CN102276521A - Kukoamine B analogue, and pharmaceutically acceptable salt, preparation method and application thereof - Google Patents

Kukoamine B analogue, and pharmaceutically acceptable salt, preparation method and application thereof Download PDF

Info

Publication number
CN102276521A
CN102276521A CN2011101642384A CN201110164238A CN102276521A CN 102276521 A CN102276521 A CN 102276521A CN 2011101642384 A CN2011101642384 A CN 2011101642384A CN 201110164238 A CN201110164238 A CN 201110164238A CN 102276521 A CN102276521 A CN 102276521A
Authority
CN
China
Prior art keywords
acid
chrysamine
bitter
analogue
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN2011101642384A
Other languages
Chinese (zh)
Inventor
姚小青
郑江
孙长海
刘鑫
董凯
郑新川
王�琦
王宁
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
First Affiliated Hospital of TMMU
Tianjin Chase Sun Pharmaceutical Co Ltd
Original Assignee
First Affiliated Hospital of TMMU
Tianjin Chase Sun Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by First Affiliated Hospital of TMMU, Tianjin Chase Sun Pharmaceutical Co Ltd filed Critical First Affiliated Hospital of TMMU
Priority to CN2011101642384A priority Critical patent/CN102276521A/en
Publication of CN102276521A publication Critical patent/CN102276521A/en
Pending legal-status Critical Current

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a kukoamine B analogue having a structure shown as the formula (1) or a pharmaceutical salt thereof, and a preparation method and application thereof. In the formula (1), R1, R2, R3 and R4 can independently be H, alkyl with less than 3 carbon atoms and protective groups of hydroxyls, such as formoxyl, ethanoyl, benzyl and the like; X1-X3 can independently be C atom or N atom; when one is the N atom, other two are the C atoms; X4-X6 can independently be the C atom or the N atom; when one is the N atom, other two are the C atoms; and n1-n5 can independently be alkyl with less than 4 carbon atoms.

