CN103819356A - Preparation method and use of kukoamine B analogue or medicinal salts thereof - Google Patents
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Abstract
The invention relates to a kukoamine B analogue with a structure shown in a formula (1), medicinal salts of the analogue, and a preparation method and use of the analogue and the medicinal salts.
Description
Technical field
The invention belongs to medical technical field, particularly the analogue of multiple Kukoamine B or its pharmaceutical salts and preparation method thereof and Kukoamine B analogue and the purposes of its salt for the preparation of prevention and treatment medication for treating pyemia.
Background technology
Sepsis is systemic inflammatory response syndrome (the systemic inflammatory response syndrome of infective agent mediation, SIRS), be the patients' such as burn, wound, tumour and infectious diseases common complication, now become the primary factor that causes intensive care unit(ICU) (ICU) death that generally acknowledge in the whole world.Pyemic existing clinical treatment means are mainly early application microbiotic and correct hypoxia-ischemia infringement, adopt the method for conventional treatment organ failure and shock, there is no specific treatment measure.Pharmacological agent is conventionally empirically to use the nonspecific drugs such as glucocorticosteroid, Regular Insulin, immunomodulator as main, but curative effect is not affirmed always.The nineties in 20th century, the monoclonal antibody HA-1A(Centoxin of anti-lipid A) once during the Gulf War for U.S. army's war wound and burn after pyemic treatment, this medicine also once used in Some European country and Japan Clinic, but because having on the contrary detrimental action to septic shock, within 1992, fail to obtain the approval of U.S. FDA, also disappear from European market immediately.Recombinant activated human protein c (recombinant human activated protein C, rhAPC) is the current pyemic medicine of unique treatment of being ratified by FDA (trade(brand)name Xigris).Clinical test results shows that rhAPC can reduce by 28 days mortality ratio of septic, goes on the market through FDA approval November calendar year 2001.But but showing rhAPC group mortality ratio and the control group of 28 days, the clinical test results for the second time of 2005 there is no difference.In the clinical trial of 2007, rhAPC does not only have the effect that improves septic survival rate, also there is the side effect that causes patient's severe haemorrhage tendency, mechanism's suggestion of therefore organizing this clinical trial not recommendation its as the pyemic clinical medicine for the treatment of.
Pathogenic agent associated molecular pattern (pathogen-associated molecular patterns, and pattern recognition receptors (pattern recognition receptors PAMPs), PRRs) discovery, make the mankind to pyemic noegenesis qualitative leap.Now confirm that pyemic pathogenesis is that pathogenic agent is invaded after body, the PAMPs(of its thalline mainly comprises lipopolysaccharides/intracellular toxin (lipopolysaccharide/endotoxin, LPS), bacterial genomes DNA(CpG DNA) and peptidoglycan (peptideglycan, PGN) etc.) by inflammatory response cell film in body non-specific immunity system/cell in corresponding PRRs identify, cause inflammatory response cell activation, discharge inflammatory mediator and cause systemic inflammatory reaction, and then cause the damage of histoorgan.Therefore, important effect molecule in the past antagonism inflammatory reaction, correct the disorder of the systems such as blood coagulation, complement, and when the treatment measure such as single antagonism LPS failure, find the simultaneously multiple main PAMPs(LPS of antagonism, CpG DNA and PGN etc.) medicine, block pyemic generation from source and may bring breakthrough for its treatment.
Kukoamine B (kukoamine B), has another name called Root-bark of Chinese Wolfberry second element, is from Chinese medicine Root-bark of Chinese Wolfberry, to separate the naturally occurring alkaloid compound of one obtaining, and chemical structure is as follows:
Kukoamine B is found in nineteen ninety-five by Japanese Shinji Funayama the earliest from Root-bark of Chinese Wolfberry, has (S.Funayama, G.Zhang and S.Nozoe.Phytochemistry.1995 with free alkali form; 38:1529-1531).Kukoamine B content difference in the Root-bark of Chinese Wolfberry medicinal material of the different places of production, collection period is larger, therefore from plant, directly extracts, separation and purifying Kukoamine B are in order to preparation prevention and treat pyemic medicine and have the shortcomings such as source is unstable, production cost is high, energy consumption is large.Third Military Medical University's application patent of invention: Kukoamine B Salt And Preparation Method and purposes (application number: 201010539028.4), this patent of invention discloses chemical structure and chemical synthesis process and the effect in treatment medication for treating pyemia thereof of Kukoamine B salt compound.The synthetic reaction process through 14 steps of Kukoamine B salt compound, just finally obtains Kukoamine B salt compound, and reaction scheme is long.
Summary of the invention
The present invention is directed to the deficiency of above-mentioned Kukoamine B or its analogue, a kind of analogue or its pharmaceutical salts of Kukoamine B are being provided.
Technical scheme of the present invention is:
Analogue or its pharmaceutical salts that a kind of Kukoamine B is provided, described Kukoamine B analogue has following chemical structure
Wherein, R
1for OH or OCH
3and other active groups, R
2for H or CH
3and other active group, n=0-2.
