica gel is an amount of
Magnesium Stearate is an amount of
Carboxymethylstach sodium is an amount of
Prepare 1000 altogether
2, preparation technology:
1) raw material pulverizing is crossed 100 mesh sieves, all the other auxiliary materials are crossed 100 mesh sieves respectively, and are standby.
2) take by weighing raw material and auxiliary material according to recipe quantity.
3) hypromellose 2% the aqueous solution made soluble in water is standby.
4) compound 1 (or compound 7 or compound 21 or compound 30), pregelatinized Starch, low-substituted hydroxypropyl cellulose, Microcrystalline Cellulose are mixed, the adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable softwood.
5) cross 20 mesh sieve system particles.
6) particle is dried under 60 ℃ condition.
7) dry good particle adds Magnesium Stearate, micropowder silica gel and carboxymethylstach sodium, crosses the whole grain of 18 mesh sieves, mixes.
8) sampling, the work in-process chemical examination.
9) the sheet weight sheet of determining according to chemical examination.
10) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 7 The compounds of this invention capsules
1, prescription
Compound 1 or 7 or 21 or 30 10～500mg
Pregelatinized Starch is an amount of
Low-substituted hydroxypropyl cellulose is an amount of
Microcrystalline Cellulose is an amount of
The 2%HPMC aqueous solution is an amount of
Micropowder silica gel is an amount of
Magnesium Stearate is an amount of
Prepare 1000 altogether
2, preparation technology:
1) raw material pulverizing is crossed 100 mesh sieves, all the other auxiliary materials are crossed 100 mesh sieves respectively, and are standby.
2) take by weighing raw material and auxiliary material according to recipe quantity.
3) hypromellose 2% the aqueous solution made soluble in water is standby.
4) compound 1 (or compound 7 or compound 21 or compound 30), pregelatinized Starch, low-substituted hydroxypropyl cellulose, Microcrystalline Cellulose are mixed, the adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable softwood.
5) cross 20 mesh sieve system particles.
6) particle is dried under 60 ℃ condition.
7) dry good particle adds Magnesium Stearate, micropowder silica gel, crosses the whole grain of 18 mesh sieves, mixes.
8) sampling, the work in-process chemical examination.
9) loading amount of determining according to chemical examination incapsulates.
10) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 8 The compounds of this invention suppositorys
1, prescription:
Compound 1 or 7 or 21 or 30 10～500mg
PEG1000 is an amount of
PEG4000 is an amount of
Propylene glycol is an amount of
Water for injection is an amount of
Prepare 1000 pieces altogether
2, concrete steps:
1) raw material and auxiliary material were pulverized 100 mesh sieves, standby.
2) take by weighing raw material and auxiliary material according to recipe quantity.
3) compound 1 (or compound 7 or compound 21 or compound 30) is joined in the PEG matrix of fusing, add propylene glycol, it is an amount of to add water, stirs.
4) before solidifying in the impouring mould, cold slightly, scrape mould, cooling, the demoulding.
5) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 9 The compounds of this invention ointments
1, prescription
Compound 1 or 7 or 21 or 30 10～500mg
Stearic acid is an amount of
Trolamine is an amount of
Glycerine is an amount of
Lanolin is an amount of
Liquid Paraffin is an amount of
Prepare 1000g altogether
2, preparation technology:
1) get stearic acid, lanolin, Liquid Paraffin and put in the container, heating in water bath makes fusing, oil phase, 80 ℃ of insulations are standby.
2) get trolamine in addition and be dissolved in the distilled water, be heated to 80 ℃, get water.
3) water is slowly added in the oil phase, constantly be stirred to white fine and smooth paste according to same direction.
4) compound 1 (or compound 7 or compound 21 or compound 30) is ground well back and matrix mixing with a small amount of Liquid Paraffin.
5) under 80 ℃ of keeping warm modes, tubulature.
6) finished product is examined entirely, the packing warehouse-in.
Claims (9)
1. one kind has the compound shown in the general formula (1):
Wherein: R
1And R
2Identical or different, and independently represent C
1-C
5Alkoxyl group or R
1-R
2Be methylene-dioxy (O-CH
2-O-);
R
3Be hydrogen, C
1-C
10Alkyl, C
1-C
5Alkoxyl group;
R
4Be hydrogen, C
1-C
10Alkyl;
R
5Be hydrogen, fluorine, chlorine, bromine, iodine;
R
6And R
7Identical or different, and represent C
1-C
5Alkoxyl group;
R
8Be hydrogen, C
1-C
10Alkyl, C
1-C
5Alkoxyl group;
R
3And R
4Be not hydrogen simultaneously; R
3, R
5, R
8Be not hydrogen simultaneously; R
4, R
5, R
8Be not hydrogen simultaneously;
A
-Be selected from acetate moiety, methanesulfonate, tosylate, maleate, amber acid radical, tartrate anion, citrate, fumarate, Aspartic Acid root, salicylate, glycerine acid group, xitix root, fumaric acid radical, nitrate radical, sulfate radical, phosphate radical, chlorion, bromide anion or iodide ion.