Description

Bitter chrysamine category-B is like thing and its drug acceptable salt and preparation method and purposes
Technical field
The invention belongs to medical technical field, the analogue of particularly multiple bitter chrysamine B or its pharmaceutical salts and preparation method thereof are used to prepare the purposes of preventing and treating medication for treating pyemia with bitter chrysamine category-B like thing and its salt.
Background technology
Sepsis is systemic inflammatory response syndrome (the systemic inflammatory response syndrome of infective agent mediation, SIRS), be 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 stage use microbiotic and correct the infringement of ischemic hypoxemia, adopt the method for conventional treatment organ failure and shock, still do not have the specific treatment measure.Pharmacological agent is usually using nonspecific drugs such as glucocorticosteroid, Regular Insulin, immunomodulator empirically, but curative effect is always by certainly.The nineties in 20th century, the monoclonal antibody HA-1A (Centoxin) of anti-lipid A once was used for U.S. army's war wound and the burn pyemic treatment in back during the Gulf War, this medicine is also once in Europe part country and Japanese clinical use, but because of the Sepsis shock is had detrimental action on the contrary, failed to obtain the approval of U.S. FDA in 1992, also disappear immediately from the European market.(recombinant human activated protein C rhAPC) is present unique pyemic medicine of being ratified by FDA of treatment (trade(brand)name Xigris) to recombinant activated human protein c.Clinical test results shows that rhAPC can reduce by 28 days mortality ratio of Sepsis patient, goes on the market through the FDA approval November calendar year 2001.Yet but showing rhAPC group 28 days mortality ratio and control group, the clinical test results second time in 2005 do not have difference.In the clinical trial in 2007, rhAPC does not only have the effect that improves Sepsis patient survival rate, also have the side effect that causes patient's severe haemorrhage tendency, therefore organize mechanism's suggestion of this clinical trial not recommend to use it as the pyemic clinical medicine of treatment.
Pathogenic agent associated molecular pattern (pathogen-associated molecular patterns, PAMPs) and pattern recognition acceptor (pattern recognition receptors, PRRs) discovery, make human to pyemic noegenesis qualitative leap.Confirmed that now pyemic pathogenesis is after pathogenic agent is invaded 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 on the inflammatory response cell film in the body non-specific immunity system/cell in corresponding PRRs identification, cause the 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 systems such as blood coagulation, complement, and when treatment measure such as the single antagonism LPS failure, seek the medicine of a plurality of main PAMPs of antagonism (LPS, CpG DNA and PGN etc.) simultaneously, block pyemic generation from the source and may bring breakthrough for its treatment.
Bitter chrysamine B (kukoamine B) has another name called Root-bark of Chinese Wolfberry second element, is to separate a kind of naturally occurring alkaloid compound that obtains from the Chinese medicine Root-bark of Chinese Wolfberry, and chemical structure is as follows:
Figure BDA0000068979450000021
Bitter chrysamine B is found from Root-bark of Chinese Wolfberry in nineteen ninety-five by the Shinji Funayama of Japan the earliest, has (S.Funayama, G. Zhang and S.Nozoe.Phytochemistry.1995 with free alkali form; 38:1529-1531).People such as the Zheng Jiang of Third Military Medical University disclose the purposes (Chinese patent application 201010156503.X) of bitter chrysamine B in preparation prevention and treatment Sepsis and autoimmune disorder medicine.But it does not synthesize best compound and the medicinal forms thereof that better is more suitable for drug use to find to bitter chrysamine category-B like thing.
Summary of the invention
The present invention is directed to above-mentioned deficiency, a series of bitter chrysamine category-Bs of design synthetic are used for prevention and treatment Sepsis and autoimmune disorder like thing and pharmacy acceptable salt thereof.The present invention also provides the purposes of pharmaceutical composition in preparation prevention and treatment medication for treating pyemia of these compounds.Use these compounds and the pharmaceutical composition that comprises these compounds, for pyemic treatment provides some new selectable medicine bases.
Technical scheme of the present invention is:
Analogue or its pharmaceutical salts of a kind of bitter chrysamine B are provided, it is characterized in that: described bitter chrysamine category-B has following chemical structure like thing
Figure BDA0000068979450000022
Formula (I)
Wherein, R 1, R 2, R 3, R 4Can independently be H, the alkyl that 3 carbon are following, formyl radical, ethanoyl, the protecting group of hydroxyls such as benzyl; X 1-3Can independently be C atom or N atom, when one of them is all the other two of N atomic time to be the C atom; X 4-6Can independently be C atom or N atom, when one of them is all the other two of N atomic time to be the C atom; n 1-5Can independently be the following alkyl of 4 carbon.
The analogue of preferred bitter chrysamine B is:
Compound 1
Figure BDA0000068979450000031
Compound m
Figure BDA0000068979450000032
Compound n