The analogue of preferred Kukoamine B is:
The pharmaceutical salts of the analogue of Kukoamine B of the present invention is the mineral acid of oxygen-free acid or oxygen acid or the organic acid of carboxylic acid or alcohol acid or sulfonic acid or acidic amino acid.
Described oxygen-free acid is any one in hydrochloric acid and Hydrogen bromide.
Described oxygen acid is any one in sulfuric acid, phosphoric acid and nitric acid.
Described mineral acid is any one in hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid.
Described carboxylic acid is any one in acetic acid, propionic acid, butyric acid, oxalic acid, propanedioic acid, succsinic acid, hexanodioic acid, phenylformic acid, phenylpropionic acid, styracin, stearic acid, trifluoracetic acid, toxilic acid, fumaric acid, nicotinic acid and palmitinic acid.
Described alcohol acid is any one in oxysuccinic acid, citric acid, lactic acid, hydroxybutyric acid, lactobionic acid, tartrate, amygdalic acid, gluconic acid, glucuronic acid and xitix.
Described sulfonic acid is any one in methylsulfonic acid, Phenylsulfonic acid, tosic acid and camphorsulfonic acid.
Described acidic amino acid is any one in L-glutamic acid and aspartic acid.
Described organic acid is any one in acetic acid, toxilic acid, succsinic acid, oxysuccinic acid, lactic acid, tartrate, methylsulfonic acid, tosic acid, L-glutamic acid and aspartic acid.
Acid in the salt of described Kukoamine B analogue is extensively selected from multiple mineral acid and/or organic acid, mainly all kinds of acid from pharmaceutically allowing to use, to choose respectively 2～3 representative acid the common problem of preparing Kukoamine B salt is described, comprise and in the oxygen-free acid from mineral acid, choose hydrochloric acid and Hydrogen bromide, in oxygen acid, choose sulfuric acid and phosphoric acid, in carboxylic acid in organic acid, choose acetic acid, toxilic acid and succsinic acid, in alcohol acid, choose oxysuccinic acid, lactic acid and tartrate, in sulfonic acid, choose methylsulfonic acid and tosic acid, in acidic amino acid, choose L-glutamic acid and aspartic acid.Although applicant's experiment has only proposed these four kinds of mineral acids and ten kinds of organic acids, other mineral acids and/or organic acid (comprise the present invention that exemplified and acid that do not exemplify) are all to prepare in the same manner Kukoamine B salt.
The salt of preferred Kukoamine B analogue of the present invention is hydrochloride, hydrobromate, vitriol, phosphoric acid salt, acetate.
Most preferred is hydrochloride, hydrobromate.
The present invention also provides the pharmaceutical composition that contains Kukoamine B analogue and salt thereof, and pharmaceutical composition prevents and treat the application in pyemic medicine in preparation.
Pharmaceutical composition of the present invention can be prepared into any pharmaceutical dosage form, as can be through the formulation of gastrointestinal administration, as with formulation administrations such as powder, tablet, granule, capsule, solution, emulsion, suspensoids; Or the non-formulation through gastrointestinal administration, as drug administration by injection, cavity/canal drug administration, the mode administrations such as mucosa delivery.For adult, dosage is advisable with per kilogram of body weight 0.1～15mg every day, and application method can be for once a day or repeatedly.
The pharmaceutical composition of Kukoamine B analogue of the present invention and salt thereof, comprises Kukoamine B analogue and salt thereof as activeconstituents and pharmaceutically acceptable carrier and/or thinner.
Pharmaceutical composition of the present invention, the preparation of its oral administration can contain conventional vehicle, such as tackiness agent, weighting agent, thinner, tablet agent, lubricant, disintegrating agent, tinting material, seasonings and wetting agent, can carry out dressing to tablet if desired.
Applicable weighting agent comprises Mierocrystalline cellulose, mannitol, lactose and other similar weighting agent.Suitable disintegrating agent comprises starch, polyvinylpyrrolidone and starch derivative, for example sodium starch glycollate.Suitable lubricant comprises, for example Magnesium Stearate.The acceptable wetting agent of suitable medicine comprises sodium lauryl sulphate.
Can, by mixing, fill, the method that compressing tablet etc. are conventional is prepared solid oral composition.Repeatedly mix in those compositions that can make active substance be distributed in a large amount of weighting agents of whole use.
The form of oral liquid can be for example water-based or oily suspensions, solution, emulsion, syrup or elixir, or can be a kind of used water before use or the composite drying products of other suitable carrier.This liquid preparation can contain conventional additive, such as suspension agent, for example sorbyl alcohol, syrup, methylcellulose gum, gelatin, Natvosol, carboxymethyl cellulose, aluminium stearate gel or hydrogenation edible-fat, emulsifying agent, for example Yelkin TTS, anhydro sorbitol monooleate or gum arabic; Non-aqueous carrier (they can comprise edible oil), for example Prunus amygdalus oil, fractionated coconut oil, such as oily ester, propylene glycol or the ethanol of the ester of glycerine; Sanitas, for example para hydroxybenzene methyl esters or propylparaben or Sorbic Acid, and if need, can contain conventional flavouring agent or tinting material.