2. compound as claimed in claim 1,
Wherein: R
1And R
2Identical or different, and independently represent C
1-C
3Alkoxyl group or R
1-R
2Be methylene-dioxy (O-CH
2-O-);
R
3Be hydrogen, C
1-C
5Alkoxyl group;
R
4Be hydrogen, C
1-C
8Alkyl;
R
5Be hydrogen, chlorine, bromine;
R
6And R
7Identical or different, and represent C
1-C
3Alkoxyl group;
R
8Be hydrogen, C
1-C
8Alkyl, C
1-C
3Alkoxyl group;
R
3And R
4Be not hydrogen simultaneously; R
3, R
5, R
8Be not hydrogen simultaneously; R
4, R
5, R
8Be not hydrogen simultaneously;
A
-Be selected from chlorion, bromide anion or iodide ion.
3. compound as claimed in claim 1, wherein R
1-R
2Be methylene-dioxy (O-CH
2-O-), R
3Be methoxyl group, R
4Be hydrogen, R
5Be bromine, R
8Be methyl, R
6, R
7Be methoxyl group, A
-Be chlorion;
Or R
1-R
2Be methylene-dioxy (O-CH
2-O-), R
3Be methoxyl group, R
4Be hydrogen, R
5Be chlorine, R
8Be methyl, R
6, R
7Be methoxyl group, A
-Be chlorion;
Or R
1-R
2Be methylene-dioxy (O-CH
2-O-), R
3Be oxyethyl group, R
4Be hydrogen, R
5Be bromine, R
8Be methyl, R
6, R
7Be methoxyl group, A
-Be chlorion;
Or R
1-R
2Be methylene-dioxy (O-CH
2-O-), R
3Be oxyethyl group, R
4Be hydrogen, R
5Be chlorine, R
8Be methyl, R
6, R
7Be methoxyl group, A
-Be chlorion;
Or R
1-R
2Be methylene-dioxy (O-CH
2-O-), R
3Be methoxyl group, R
4Be hydrogen, R
5Be bromine, R
8Be ethyl, R
6, R
7Be methoxyl group, A
-Be chlorion;
Or R
1-R
2Be methylene-dioxy (O-CH
2-O-), R
3Be methoxyl group, R
4Be hydrogen, R
5Be chlorine, R
8Be ethyl, R
6, R
7Be methoxyl group, A
-Be chlorion;
Or R
1-R
2Be methylene-dioxy (O-CH
2-O-), R
3Be methoxyl group, R
4Be hydrogen, R
5Be bromine, R
8Be n-hexyl, R
6, R
7Be methoxyl group, A
-Be chlorion;
Or R
1-R
2Be methylene-dioxy (O-CH
2-O-), R
3Be methoxyl group, R
4Be hydrogen, R
5Be chlorine, R
8Be n-hexyl, R
6, R
7Be methoxyl group, A
-Be chlorion;
Or R
1-R
2Be methylene-dioxy (O-CH
2-O-), R
3Be methoxyl group, R
4Be hydrogen, R
5Be bromine, R
8Be methyl, R
6, R
7Be methoxyl group, A
-Be iodide ion;
Or R
1-R
2Be methylene-dioxy (O-CH
2-O-), R
3Be methoxyl group, R
4Be hydrogen, R
5Be bromine, R
8Be n-hexyl, R
6, R
7Be methoxyl group, A
-Be iodide ion;
Or R
1Be methoxyl group, R
2Be methoxyl group, R
3Be methoxyl group, R
4Be hydrogen, R
5Be bromine, R
8Be methyl, R
6, R
7Be methoxyl group, A
-Be chlorion;
Or R
1Be methoxyl group, R
2Be methoxyl group, R
3Be methoxyl group, R
4Be hydrogen, R
5Be bromine, R
8Be n-hexyl, R
6, R
7Be methoxyl group, A
-Be chlorion;
Or R
1Be propoxy-, R
2Be propoxy-, R
3Be methoxyl group, R
4Be hydrogen, R
5Be bromine, R
8Be methyl, R
6, R
7Be methoxyl group, R
7, R
8Be methoxyl group, A
-Be chlorion;
Or R
1Be propoxy-, R
2Be propoxy-, R
3Be methoxyl group, R
4Be hydrogen, R
5Be bromine, R
8Be n-hexyl, R
6, R
7Be methoxyl group, A
-Be chlorion.