Figure BDA0000068979450000033
Compound o
Figure BDA0000068979450000034
Compound k
Figure BDA0000068979450000035
The analogue of most preferred bitter chrysamine B is compound k and pharmaceutical salts thereof.
The pharmaceutical salts of the analogue of bitter chrysamine 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 the Hydrogen bromide.
Described oxygen acid is any one in sulfuric acid, phosphoric acid and the nitric acid.
Described mineral acid is any one in hydrochloric acid, Hydrogen bromide, sulfuric acid and the 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 the 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 the xitix.
Described sulfonic acid is any one in methylsulfonic acid, Phenylsulfonic acid, tosic acid and the camphorsulfonic acid.
Described acidic amino acid is any one in L-glutamic acid and the 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 the aspartic acid.
Described bitter chrysamine category-B extensively is selected from multiple mineral acid and/or organic acid like the acid in the salt of thing, mainly be from all kinds of acid that pharmaceutically allow to use, to choose 2～3 representative acid respectively the common problem for preparing bitter chrysamine B salt is described, comprise and choose hydrochloric acid and Hydrogen bromide in the oxygen-free acid from mineral acid, choose sulfuric acid and phosphoric acid in the oxygen acid, choose acetic acid in the carboxylic acid in the organic acid, toxilic acid and succsinic acid, choose oxysuccinic acid in the alcohol acid, lactic acid and tartrate, choose methylsulfonic acid and tosic acid in the sulfonic acid, choose L-glutamic acid and aspartic acid in the acidic amino acid.Though 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 (comprising exemplified and the acid that do not exemplify of the present invention) all are to prepare bitter chrysamine B salt in the same manner.
Preferred bitter chrysamine category-B of the present invention is hydrochloride, hydrobromate, vitriol, phosphoric acid salt, acetate like the salt of thing.
Most preferred is hydrochloride, hydrobromate.
Therefore most preferred of the present invention is compound k and hydrochloride or hydrobromate.
The present invention also provides and contains the pharmaceutical composition of bitter chrysamine category-B like thing and salt thereof, and they are in the prevention of preparation with treat application in the pyemic medicine, pharmaceutical composition of the present invention can be prepared into any pharmaceutical dosage form, as can be, as with formulation administrations such as powder, tablet, granule, capsule, solution, emulsion, suspensoids through the formulation of gastrointestinal administration; Or non-formulation through gastrointestinal administration, as drug administration by injection, cavity/canal drug administration, mode administrations such as mucosa delivery.For the 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.
Bitter chrysamine category-B of the present invention is like the pharmaceutical composition of thing and salt thereof, comprise that bitter chrysamine category-B is similar to and salt as activeconstituents and pharmaceutically acceptable carrier and/or thinner.
Bitter chrysamine category-B of the present invention can be used for preparation prevention and treatment medication for treating pyemia like thing and salt thereof.
The applicant shows by the pharmacologically active experiment:
Bitter chrysamine category-B of the present invention is stronger than the binding ability of bitter chrysamine B with the binding ability of the active centre lipid A of LPS like thing, indivedual analogues is arranged even considerably beyond the binding ability of bitter chrysamine B; These analogues with strong binding ability external in dose-dependent mode in and LPS; These analogues with strong binding ability suppress LPS respectively in dose-dependent mode and CpG DNA induces the RAW264.7 cell to discharge inflammatory mediator.
The present invention uses the pharmaceutical composition of bitter chrysamine category-B like thing and salt thereof, is different from medicines such as existing glucocorticosteroid, Regular Insulin, anti-inflammatory medium medicine, anticoagulant, anti-LPS polypeptide and lipid A monoclonal antibody; Good effect, thus can significantly suppress its inductive inflammatory reaction by a plurality of 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 and describes like the common problem of thing pharmacy acceptable salt preparing bitter chrysamine category-B, 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 prepares bitter chrysamine category-B like the thing pharmacy acceptable salt.Therefore should illustrate; substitute mineral acid and/or the organic acid that the present invention enumerates with other mineral acids and/or organic acid; all should belong to technical scheme content of the present invention and scope of patent protection, those skilled in the art are in any change of under the enlightenment of this explanation the invention process being done all within the claim scope in the application.
LPS and CpG DNA are the crucial virulence factors that causes the Sepsis morbidity, 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 the detailed descriptions to one of them analog compounds k of the present invention, have disclosed main synthetic route and experimental technique that other compounds of the present invention use by this explanation.Should be appreciated that the following stated only is preferred embodiment of the present invention, it does not limit the present invention in any form.Should illustrate, if do not break away from the spirit and scope of the present invention, the present invention be made amendment or is equal to replacement, all should be encompassed in the middle of the protection domain of claim of the present invention.