For injection, the liquid unit dosage of preparation contains active substance of the present invention and sterile carrier.According to carrier and concentration, this compound can be suspended or dissolve.The preparation of solution, normally by active substance being dissolved in a kind of carrier, being packed into filter-sterilized before a kind of suitable bottle or ampoule, then seals.Auxiliary material for example a kind of local anesthetic, sanitas and buffer reagent also can be dissolved in this carrier.In order to improve its stability, can be by freezing this composition after packing bottle into, and under vacuum, water is removed.
Pharmaceutical composition of the present invention, in the time being prepared into medicament, optionally add applicable medicine acceptable carrier, described medicine acceptable carrier is selected from: N.F,USP MANNITOL, sorbyl alcohol, Sodium Pyrosulfite, sodium bisulfite, Sulfothiorine, cysteine hydrochloride, Thiovanic acid, methionine(Met), vitamins C, EDETATE SODIUM, Ethylenediaminetetraacetic Acid Calcium Salt, the alkali-metal carbonate of monovalence, acetate, phosphoric acid salt or its aqueous solution, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acid, sodium-chlor, Repone K, Sodium.alpha.-hydroxypropionate, Xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivative, Mierocrystalline cellulose and derivative thereof, alginate, gelatin, polyvinylpyrrolidone, glycerine, POLYSORBATE 80, agar, calcium carbonate, Calcium hydrogen carbonate, tensio-active agent, polyoxyethylene glycol, cyclodextrin, beta-cyclodextrin, phospholipid material, kaolin, talcum powder, calcium stearate, Magnesium Stearate etc.
The present invention also provides the preparation method of Kukoamine B analogue and salt thereof.
Kukoamine B analogue structure of the present invention is as follows
Wherein, R
1for OH or OCH
3and other active groups, R
2for H or CH
3and other active group, n=0-2.
The preparation method of this analogue, comprises the following steps:
Putriscine and vinyl cyanide generation addition reaction, obtain holding the dicyano compound of position.
3 of above-mentioned dicyano compound and protection, the reaction of 4-dihydroxy phenyl propionic acid, obtains bisamide dicyanogen methyl isophorone compound.
Above-mentioned bisamide dicyanogen methyl isophorone compound obtains the mesylate of target compound A2 through cyano group hydro-reduction and subsequent step.
Kukoamine B analogue of the present invention and salt thereof can be for the preparation of prevention and treatment medication for treating pyemia.
Applicant tests demonstration by pharmacologically active:
Kukoamine B analogue of the present invention is stronger than the binding ability of Kukoamine B with the binding ability of the active centre lipid A of LPS, has indivedual analogues even considerably beyond the binding ability of Kukoamine B; These analogues with stronger binding ability are in vitro with in dose-dependent mode and LPS; These analogues with stronger binding ability suppress respectively LPS in dose-dependent mode and CpG DNA induction RAW264.7 cell discharges inflammatory mediator.
The present invention uses the pharmaceutical composition of Kukoamine B analogue and salt thereof, is different from the medicines such as existing glucocorticosteroid, Regular Insulin, anti-inflammatory medium medicine, anticoagulant, anti-LPS polypeptide and lipid A monoclonal antibody; Good effect, thus the inflammatory reaction of its induction can significantly be suppressed by the multiple cause of disease molecules of while antagonism, for pyemic treatment provides more selectable micromolecular compound.
The present invention extensively chooses multiple mineral acid and/or organic acid describes the common problem of preparing Kukoamine B analogue pharmacy acceptable salt, the technician of chemistry and pharmaceutical field is appreciated that, use similar mineral acid and/or the organic acid all can be in an identical manner, the method for knowing by chemical field be prepared Kukoamine B analogue pharmacy acceptable salt.Therefore should illustrate; mineral acid and/or the organic acid enumerated with other mineral acids and/or the alternative the present invention of organic acid; all should belong to technical scheme content of the present invention and scope of patent protection, any variation that those skilled in the art do the invention process under the enlightenment of this explanation is all within the application's claim scope.
LPS and CpG DNA are the crucial virulence factors that causes pathogenesis of sepsis, and medicine has reflected that to the antagonism of LPS and CpG DNA it is to pyemic preventive and therapeutic effect.
Embodiment
Following examples are that Kukoamine B analogue of the present invention is described in detail, have disclosed by this explanation main synthetic route and experimental technique that other compounds of the present invention use.Should be appreciated that the following stated is only preferred embodiment of the present invention, it does not limit the present invention in any form.Should illustrate, if do not depart from the spirit and scope of the present invention, the present invention is modified or is equal to replacement, all should be encompassed in the middle of the protection domain of claim of the present invention.
