CN105693813A - Preparation and medical application of glycyrrhizic acid berberine coupling compound - Google Patents
Preparation and medical application of glycyrrhizic acid berberine coupling compound Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims description 8
- 238000002360 preparation method Methods 0.000 title claims description 5
- VTAJIXDZFCRWBR-UHFFFAOYSA-N Licoricesaponin B2 Natural products C1C(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2)C(O)=O)C)(C)CC2)(C)C2C(C)(C)CC1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O VTAJIXDZFCRWBR-UHFFFAOYSA-N 0.000 title abstract description 13
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 title abstract description 13
- 229960004949 glycyrrhizic acid Drugs 0.000 title abstract description 13
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 title abstract description 13
- 239000001685 glycyrrhizic acid Substances 0.000 title abstract description 13
- 235000019410 glycyrrhizin Nutrition 0.000 title abstract description 13
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 title abstract description 13
- YBHILYKTIRIUTE-UHFFFAOYSA-N berberine Chemical compound C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 YBHILYKTIRIUTE-UHFFFAOYSA-N 0.000 title description 20
- 229940093265 berberine Drugs 0.000 title description 20
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 title description 20
- 230000008878 coupling Effects 0.000 title 1
- 238000010168 coupling process Methods 0.000 title 1
- 238000005859 coupling reaction Methods 0.000 title 1
- 239000008280 blood Substances 0.000 claims abstract description 12
- 210000004369 blood Anatomy 0.000 claims abstract description 12
- 208000031226 Hyperlipidaemia Diseases 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- VKJGBAJNNALVAV-UHFFFAOYSA-M Berberine chloride (TN) Chemical compound [Cl-].C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 VKJGBAJNNALVAV-UHFFFAOYSA-M 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- -1 acids compound Chemical class 0.000 claims description 6
- 230000001476 alcoholic effect Effects 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 241001597008 Nomeidae Species 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 239000000047 product Substances 0.000 claims description 3
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims 8
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000009472 formulation Methods 0.000 claims 1
- 238000002347 injection Methods 0.000 claims 1
- 239000007924 injection Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 239000012188 paraffin wax Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 7
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 abstract description 6
- 241001465754 Metazoa Species 0.000 abstract description 3
- 238000002474 experimental method Methods 0.000 abstract description 3
- 150000002632 lipids Chemical class 0.000 abstract description 3
- 230000009467 reduction Effects 0.000 abstract description 3
- 206010061218 Inflammation Diseases 0.000 abstract description 2
- 210000004204 blood vessel Anatomy 0.000 abstract description 2
- 235000012000 cholesterol Nutrition 0.000 abstract description 2
- 238000011161 development Methods 0.000 abstract description 2
- 230000004054 inflammatory process Effects 0.000 abstract description 2
- 150000003904 phospholipids Chemical class 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract 3
- 230000001737 promoting effect Effects 0.000 abstract 2
- 206010003210 Arteriosclerosis Diseases 0.000 abstract 1
- 241000700159 Rattus Species 0.000 abstract 1
- 208000011775 arteriosclerosis disease Diseases 0.000 abstract 1
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 10
- 150000007513 acids Chemical class 0.000 description 8
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- MPDGHEJMBKOTSU-UHFFFAOYSA-N Glycyrrhetinsaeure Natural products C12C(=O)C=C3C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C1(C)CCC1C2(C)CCC(O)C1(C)C MPDGHEJMBKOTSU-UHFFFAOYSA-N 0.000 description 6
- 229960003720 enoxolone Drugs 0.000 description 6
- WNIFXKPDILJURQ-UHFFFAOYSA-N stearyl glycyrrhizinate Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C)CCC(C(=O)OCCCCCCCCCCCCCCCCCC)(C)CC5C4=CC(=O)C3C21C WNIFXKPDILJURQ-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
- 230000001603 reducing effect Effects 0.000 description 4
- 108010007622 LDL Lipoproteins Proteins 0.000 description 3
- 102000007330 LDL Lipoproteins Human genes 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 241000699800 Cricetinae Species 0.000 description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 description 2
- 206010022678 Intestinal infections Diseases 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 201000005577 familial hyperlipidemia Diseases 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 206010025482 malaise Diseases 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 108010028554 LDL Cholesterol Proteins 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 201000002014 Suppurative Otitis Media Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012109 statistical procedure Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/256—Polyterpene radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides a preparing method of a derivative of the formula (I) and application of the derivative to drugs for treating hyperlipidemia and lowering lipid. It is found through pharmacology experiments that the derivative has multi-value drug activity and especially the easy absorbing property which is not possessed by glycyrrhizic acid drugs, and specifically, the derivative shows an excellent effect of adjusting blood lipid of hyperlipidemia rats in the animal experiments. The derivative has the main effects of promoting decrease of cholesterol content, promoting obvious reduction of phospholipid, inhibiting the inflammatory reaction of the organism and the blood vessel wall and preventing occurrence and development of arteriosclerosis.