Embodiment 1: the cyclosubstituted bitter chrysamine category-B of pyridine is synthetic like thing
Figure BDA0000068979450000051
Compound k
1.1 experimental technique: (1) is dissolved in the 20g compound a among the 60ml DMF, adds 66g salt of wormwood and 45ml Bian chlorine and is warming up to 80 ℃ of reactions.TLC monitoring, after reacting completely, direct filtration, ethyl acetate extraction, washing, the saturated common salt water washing, anhydrous sodium sulfate drying, suction filtration, concentrate compound b.The 8g dissolution of sodium hydroxide in 80ml water, is added the 43g compound b wherein, add the methyl alcohol of 80ml again, be warming up to 90 ℃ of back flow reaction.The TLC monitoring, after reacting completely, rotary evaporation is done, and in the impouring beaker, adds dense HCl to strongly-acid, filters, and collects filter cake, and drying can get silver yellow look compound c 32g, yield 72%, chemical equation is as follows:
Figure BDA0000068979450000061
(2) take by weighing the 13.1g compound c and be dissolved among the anhydrous DCM of 40ml, add 0.1ml DMF, add the thionyl chloride of 5ml, be warming up to back flow reaction 2h, concentrate rotary evaporation and do DCM and unnecessary thionyl chloride, get compound d, be directly used in next step reaction.Other takes by weighing the 13.8g Verbindung and is dissolved among the 50ml DCM, the triethylamine that adds 12ml, the compound d that obtains above with the DCM of 20ml dissolving is added dropwise to wherein then, add 50ml water after reacting completely, organic phase is washed anhydrous sodium sulfate drying with saturated solution of potassium carbonate, HCl solution, water, saturated salt solution successively, leave standstill, suction filtration be spin-dried for red oil g 25g, yield 90%, chemical equation is as follows:
Figure BDA0000068979450000062
(3) take by weighing 13g compound f and be dissolved among the DCM of 20ml, add 10ml TFA, stirring at room.The TLC monitoring after reacting completely, after concentrated rotary evaporation is done DCM, adds 30ml ethyl acetate and 20ml water, the organic phase washing, the saturated common salt water washing, anhydrous sodium sulfate drying leaves standstill, suction filtration, concentrate oily matter g12g, yield 90%, chemical equation is as follows:
Figure BDA0000068979450000063
(4) take by weighing 10g compound g and be dissolved among the 20ml MeOH, add the 4ml triethylamine, be warming up to 60 ℃, in the process that stirs, slowly splash into the mixing solutions of 1.2ml vinyl cyanide and 15ml methyl alcohol.After waiting to dropwise, reduce to the stirring at room reaction gradually.The TLC monitoring after reacting completely, directly concentrates the dried organic solvent of removing of rotary evaporation, gets compound h, and chemical equation is as follows:
Figure BDA0000068979450000071
(5) take by weighing 19.6g compound g in addition and be dissolved among the DCM of 50ml, add the 12ml triethylamine, the ice-water bath cooling.To be added dropwise to then in the top solution by of the DCM dissolving of the freshly prepd compound d of 10.5g compound c with 20ml.TLC monitoring, after reacting completely, suction filtration concentrates, and use ethyl acetate extraction, washs with saturated solution of potassium carbonate, 1mol/LHCl solution, water, saturated salt solution successively, anhydrous sodium sulfate drying leaves standstill, suction filtration, rotary evaporation dried oily matter.Column chromatography can get compound i 18g, yield 75%, and chemical equation is as follows:
Figure BDA0000068979450000072
(6) take by weighing the 20g compound i in autoclave, add the methanol solution of saturated ammonia: THF and be 3: 1 solution 400ml, ventilation is under 1～2MPa reaction system, 50 ℃ of stirring reactions.The TLC monitoring, after reacting completely, suction filtration concentrates and promptly gets blue oily compound j19g, yield 94%, chemical equation is as follows:
Figure BDA0000068979450000073
(7) taking by weighing compound j1g adds in 30 methyl alcohol, add 0.2g Pd/C catalyzer, ventilation is under the hydrogen pressure of 10MPa reaction system, is warming up under 45 ℃ of conditions and reacts, the monitoring of TLC thin layer, after reacting completely, suction filtration concentrates and obtains oily matter 0.5g, productive rate 95%, chemical equation is as follows:
Figure BDA0000068979450000081
Other bitter chrysamine category-Bs are as follows like the preparation method of thing:
Figure BDA0000068979450000082
Formula (I)
Other bitter chrysamine category-B like thing suc as formula shown in (I), wherein, R 1, R 2, R 3, R 4Can independently be H, the alkyl that 3 carbon are following, formyl radical, ethanoyl, the protecting group of hydroxyls such as benzyl; X 1-3Can independently be C atom or N atom, when one of them is all the other two of N atomic time to be the C atom; X 4-6Can independently be C atom or N atom, when one of them is all the other two of N atomic time to be the C atom; n 1-5Can independently be the following alkyl of 4 carbon, identical like the synthesis step of thing with embodiment 1 through these bitter chrysamine category-Bs after the above-mentioned change.