Embodiment 1: Kukoamine B analogue (A2) synthetic
1.1 experimental techniques:
(1) compound 1 is synthetic:
16.7g butanediamine (0.19mol) is dissolved in 400ml methyl alcohol, under stirring at room temperature, splash into vinyl cyanide (27.2ml, methyl alcohol (200ml) solution 0.40mol), after dropping finishes, room temperature reaction 5 ± 2h, monitor reaction end by thin-layer chromatography, until react completely.Concentrate to obtain compound 1, colourless to yellow oil 34.9g, yield 94.7%.
(2) compound 2 is synthetic:
34.9g compound 1 (0.18mol), 56.3ml triethylamine (0.40mol) is dissolved in the methylene dichloride that 400ml is dry, by 34.3g3,4-dimethoxy benzene propionyl chloride (0.19mol) is dissolved in dry methylene chloride 200ml and dissolves, under stirring, ice bath slowly splashes into, after dropping finishes, under condition of ice bath, continue reaction, monitor reaction end (silica-gel plate: GF by thin-layer chromatography
254, developping agent: methylene dichloride: methyl alcohol=10:1, inspects under ultraviolet lamp), until react completely.Concentrated organic solvent, adds dilute hydrochloric acid 500ml, ethyl acetate 400ml × 3 extraction, saturated sodium-chloride washing, and anhydrous sodium sulfate drying, suction filtration, concentrates to obtain compound 2, and tawny is to dark oil thing 141.3g, yield 88.8%.
(3) compound 3 is synthetic:
141.3g compound 2 (0.16mol) is dissolved in 20ml tetrahydrofuran (THF), add methanol solution 1000ml and the Raney Ni6g of saturated ammonia, drain after air, under the hydrogen pressure of about 3-8MPa, 50 ℃ of stirring reaction 8 ± 2h in autoclave, monitor reaction end by thin-layer chromatography, until react completely.Suction filtration (diatomite drainage), concentrates to obtain compound 3, green oily matter 124.7g, yield 87.5%.
(4) compound 4 is synthetic:
124.7g compound 3 (0.14mol), 39.2ml triethylamine (0.30mol) is dissolved in the methylene dichloride of 400ml, under ice bath stirs, slowly splash into chloroformic acid benzyl ester (40.6ml, methylene dichloride (100ml) solution 0.29mol), after dropping finishes, under condition of ice bath, continue reaction, monitor reaction end (until react completely by thin-layer chromatography.Add dilute hydrochloric acid 1000ml, the extraction of methylene dichloride 600ml × 3, saturated common salt washing, anhydrous sodium sulfate drying, suction filtration, concentrates to obtain crude product.Column chromatography, obtains sterling compound 4, and micro-yellow is to yellow oil 114.1g, yield 71.4%.
(5) compound 5 is synthetic:
114.1g compound 4 (0.10mol) is dissolved in 300ml tetrahydrofuran (THF), add 1000ml methyl alcohol, first use organic membrane filtration, add again 16.4ml methylsulfonic acid (0.25mol), after 11.4g10% palladium/carbon, drain air, room temperature reaction 15 ± 2h under hydrogen normal pressure, monitor reaction end by thin-layer chromatography, until react completely.Filter, dry ethyl acetate washing, vacuum-drying obtains sterling compound 5, white to off-white powder 50.6g, yield 70.0%.
The chemical structure of compound 5 is carried out
1h NMR measures:
1H?NMR:6.8(2H),6.7(4H),5.4(4H),5.1(4H),3.2(8H),2.9(4H),2.8(6H),2.6(4H),2.5(4H),1.9(4H),1.6(4H)。
ESI-MS(M+1):531.3。
The chemical formula that mensuration obtains this material is:
The preparation method of other Kukoamine B analogues is as follows:
Wherein, R is OH or OCH
3and other active groups, n=0-2.
Embodiment 2: Kukoamine B analogue organic acid salt synthetic
Experimental technique: the synthetic middle methylsulfonic acid of compound 5 in embodiment 1 is changed to corresponding organic acid, obtains corresponding organic acid salt, as malate, lactic acid salt, succinate, mesylate etc.
Embodiment 3: Kukoamine B analogue inorganic acid salt synthetic
Experimental technique: the synthetic middle methylsulfonic acid of compound 5 in embodiment 1 is changed to corresponding mineral acid, obtains corresponding inorganic acid salt, example hydrochloric acid salt, vitriol, phosphoric acid salt, hydrobromate etc.
Embodiment 4: Kukoamine B analogue discharges the impact of TNF-α on LPS induction RAW264.7 cell
Experimental technique: adopt and contain 10%NCS(v/v) DMEM nutrient solution by RAW264.7 cell dilution to 1 × 10
6/ mL, adds 96 orifice plates (200 μ l/ hole), the CO that is 5% at 37 ℃, volume fraction
2under condition, hatch 4h adherent after; Change fresh medium, adding final concentration is the various Kukoamine B analogues of 100 μ g/ml, adds immediately LPS(final concentration 100ng/ml), establish the blank group (medium) that does not add any stimulator simultaneously, continue to hatch 4h; Get supernatant and operate according to ELISA test kit operation instructions, detect the concentration of TNF-α, result represents with means standard deviation.