Description
Technical field
The present invention relates to food pharmaceutical technical field, be specifically related to the application in treatment hyperlipidemia, reduction blood fat product of a kind of Radix Glycyrrhizae acids berberine conjugates。
Background technology
Between past 20 years, the food consumption of people and diet structure there occurs very big change, and the sickness rate that the most active effects thus brought is exactly hyperlipidemia constantly promotes。In the blood safety seminar a few days ago held, expert estimates, in the middle of the adult in more than 30 years old, the whole nation, the sickness rate of hyperlipidemia is at about 10%-20%, and hyperlipemia number is up to 90,000,000。The relevant statistics of Ministry of Public Health displays that, last year just has one to die from cardiovascular and cerebrovascular disease in the middle of every 3 dead Chinese, and hyperlipidemia causes that atherosclerosis is the arch-criminal of cardiovascular and cerebrovascular disease。Namely foreign scholar proved as far back as the seventies, and glycyrrhizic acid has reduction animal lipid effect, and is being clinically used for the treatment of hypercholesterolemia。
Berberine BBR (Berberine, BBR) is the main active of Rhizoma Coptidis, and in Rhizoma Coptidis, BBR content is the highest, accounts for 5.2-7.69%。Rhizoma Coptidis bitter in the mouth, has heat clearing away, removing toxic substances, pathogenic fire purging and controls effect of diabetes。Thought more in the past oral after not easily absorb, intestinal infection that dysentery bacterium, escherichia coli, staphylococcus aureus are caused, eye conjunctivitis, suppurative otitis media etc. are effective, and clinic is mainly used in the treatment of intestinal infection。Along with going deep into of research, find that it has the pharmacological actions such as arrhythmia, vasodilator, protection cardiac muscle, antiplatelet aggregation, blood sugar lowering, blood fat reducing, antiinflammatory, antiviral, antitumor in recent years successively。
Water solublity yet with Radix Glycyrrhizae acids is poor, and oral administration biaavailability is low, limits giving full play to of its drug effect。And berberine hydrochloride water solublity is only small, fat-soluble less, gastrointestinal absorption is bad, causes that its oral administration biaavailability is low, have impact on its whole body therapeutic effect。Although, Radix Glycyrrhizae acids medicine, berberine has many similar pharmacologically actives, but all because of the low use limited to a certain extent clinically of bioavailability, therefore find a kind of bioavailability improving Radix Glycyrrhizae acids medicine and berberine and play both synergistic method and will have very important meaning clinically。
Summary of the invention:
The present invention provide the derivative preparation method of formula (I) and its as treatment hyperlipidemia, reduce application in the medicine of blood fat。Found by the experiment of pharmacology's aspect, this analog derivative has the pharmaceutically active of various value, particularly its performance easily absorbed is not available for Radix Glycyrrhizae acids medicine, and specifically this analog derivative demonstrates excellent adjustment hyperlipemia rat blood fat in zoopery。Its Main Function is embodied in and promotes cholesterol level to reduce, and phospholipid is decreased obviously, it is suppressed that the inflammatory reaction of body and blood vessel wall, it is prevented that atherosclerotic generation and development。
The present invention provides the derivant of formula (I), and structure is as follows:
In formula (I), R is
R1=H or C1～C18 straight or branched alkane。
1. the derivative preparation method of formula (I), comprises the following steps:
(1) berberine hydrochloride is dissolved in 0.01～5mol/L inorganic alkali solution；
(2) in the solution of step (1) gained, formula (I) described respective acids compound solution, 60-70 DEG C of heated and stirred 1-8h are added；
(3) product carries out sucking filtration, filtrate while hot be recycled to original volume 1/3, cooling crystallization, filter, be drying to obtain formula (I) described compound；