4. compound as claimed in claim 1, wherein R
1-R
2Be methylene-dioxy (O-CH
2-O-), R
3Be hydrogen, R
4Be methyl, R
5Be hydrogen, R
8Be methyl, R
6, R
7Be methoxyl group, A
-Be chlorion;
Or R
1-R
2Be methylene-dioxy (O-CH
2-O-), R
3Be hydrogen, R
4Be ethyl, R
5Be hydrogen, R
8Be ethyl, R
6, R
7Be methoxyl group, A
-Be chlorion;
Or R
1-R
2Be methylene-dioxy (O-CH
2-O-), R
3Be hydrogen, R
4Be n-hexyl, R
5Be hydrogen, R
8Be n-hexyl, R
6, R
7Be methoxyl group, A
-Be chlorion;
Or R
1-R
2Be methylene-dioxy (O-CH
2-O-), R
3Be hydrogen, R
4Be n-octyl, R
5Be hydrogen, R
8Be n-octyl, R
6, R
7Be methoxyl group, A
-Be chlorion;
Or R
1-R
2Be methylene-dioxy (O-CH
2-O-), R
3Be hydrogen, R
4Be methyl, R
5Be hydrogen, R
8Be methyl, R
6, R
7Be methoxyl group, A
-Be iodide ion;
Or R
1-R
2Be methylene-dioxy (O-CH
2-O-), R
3Be hydrogen, R
4Be ethyl, R
5Be hydrogen, R
8Be ethyl, R
6, R
7Be methoxyl group, A
-Be iodide ion;
Or R
1-R
2Be methylene-dioxy (O-CH
2-O-), R
3Be hydrogen, R
4Be n-hexyl, R
5Be hydrogen, R
8Be n-hexyl, R
6, R
7Be methoxyl group, A
-Be iodide ion;
Or R
1-R
2Be methylene-dioxy (O-CH
2-O-), R
3Be hydrogen, R
4Be n-octyl, R
5Be hydrogen, R
8Be n-octyl, R
6, R
7Be methoxyl group, A
-Be iodide ion;
Or R
1Be propoxy-, R
2Be propoxy-, R
3Be hydrogen, R
4Be methyl, R
5Be hydrogen, R
8Be methyl, R
6, R
7Be methoxyl group, R
7, R
8Be methoxyl group, A
-Be chlorion;
Or R
1Be propoxy-, R
2Be propoxy-, R
3Be hydrogen, R
4Be n-octyl, R
5Be hydrogen, R
8Be n-octyl, R
6, R
7Be methoxyl group, A
-Be chlorion.
5. the pharmaceutical composition that comprises the described arbitrary compound of claim 1 and pharmaceutical carrier and/or thinner.
6. pharmaceutical composition as claimed in claim 6 wherein contains the active ingredient of the described compound 10mg～500mg of claim 1 Chinese style (1).
7. pharmaceutical composition as claimed in claim 6 is pharmaceutically acceptable arbitrary formulation.
8. the pharmaceutically acceptable formulation of pharmaceutical composition as claimed in claim 8 is oral preparations or injection or external preparation.
The described arbitrary compound of claim 1 preparation be used for the treatment of and/or the medicine of prophylaxis against infection diseases in application.
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| KR101603279B1 (en) * | 2013-12-31 | 2016-03-15 | 한국화학연구원 | Pharmaceutical composition for prevention or treatment of diseases induced by activation of NFAT5 containing protoberberine derivative or pharmaceutically acceptable salts as an active ingredient |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1071666A (en) * | 1991-10-21 | 1993-05-05 | 中国药科大学 | Tetrahydroberberine type quaternary ammonium componnd and preparation method thereof |
| CN1295573A (en) * | 1998-04-24 | 2001-05-16 | 韩华石油化学株式会社 | Pharmaceutically available protoberberine salt derivatives, and protoberberine derivatives and salt thereof |
| CN1629160A (en) * | 2003-12-15 | 2005-06-22 | 李耐三 | Preparation of 13-hexyl berberine salt and its anti-virus and antibacterial action |
-
2006
- 2006-10-14 CN CN2006101358955A patent/CN101161652B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1071666A (en) * | 1991-10-21 | 1993-05-05 | 中国药科大学 | Tetrahydroberberine type quaternary ammonium componnd and preparation method thereof |
| CN1295573A (en) * | 1998-04-24 | 2001-05-16 | 韩华石油化学株式会社 | Pharmaceutically available protoberberine salt derivatives, and protoberberine derivatives and salt thereof |
| CN1629160A (en) * | 2003-12-15 | 2005-06-22 | 李耐三 | Preparation of 13-hexyl berberine salt and its anti-virus and antibacterial action |
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Effective date of registration: 20190613 Address after: 101113 Room 301, Building 3, East of Qishanzhuang Village, Zhangjiawan Town, Tongzhou District, Beijing (in Beijing Sihuan Pharmaceutical Co., Ltd.) Co-patentee after: Langfang high Bojing State Pharmaceutical Co. Ltd. Patentee after: Beijing Aohe Pharmaceutical Research Institute Co., Ltd. Address before: 250101 No. 2518 Tianchen Street, Jinan High-tech Development Zone, Shandong Province Co-patentee before: Langfang high Bojing State Pharmaceutical Co. Ltd. Patentee before: Shandong Xuanzhu Medical Technology Co., Ltd. |
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Effective date of registration: 20210722 Address after: 135000 1688 Wutong Road, Meihekou, Tonghua, Jilin Patentee after: JILIN JINSHENG PHARMACEUTICAL Co.,Ltd. Address before: 101113 Room 301, Building 3, East of Qishanzhuang Village, Zhangjiawan Town, Tongzhou District, Beijing (in Beijing Sihuan Pharmaceutical Co., Ltd.) Patentee before: Beijing Aohe Pharmaceutical Research Institute Co.,Ltd. Patentee before: Langfang high Bojing State Pharmaceutical Co.,Ltd. |
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