Experimental result: the TNF-α that Kukoamine B analogue can suppress LPS induction discharges, and has significant difference (p<0.01) compared with control group.A large amount of or the sustained release of TNF-α is significant to the pathology damage of Sepsis and autoimmune disorder, therefore suppresses the release of TNF-α and can effectively bring into play the preventive and therapeutic effect to Sepsis and autoimmune disorder, and result is as shown in table 1.
Table 1, Kukoamine B analogue suppress LPS induction RAW264.7 cell and discharge inflammatory mediator
The salt of embodiment 5 Kukoamine B analogues suppresses LPS induction RAW264.7 cell and discharges inflammatory mediator experiment:
Experimental technique: adopt DMEM nutrient solution by RAW264.7 cell dilution to 1 × 10
6/ ml, adds 96 orifice plates (200 μ l/ hole), the CO that is 5% at 37 ℃, volume fraction
2under condition, hatch 4 hours, adherent rear replacing cell conditioned medium is the DMEM nutrient solution of 200 μ l serum-frees, then add LPS(final concentration 100ng/ml), add respectively final concentration is that the salt of the various Kukoamine B analogues of 100 μ M (comprises hydrochloride simultaneously, hydrobromate, vitriol, phosphoric acid salt, acetate, malate, lactic acid salt), blank group (Medium) does not add LPS, continues to hatch 4 hours, gets supernatant, the concentration that detects TNF-α according to ELISA test kit operation instructions, experimental result is in table 2.
Table 2, chrysamine category-B suppress LPS induction RAW264.7 cell like the salt of thing and discharge inflammatory mediator
Experimental result shows that the salt of most Kukoamine B analogues all can suppress LPS induction RAW264.7 cell and discharge inflammatory mediator TNF-α.
Embodiment 6: Kukoamine B analogue (B1, B2, B3) pharmaceutical salts synthetic
The concrete preparation method of compd B 2 mesylates:
(1) compound 6 is synthetic:
16.7g1,4-butanediamine (0.19mol) is dissolved in 400ml methyl alcohol, under stirring at room temperature, splash into vinyl cyanide (27.2ml, methyl alcohol (200ml) solution 0.40mol), after dropping finishes, room temperature reaction 5 ± 2h, monitors reaction end by thin-layer chromatography, until react completely.Concentrate to obtain compound 6, colourless to yellow oil 34.9g, yield 94.7%.
(2) compound 7 is synthetic:
34.9g compound 6 (0.18mol), 56.3ml triethylamine (0.40mol) is dissolved in the methylene dichloride that 400ml is dry, by 84g3,4-dimethoxy benzene propionyl chloride (0.37mol) is dissolved in dry methylene chloride 200ml and dissolves, under stirring, ice bath slowly splashes into, after dropping finishes, under condition of ice bath, continue reaction, monitor reaction end (silica-gel plate: GF by thin-layer chromatography
254, developping agent: methylene dichloride: methyl alcohol=10:1, inspects under ultraviolet lamp), until react completely.Concentrated organic solvent, adds dilute hydrochloric acid 500ml, ethyl acetate 400ml × 3 extraction, saturated sodium-chloride washing, and anhydrous sodium sulfate drying, suction filtration, concentrates to obtain compound 7, tawny oily matter 92g, yield 88%.
(3) compound 8 is synthetic:
92g compound 7 (0.16mol) is dissolved in 20ml tetrahydrofuran (THF), add methanol solution 1000ml and the Raney Ni6g of saturated ammonia, drain after air, under the hydrogen pressure of about 3-8MPa, 50 ℃ of stirring reaction 8 ± 2h in autoclave, monitor reaction end by thin-layer chromatography, until react completely.Suction filtration (diatomite drainage), concentrates to obtain compound 8, green oily matter 82g, yield 88%.
(4) compound 9 is synthetic:
82g compound 8 (0.14mol), 39.2ml triethylamine (0.30mol) is dissolved in the methylene dichloride of 400ml, under ice bath stirs, slowly splash into chloroformic acid benzyl ester (40.6ml, methylene dichloride (100ml) solution 0.29mol), after dropping finishes, under condition of ice bath, continue reaction, monitor reaction end (until react completely by thin-layer chromatography.Add dilute hydrochloric acid 1000ml, the extraction of methylene dichloride 600ml × 3, saturated common salt washing, anhydrous sodium sulfate drying, suction filtration, concentrates to obtain crude product.Column chromatography, obtains sterling compound 9, and micro-yellow is to yellow oil 92g, yield 79%.
(5) compound 10 is synthetic:
92g compound 9 (0.11mol) is dissolved in 300ml tetrahydrofuran (THF), add 1000ml methyl alcohol, first use organic membrane filtration, add again 16.4ml methylsulfonic acid (0.25mol), after 11.4g10% palladium/carbon, drain air, room temperature reaction 15 ± 2h under hydrogen normal pressure, monitor reaction end by thin-layer chromatography, until react completely.Filter, dry ethyl acetate washing, vacuum-drying obtains sterling compound 10, white to off-white powder 54g, yield 73%.