Embodiment 2: bitter chrysamine category-B is synthetic like the thing organic acid salt
Experimental technique: be dissolved in the ethanol like thing with obtaining bitter chrysamine category-B among the embodiment 1, splash into corresponding organic acid again with dissolve with ethanol, regulate pH value to 7, with the ethanol evaporate to dryness, the solid that obtains obtains corresponding organic acid salt with ethyl alcohol recrystallization, as malate, and lactic acid salt, succinate, mesylate etc.
Embodiment 3: bitter chrysamine category-B is synthetic like the thing inorganic acid salt
Experimental technique: be dissolved in the ethanol like thing obtaining bitter chrysamine category-B among the embodiment 1, splash into the corresponding mineral acid of dilute with water again, regulate pH value to 7, with the ethanol evaporate to dryness, the solid that obtains obtains corresponding organic acid salt with ethyl alcohol recrystallization, example hydrochloric acid salt, vitriol, phosphoric acid salt hydrobromate etc.
Embodiment 4: bitter chrysamine category-B is measured like the salt of thing and the avidity of lipid A
Experimental technique: get bitter chrysamine category-B that embodiment 1 obtains like thing, with embodiment 2,3 method is prepared into each 1mg of following hydrochloride, hydrobromate, vitriol, phosphoric acid salt, acetate, maleate, succinate, malate, lactic acid salt, tartrate, mesylate, tosilate, glutaminate and aspartate, adding PBS (0.01M, pH 7.4) 1ml respectively fully dissolves.Get each 5 μ l of above-mentioned solution and add (sample pool contains 45 μ l PBS) in the affinity sensor sample pool that is coated with lipid A in advance respectively, react, the record physiological curve.
Experimental result shows that most bitter chrysamine category-Bs all can combine with lipid A external like the salt of thing, wherein the binding ability of the salt of compound k is better than the salt of all the other analogues, and the binding ability of hydrochloride, hydrobromate, vitriol, phosphoric acid salt, acetate is the strongest in the various salt of k.
Table 1 and the binding data of lipid A reaction in the time of 3 minutes
The LPS value Hydrochloride Hydrobromate Vitriol Phosphoric acid salt Acetate Malate Lactic acid salt
Compound k 2230 2456 2130 1896 1635 1564 1325
Bitter chrysamine B 998 926 540 2570 1480 1368 1765
Compound l 1874 2086 1907 2015 1532 1435 1247
Compound m 1986 2165 1654 1635 1765 1232 1202
Compound n 1765 1985 1746 2145 1543 1098 980
Compound o 1954 2342 1436 1789 1345 1123 1109
Embodiment 5: bitter chrysamine category-B like the salt of thing external in and the LPS experiment
Experimental technique: experimentize according to 32Well Kinetic Tube Reader (ATi321-06) intracellular toxin detector operation instructions, adopt dynamic turbidimetric to detect and respectively organize LPS value, each concentration duplicate detection 3 times;
Experimental result shows that most bitter chrysamine category-Bs all can be in external and LPS like the salt of thing, wherein the neutralising capacity of the salt of compound k is better than the salt of all the other analogues, and the binding ability of hydrochloride, hydrobromate, vitriol, phosphoric acid salt, acetate is the strongest in the various salt of k.
Table 2
? Hydrochloride Hydrobromate Vitriol Phosphoric acid salt Acetate Malate Lactic acid salt
Compound k 0.18 0.13 0.14 0.15 0.15 0.24 0.26
Bitter chrysamine B 0.24 0.18 0.26 0.17 0.15 0.18 0.19
Compound l 0.21 0.16 0.18 0.19 0.17 0.21 0.26
Compound m 0.22 0.20 0.22 0.14 0.16 0.19 0.19
Compound n 0.19 0.14 0.16 0.15 0.18 0.23 0.27
Compound o 0.25 0.17 0.17 0.15 0.14 0.21 0.22
[0082]Embodiment 6: bitter chrysamine category-B suppresses the experiment that LPS induces RAW264.7 cell release inflammatory mediator like the salt of thing
17.1 experimental technique: adopt the DMEM nutrient solution with RAW264.7 cell dilution to 1 * 10 6/ ml adds 96 orifice plates (200 μ l/ hole), is 5% CO at 37 ℃, volume fraction 2Hatched under the condition 4 hours, it is the DMEM nutrient solution of 200 μ l serum-frees that cell conditioned medium is changed in adherent back, add LPS (final concentration 100ng/ml) then, adding final concentration simultaneously respectively is 0,50,100, the various bitter chrysamine category-B of 200 μ M (comprises bitter chrysamine B malate like the salt of thing, succinate, lactic acid salt, tartrate, mesylate, tosilate, glutaminate, acetate, hydrochloride and vitriol), blank group (Medium) does not add LPS, continued to hatch 4 hours, get supernatant, detect the concentration of TNF-α according to ELISA test kit operation instructions.
Experimental result shows that most bitter chrysamine category-Bs all can suppress LPS like the salt of thing and induce the RAW264.7 cell to discharge inflammatory mediator TNF-α, wherein the inhibition ability of the salt of compound k is better than the salt of all the other analogues, and the binding ability of hydrochloride, hydrobromate, vitriol, phosphoric acid salt, acetate is the strongest in the various salt of k.
Table 3
100um Hydrochloride Hydrobromate Vitriol Phosphoric acid salt Acetate Malate Lactic acid salt
Compound k 2892 3123 3051 2985 3203 3578 3980
Bitter chrysamine B 4012 3876 4250 4104 4435 2786 2810
Compound l 3024 3249 3420 3568 3762 3980 3782
Compound m 2980 3428 3523 3123 3324 3643 3653
Compound n 3214 3543 3245 3213 3423 3214 3657
Compound o 2789 3143 3124 3215 3521 3425 3823