2. the inorganic alkali solution in step (1): it is characterized in that berberine hydrochloride and inorganic base molar ratio are 1:1～1:3, it is preferable that 1:1.0～1.05；Wherein inorganic base is one or more in sodium hydroxide, potassium hydroxide, calcium hydroxide；Solution is 0-100% (volume ratio) methanol, ethanol, aqueous isopropanol, it is preferable that 70% alcoholic solution；
3. in step (2), respective acids compound solution refers to, refers to that respective acids compound is dissolved in 0-100% (volume ratio) methanol, ethanol, aqueous isopropanol, it is preferable that 70% alcoholic solution；
The present invention provides the derivant of formula (I) to make acceptable dosage form clinically through common process or the pharmaceutically acceptable excipient of indirect addition, is used for clinically treating hyperlipidemia, reducing blood fat。
Specific embodiment
By following example to better illustrate the present invention。But the present invention is not by the restriction of following embodiment。
Embodiment 1
The synthesis of glycyrrhizic acid berberine conjugates
Take berberine hydrochloride 3.7g, add in 250ml there-necked flask, add 100ml ethanol, regulate pH to 7-8 with the sodium hydroxide of 3mol/l, it is warming up to 60-70 DEG C, stirring and dissolving, adds 8.2g glycyrrhizic acid, keeps this temperature stirring 1-2h, filtered while hot, filtrate is concentrated into original volume 1/3rd, cooling crystallization, filters, is drying to obtain glycyrrhizic acid berberine conjugates 9.3g, yield 80%。
Embodiment 2
The synthesis of glycyrrhizic acid berberine conjugates
Take berberine hydrochloride 3.7g, add in 250ml there-necked flask, add 100ml ethanol, regulate pH to 7-8 with the sodium hydroxide of 3mol/l, it is warming up to 60-70 DEG C, stirring and dissolving, adds 8.9g glycyrrhizic acid, keeps this temperature stirring 1-2h, filtered while hot, filtrate is concentrated into original volume 1/3rd, cooling crystallization, filters, is drying to obtain glycyrrhizic acid berberine conjugates 9.7g, yield 84%。
Embodiment 3
The synthesis of glycyrrhizic acid berberine conjugates
Take berberine hydrochloride 3.7g, add in 250ml there-necked flask, add 150ml ethanol, regulate pH to 7-8 with the sodium hydroxide of 3mol/l, it is warming up to 60-70 DEG C, stirring and dissolving, adds 9.5g glycyrrhizic acid, keeps this temperature stirring 1-2h, filtered while hot, filtrate is concentrated into original volume 1/3rd, cooling crystallization, filters, is drying to obtain glycyrrhizic acid berberine conjugates 10.2g, yield 92%。ESI-MS (M++H)m/zcalcdforC20H18NO4 +337.12found337.26；ESI-MS (M++H)m/zcalcdforC42H62O16823.40found823.34。
Embodiment 4
The synthesis of enoxolone berberine conjugates
Take berberine hydrochloride 3.7g, add in 250ml there-necked flask, add 100ml ethanol, regulate pH to 7-8 with the sodium hydroxide of 3mol/l, it is warming up to 60-70 DEG C, stirring and dissolving, adds 4.7g enoxolone, keeps this temperature stirring 1-2h, filtered while hot, filtrate is concentrated into original volume 1/3rd, cooling crystallization, filters, is drying to obtain enoxolone berberine conjugates 6.5g, yield 81%。
Embodiment 5
The synthesis of enoxolone berberine conjugates
Take berberine hydrochloride 3.7g, add in 250ml there-necked flask, add 100ml ethanol, regulate pH to 7-8 with the sodium hydroxide of 3mol/l, it is warming up to 60-70 DEG C, stirring and dissolving, adds 5.2g enoxolone, keeps this temperature stirring 1-2h, filtered while hot, filtrate is concentrated into original volume 1/3rd, cooling crystallization, filters, is drying to obtain enoxolone berberine conjugates 6.9g, yield 86%。ESI-MS (M++H)m/zcalcdforC20H18NO4 +337.12found337.26；ESI-MS (M++H)m/zcalcdforC30H46O4471.34found471.38。
The effect for reducing blood fat of embodiment 6 Radix Glycyrrhizae acids berberine conjugates