Chemical structure to compound 10 is measured, measuring method:
1H?NMR:6.8(2H),6.7(4H),5.1(4H),3.8(12H),3.2(8H),2.9(4H),2.8(6H),2.6(4H),2.5(4H),1.9(4H),1.6(4H)。
ESI-MS(M+1):587.3
The chemical formula that mensuration obtains this material is:
Use 1,3-propylene diamine as starting raw material, obtain compound B-11.Use 1,5-pentamethylene diamine as starting raw material, obtain compd B 3.
Synthesizing of Kukoamine B analogue organic acid salt
Experimental technique: the synthetic middle methylsulfonic acid of compound 10 in embodiment 6 is changed to corresponding organic acid, obtains corresponding organic acid salt, as malate, lactic acid salt, succinate, mesylate etc.
Synthesizing of Kukoamine B analogue inorganic acid salt
Experimental technique: just in embodiment 6, the synthetic middle methylsulfonic acid of compound 10 is changed to corresponding mineral acid, obtains corresponding inorganic acid salt, example hydrochloric acid salt, vitriol, phosphoric acid salt, hydrobromate etc.
Embodiment 7: Kukoamine B analogue (C1, C2, C3) pharmaceutical salts synthetic
The concrete preparation method of Compound C 2 mesylates:
(1) compound 11 is synthetic:
16.7g butanediamine (0.19mol) is dissolved in 400ml methyl alcohol, under stirring at room temperature, splash into vinyl cyanide (27.2ml, methyl alcohol (200ml) solution 0.40mol), after dropping finishes, room temperature reaction 5 ± 2h, monitor reaction end by thin-layer chromatography, until react completely.Concentrate to obtain compound 11, colourless to yellow oil 34.9g, yield 94.7%.
(2) compound 12 is synthetic:
34.9g compound 11 (0.18mol), 56.3ml triethylamine (0.40mol) is dissolved in the methylene dichloride that 400ml is dry, by 140.6g3,4-dibenzyloxy benzene propionyl chloride (0.37mol) is dissolved in dry methylene chloride 200ml and dissolves, under stirring, ice bath slowly splashes into, after dropping finishes, under condition of ice bath, continue reaction, monitor reaction end (silica-gel plate: GF by thin-layer chromatography
254, developping agent: methylene dichloride: methyl alcohol=10:1, inspects under ultraviolet lamp), until react completely.Concentrated organic solvent, adds dilute hydrochloric acid 500ml, ethyl acetate 400ml × 3 extraction, saturated sodium-chloride washing, and anhydrous sodium sulfate drying, suction filtration, concentrates to obtain compound 12, and tawny is to dark oil thing 141.3g, yield 88.8%.
(3) compound 13 is synthetic:
141.3g compound 12 (0.16mol) is dissolved in 20ml tetrahydrofuran (THF), add methanol solution 1000ml and the Raney Ni6g of saturated ammonia, drain after air, under the hydrogen pressure of about 3-8MPa, 50 ℃ of stirring reaction 8 ± 2h in autoclave, monitor reaction end by thin-layer chromatography, until react completely.Suction filtration (diatomite drainage), concentrates to obtain compound 13, green oily matter 124.7g, yield 87.5%.
(4) compound 14 is synthetic:
124.7g compound 13 (0.14mol) is in cooling lower slowly adding in 72g90% aqueous formic acid, drip 63ml37% formaldehyde solution, be heated to reflux, produce a large amount of bubbles, back flow reaction 8 hours, cooling, add 4N hydrochloric acid, be spin-dried for, add 100ml water and 500ml methylene dichloride, add 18N aqueous sodium hydroxide solution, separatory, uses dichloromethane extraction 2 times, merges organic phase, anhydrous sodium sulfate drying, suction filtration, is spin-dried for, and obtains sterling compound 14, micro-yellow is to yellow oil 83g, yield 65%.
(5) compound 15 is synthetic:
83g compound 14 (0.09mol) is dissolved in 300ml tetrahydrofuran (THF), add 1000ml methyl alcohol, first use organic membrane filtration, add again 16.4ml methylsulfonic acid (0.25mol), after 11.4g10% palladium/carbon, drain air, room temperature reaction 15 ± 2h under hydrogen normal pressure, monitor reaction end by thin-layer chromatography, until react completely.Filter, dry ethyl acetate washing, vacuum-drying obtains sterling compound 15, white to off-white powder 50.6g, yield 70.0%.
The chemical structure of compound 15 is carried out
1h NMR measures:
1H?NMR:6.8(2H),6.7(4H),5.4(4H),3.2(8H),2.9(4H),2.8(6H),2.6(4H),2.5(4H)，3(12H),1.9(4H),1.6(4H)。
ESI-MS(M+1):587.3。
The chemical formula that mensuration obtains this material is:
Use 1,3-propylene diamine as starting raw material, obtain Compound C 1.Use 1,5-pentamethylene diamine as starting raw material, obtain Compound C 3.