Claims (10)

1. the analogue of a bitter chrysamine B or its pharmaceutical salts is characterized in that: described bitter chrysamine category-B has following chemical structure like thing
Figure FDA0000068979440000011
Formula (I)
Wherein, R 1, R 2, R 3, R 4Can independently be H, the alkyl that 3 carbon are following, formyl radical, ethanoyl, the protecting group of hydroxyls such as benzyl; X 1-3Can independently be C atom or N atom, when one of them is all the other two of N atomic time to be the C atom; X 4-6Can independently be C atom or N atom, when one of them is all the other two of N atomic time to be the C atom; n 1-5Can independently be the following alkyl of 4 carbon, wherein said pharmaceutical salts be 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 bitter chrysamine B according to claim 1 or its pharmaceutical salts is characterized in that, the analogue of described bitter chrysamine B is following compound
Compound 1
Compound m
Figure FDA0000068979440000013
Compound n
Figure FDA0000068979440000014
Compound o
Figure FDA0000068979440000021
Compound k
Figure FDA0000068979440000022
3. the analogue of bitter chrysamine 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 the Hydrogen bromide.
4. the analogue of bitter chrysamine 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 the nitric acid.
5. the analogue of bitter chrysamine 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 the palmitinic acid.
6. the analogue of bitter chrysamine 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 the xitix.
7. the analogue of bitter chrysamine 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 the camphorsulfonic acid.
8. the analogue of bitter chrysamine 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 the aspartic acid.
9. pharmaceutical composition comprises analogue or its pharmaceutical salts of claim 1 or 2 described bitter chrysamine B.
10. analogue or its pharmaceutical salts of claim 1 or 2 bitter chrysamine B and the application of composition in preparation prevention and treatment medication for treating pyemia that contain them.
CN2011101642384A 2011-06-17 2011-06-17 Kukoamine B analogue, and pharmaceutically acceptable salt, preparation method and application thereof Pending CN102276521A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN2011101642384A CN102276521A (en) 2011-06-17 2011-06-17 Kukoamine B analogue, and pharmaceutically acceptable salt, preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN2011101642384A CN102276521A (en) 2011-06-17 2011-06-17 Kukoamine B analogue, and pharmaceutically acceptable salt, preparation method and application thereof