Lipid-lowering test: choose hamster and feed, after high fat hypercholesterolemia (HFHC) food 10 days, to be orally administered to compound described in embodiment, measures after 25 days that T-CHOL in blood, glycerol three is cruel and the level of low density lipoprotein, LDL-C。It table is mean+SD。Administering mode: every day is administered orally, totally 25 days；Every treated animal number: n=7。Taking hematometry cholesterol, glycerol three is cruel and the level of low density lipoprotein, LDL, and carries out statistical procedures, and result is in Table 1
The effect for reducing blood fat that table 1 embodiment compound is used in combination hamster
Experimental result shows, Radix Glycyrrhizae acids berberine conjugates lipid-lowering effect is substantially better than glycyrrhizic acid and berberine monomer。
Claims (6)
1. the present invention provides the derivant of formula (I), and structure is as follows:
It is characterized in that, in formula (I), R is
R1=H or C1～C18 side chain or branched paraffin。
2. the preparation method of formula (I) compound described in claim 1, comprises the following steps:
(1) berberine hydrochloride is dissolved in 0.01～5mol/L inorganic alkali solution；
(2) in the solution of step (1) gained, formula (I) described respective acids compound solution, 60-70 DEG C of heated and stirred 1-8h are added；
(3) product carries out sucking filtration, filtrate while hot be recycled to original volume 1/3, cooling crystallization, filter, be drying to obtain formula (I) described compound。
3. the inorganic alkali solution in the step (1) described in claim 2: it is characterized in that berberine hydrochloride and inorganic base molar ratio are 1:1～1:3, it is preferable that 1:1.0～1.05；Wherein inorganic base is one or more in sodium hydroxide, potassium hydroxide, calcium hydroxide；Solution is 0-100% (volume ratio) methanol, ethanol, aqueous isopropanol, it is preferable that 70% alcoholic solution。
4. respective acids compound solution described in the step (2) described in claim 2, refers to that respective acids compound is dissolved in 0-100% (volume ratio) methanol, ethanol, aqueous isopropanol, it is preferable that 70% alcoholic solution。
5. formula (I) compound described in claim 1 makes acceptable dosage form clinically through common process or the pharmaceutically acceptable excipient of indirect addition, including injection, oral agents, it is preferable that oral formulations。
6. formula (I) compound described in claim 1 makes acceptable dosage form clinically through common process or the pharmaceutically acceptable excipient of indirect addition, is used for clinically preventing and treating hyperlipidemia, reduce blood fat。
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610150099.2A CN105693813A (en) | 2016-03-15 | 2016-03-15 | Preparation and medical application of glycyrrhizic acid berberine coupling compound |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106146489A (en) * | 2016-06-30 | 2016-11-23 | 合肥华方医药科技有限公司 | The Preparation method and use of 9 substituted double-functional group berberinc derivates |
| CN114306640A (en) * | 2022-01-27 | 2022-04-12 | 南方医科大学南方医院 | Method for increasing solubility of berberine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1563073A (en) * | 2004-04-06 | 2005-01-12 | 南开大学 | Method for preparing enoxolone |
| CN103319479A (en) * | 2012-03-20 | 2013-09-25 | 王从品 | Rheinic acid berberine ion pair compound, preparation method and applications |
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2016
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1563073A (en) * | 2004-04-06 | 2005-01-12 | 南开大学 | Method for preparing enoxolone |
| CN103319479A (en) * | 2012-03-20 | 2013-09-25 | 王从品 | Rheinic acid berberine ion pair compound, preparation method and applications |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106146489A (en) * | 2016-06-30 | 2016-11-23 | 合肥华方医药科技有限公司 | The Preparation method and use of 9 substituted double-functional group berberinc derivates |
| CN106146489B (en) * | 2016-06-30 | 2019-02-05 | 合肥华方医药科技有限公司 | The Preparation method and use of the double-functional group berberinc derivate of 9- substitutions |
| CN114306640A (en) * | 2022-01-27 | 2022-04-12 | 南方医科大学南方医院 | Method for increasing solubility of berberine |
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