Synthesizing of Kukoamine B analogue organic acid salt
Experimental technique: the synthetic middle methylsulfonic acid of compound 15 in embodiment 7 is changed to corresponding organic acid, obtains corresponding organic acid salt, as malate, lactic acid salt, succinate, mesylate etc.
Synthesizing of Kukoamine B analogue inorganic acid salt
Experimental technique: just in embodiment 7, the synthetic middle methylsulfonic acid of compound 15 is changed to corresponding mineral acid, obtains corresponding inorganic acid salt, example hydrochloric acid salt, vitriol, phosphoric acid salt, hydrobromate etc.
Embodiment 8: Kukoamine B analogue (D1, D2, D3) pharmaceutical salts synthetic
The concrete preparation method of Compound D 2 mesylates:
(1) compound 16 is synthetic:
16.7g1,4-butanediamine (0.19mol) is dissolved in 400ml methyl alcohol, under stirring at room temperature, splash into vinyl cyanide (27.2ml, methyl alcohol (200ml) solution 0.40mol), after dropping finishes, room temperature reaction 5 ± 2h, monitors reaction end by thin-layer chromatography, until react completely.Concentrate to obtain compound 16, colourless to yellow oil 34.9g, yield 94.7%.
(2) compound 17 is synthetic:
34.9g compound 16 (0.18mol), 56.3ml triethylamine (0.40mol) is dissolved in the methylene dichloride that 400ml is dry, by 84g3,4-dimethoxy benzene propionyl chloride (0.37mol) is dissolved in dry methylene chloride 200ml and dissolves, under stirring, ice bath slowly splashes into, after dropping finishes, under condition of ice bath, continue reaction, monitor reaction end (silica-gel plate: GF by thin-layer chromatography
254, developping agent: methylene dichloride: methyl alcohol=10:1, inspects under ultraviolet lamp), until react completely.Concentrated organic solvent, adds dilute hydrochloric acid 500ml, ethyl acetate 400ml × 3 extraction, saturated sodium-chloride washing, and anhydrous sodium sulfate drying, suction filtration, concentrates to obtain compound 17, tawny oily matter 92g, yield 88%.
(3) compound 18 is synthetic:
92g compound 17 (0.16mol) is dissolved in 20ml tetrahydrofuran (THF), add methanol solution 1000ml and the Raney Ni6g of saturated ammonia, drain after air, under the hydrogen pressure of about 3-8MPa, 50 ℃ of stirring reaction 8 ± 2h in autoclave, monitor reaction end by thin-layer chromatography, until react completely.Suction filtration (diatomite drainage), concentrates to obtain compound 18, green oily matter 82g, yield 88%.
(4) compound 19 is synthetic:
82g compound 18 (0.14mol), in cooling lower slowly adding in 72g90% aqueous formic acid, drips 63ml37% formaldehyde solution, is heated to reflux, and produces a large amount of bubbles, back flow reaction 8 hours, cooling, add 4N hydrochloric acid, be spin-dried for, add 100ml water and 500ml methylene dichloride, add 18N aqueous sodium hydroxide solution, separatory, uses dichloromethane extraction 2 times, merges organic phase, anhydrous sodium sulfate drying, suction filtration, is spin-dried for, sterling compound 19, micro-yellow is to yellow oil 59g, yield 66%.
(5) compound 20 is synthetic:
59g compound 19 (0.09mol) is dissolved in 300ml tetrahydrofuran (THF), adds 1000ml methyl alcohol, adds 16.4ml methylsulfonic acid (0.25mol), room temperature reaction 1h.Be spin-dried for, dry ethyl acetate washing, vacuum-drying obtains sterling compound 20, white to off-white powder 50g, yield 68%.
The chemical structure of compound 20 is carried out
1h NMR measures:
1H?NMR:6.8(2H),6.7(4H),3.8(12H),3.2(8H),2.9(4H),2.8(6H),2.6(4H),2.5(4H),2.3(12H),1.9(4H),1.6(4H)。
ESI-MS(M+1):643.5。
The chemical formula that mensuration obtains this material is:
Use 1,3-propylene diamine as starting raw material, obtain Compound D 1.Use 1,5-pentamethylene diamine as starting raw material, obtain Compound D 2.
Synthesizing of Kukoamine B analogue organic acid salt
Experimental technique: the synthetic middle methylsulfonic acid of compound 20 in embodiment 8 is changed to corresponding organic acid, obtains corresponding organic acid salt, as malate, lactic acid salt, succinate, mesylate etc.
Synthesizing of Kukoamine B analogue inorganic acid salt
Experimental technique: the synthetic middle methylsulfonic acid of compound 20 in embodiment 8 is changed to corresponding mineral acid, obtains corresponding inorganic acid salt, example hydrochloric acid salt, vitriol, phosphoric acid salt, hydrobromate etc.