Publications (1)

Publication Number Publication Date
CN102276521A true CN102276521A (en) 2011-12-14

Family

ID=45102310

Family Applications (1)

Application Number Title Priority Date Filing Date
CN2011101642384A Pending CN102276521A (en) 2011-06-17 2011-06-17 Kukoamine B analogue, and pharmaceutically acceptable salt, preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN102276521A (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104725278A (en) * 2015-01-23 2015-06-24 天津红日药业股份有限公司 Preparation method for intermediate of Kukoamine B
CN104892449A (en) * 2014-03-06 2015-09-09 王梅 Preparation method and use of spermine analogs and medicinal salts thereof
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

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104892449A (en) * 2014-03-06 2015-09-09 王梅 Preparation method and use of spermine analogs and medicinal salts thereof
CN104892449B (en) * 2014-03-06 2017-06-13 天津红日药业股份有限公司 The preparation method and purposes of a kind of spermine analogs and its pharmaceutical salts
CN104725278A (en) * 2015-01-23 2015-06-24 天津红日药业股份有限公司 Preparation method for intermediate of Kukoamine B
CN104725278B (en) * 2015-01-23 2017-01-25 天津红日药业股份有限公司 Preparation method for intermediate of Kukoamine B
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

Similar Documents

Publication Publication Date Title
CN102116772B (en) Method for screening dihydrochalcone compound
CN102464591A (en) Kukoamine B salt, preparation method thereof and purpose thereof
CN101780092B (en) Compounds and methods for delivery of prostacyclin analogs
TW201307288A (en) Compounds for the treatment of addiction
JP5529745B2 (en) Novel mangoglycoside calcium salt, process for producing the same and use thereof
WO2021164677A1 (en) Inhibitor capable of resisting fusion of respiratory syncytial virus
CN102276521A (en) Kukoamine B analogue, and pharmaceutically acceptable salt, preparation method and application thereof
WO2010060387A1 (en) The five crystal forms of the nicousamide, the preparation methods, the pharmaceutical compositions and the uses thereof
CN101534813A (en) Methods of enhancing mucosal hydration and mucosal clearance by treatment with sodium channel blockers and osmolytes
WO2015021704A1 (en) Uses of doxycycline for preparing antitumor drugs
CN101920019A (en) Hydrophilic polymer-puerarin specific conjugated non-hemolytic conjugate
CA3111403A1 (en) Matter of composition, synthesis, formulation and application of fl118 platform positions 7 and 9-derived analogues for treatment of human disease
JPS61129119A (en) Novel immunosuppressive agent
CN103819356A (en) Preparation method and use of kukoamine B analogue or medicinal salts thereof
JP2020500887A (en) Hydrobromide salts of benzodiazepine derivatives, their preparation and use
WO2019170046A1 (en) Glycopeptide compounds having activity of resisting drug-resistant bacteria, and preparation method therefor and application thereof
CN102030709B (en) Benzazepines compounds serving as vasopressin receptor antagonism
JPS63183596A (en) Glucosylmoranoline derivative
CN109232297A (en) Fragrant happy amine crystal B-type, preparation method and its composition and purposes
JP2010534709A (en) 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A derivatives and their use for treating malaria
CN103347848A (en) Hydrated n-fullerene amino acids, method for producing the latter, and pharmaceutical compositions on the basis thereof
JP2004292426A (en) Antimicrobial agent and anti-cancer agent
CN107619428A (en) Acylated derivatives and its application of the ornithine with L-aminobutanedioic acid dipeptide compound
CN107868088A (en) Benzodiazepine * class nitrogen oxides
US10245326B2 (en) Amantadine, memantine, and rimantadine conjugates and a pharmaceutical composition for treatment of neuronal disorders

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C12 Rejection of a patent application after its publication
RJ01 Rejection of invention patent application after publication

Application publication date: 20111214