Claims (10)
1. the analogue of Kukoamine B or its pharmaceutical salts, is characterized in that: described Kukoamine B analogue has following chemical structure
Wherein, R
1for OH or OCH
3and other active groups, R
2for H or CH
3and other active group, n=0-2, the pharmaceutical salts of the analogue of wherein said Kukoamine B is the mineral acid of oxygen-free acid or oxygen acid or the organic acid of carboxylic acid or alcohol acid or sulfonic acid or acidic amino acid.
2. the analogue of Kukoamine B according to claim 1 or its pharmaceutical salts, is characterized in that, the analogue of described Kukoamine B is following compounds:
3. the analogue of Kukoamine B according to claim 1 and 2 or its pharmaceutical salts, is characterized in that, wherein said oxygen-free acid is any one in hydrochloric acid and Hydrogen bromide.
4. the analogue of Kukoamine B according to claim 1 and 2 or its pharmaceutical salts, is characterized in that: wherein said oxygen acid is any one in sulfuric acid, phosphoric acid and nitric acid.
5. the analogue of Kukoamine B according to claim 1 and 2 or its pharmaceutical salts, is characterized in that: wherein said carboxylic acid is any one in acetic acid, propionic acid, butyric acid, oxalic acid, propanedioic acid, succsinic acid, hexanodioic acid, phenylformic acid, phenylpropionic acid, styracin, stearic acid, trifluoracetic acid, toxilic acid, fumaric acid, nicotinic acid and palmitinic acid.
6. the analogue of Kukoamine B according to claim 1 and 2 or its pharmaceutical salts, is characterized in that: wherein said alcohol acid is any one in oxysuccinic acid, citric acid, lactic acid, hydroxybutyric acid, lactobionic acid, tartrate, amygdalic acid, gluconic acid, glucuronic acid and xitix.
7. the analogue of Kukoamine B according to claim 1 and 2 or its pharmaceutical salts, is characterized in that: described sulfonic acid is any one in methylsulfonic acid, Phenylsulfonic acid, tosic acid and camphorsulfonic acid.
8. the analogue of Kukoamine B according to claim 1 and 2 or its pharmaceutical salts, is characterized in that: described acidic amino acid is any one in L-glutamic acid and aspartic acid.
9. a pharmaceutical composition, the analogue or its pharmaceutical salts that comprise the Kukoamine B described in claim 1 or 2.
10. the analogue of the Kukoamine B of claim 1 or 2 or its pharmaceutical salts and the composition that contains them application in preparation prevention and treatment medication for treating pyemia.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105330563A (en) * | 2015-10-12 | 2016-02-17 | 天津红日药业股份有限公司 | Reference compounds for kukoamine B quality control |
| CN105348137A (en) * | 2015-10-29 | 2016-02-24 | 重庆安体新生物技术有限公司 | Polyamine derivative medicinal salt and its preparation method and use |
| CN117105808A (en) * | 2022-08-29 | 2023-11-24 | 武汉武药科技有限公司 | Polyamine derivative medicinal salt, crystal form and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102267922A (en) * | 2011-04-27 | 2011-12-07 | 中国人民解放军第三军医大学第一附属医院 | Polyamine compounds, preparation method and application thereof |
| CN102464591A (en) * | 2010-11-10 | 2012-05-23 | 中国人民解放军第三军医大学第一附属医院 | Kukoamine B salt, preparation method thereof and purpose thereof |
-
2014
- 2014-02-12 CN CN201410048601.XA patent/CN103819356A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102464591A (en) * | 2010-11-10 | 2012-05-23 | 中国人民解放军第三军医大学第一附属医院 | Kukoamine B salt, preparation method thereof and purpose thereof |
| CN102267922A (en) * | 2011-04-27 | 2011-12-07 | 中国人民解放军第三军医大学第一附属医院 | Polyamine compounds, preparation method and application thereof |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105330563A (en) * | 2015-10-12 | 2016-02-17 | 天津红日药业股份有限公司 | Reference compounds for kukoamine B quality control |
| CN105330563B (en) * | 2015-10-12 | 2018-12-07 | 天津红日药业股份有限公司 | For the reference compound in the control of Kukoamine B quality |
| CN105348137A (en) * | 2015-10-29 | 2016-02-24 | 重庆安体新生物技术有限公司 | Polyamine derivative medicinal salt and its preparation method and use |
| CN105348137B (en) * | 2015-10-29 | 2018-06-12 | 重庆安体新生物技术有限公司 | Polyamine derivative pharmaceutical salts and preparation method and purposes |
| JP2018534364A (en) * | 2015-10-29 | 2018-11-22 | 重慶安体新生物技術有限公司 | Polyamine derivative medicinal salt and production method and use |
| CN117105808A (en) * | 2022-08-29 | 2023-11-24 | 武汉武药科技有限公司 | Polyamine derivative medicinal salt, crystal form and preparation method thereof |
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