CN1687051A - Water soluble puerarin salt compound and preparing process thereof - Google Patents
Water soluble puerarin salt compound and preparing process thereof Download PDFInfo
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- CN1687051A CN1687051A CN 200510020570 CN200510020570A CN1687051A CN 1687051 A CN1687051 A CN 1687051A CN 200510020570 CN200510020570 CN 200510020570 CN 200510020570 A CN200510020570 A CN 200510020570A CN 1687051 A CN1687051 A CN 1687051A
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- CN
- China
- Prior art keywords
- organic solvent
- puerarin
- aescine
- under reduced
- reduced pressure
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- -1 puerarin salt compound Chemical class 0.000 title claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title claims description 13
- 238000000034 method Methods 0.000 title claims description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- 239000007924 injection Substances 0.000 claims abstract description 9
- 238000002347 injection Methods 0.000 claims abstract description 9
- 239000002775 capsule Substances 0.000 claims abstract description 3
- 239000008187 granular material Substances 0.000 claims abstract description 3
- 229940040145 liniment Drugs 0.000 claims abstract description 3
- 239000000865 liniment Substances 0.000 claims abstract description 3
- 239000003826 tablet Substances 0.000 claims abstract description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- RXUWDKBZZLIASQ-UHFFFAOYSA-N Puerarin Natural products OCC1OC(Oc2c(O)cc(O)c3C(=O)C(=COc23)c4ccc(O)cc4)C(O)C(O)C1O RXUWDKBZZLIASQ-UHFFFAOYSA-N 0.000 claims description 14
- HKEAFJYKMMKDOR-VPRICQMDSA-N puerarin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=C(O)C=CC(C2=O)=C1OC=C2C1=CC=C(O)C=C1 HKEAFJYKMMKDOR-VPRICQMDSA-N 0.000 claims description 14
- 235000001014 amino acid Nutrition 0.000 claims description 12
- 150000001413 amino acids Chemical class 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- OFEJOCABYMQXPD-RGMNGODLSA-N C(CC)N[C@@H](CCO)C(=O)O.NC(=N)N Chemical compound C(CC)N[C@@H](CCO)C(=O)O.NC(=N)N OFEJOCABYMQXPD-RGMNGODLSA-N 0.000 claims description 10
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 10
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims description 10
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 claims description 10
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 10
- 229960003104 ornithine Drugs 0.000 claims description 10
- 239000000047 product Substances 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 239000004475 Arginine Substances 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 6
- 238000001556 precipitation Methods 0.000 claims description 6
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 4
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 4
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 238000004108 freeze drying Methods 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 229930182817 methionine Natural products 0.000 claims description 4
- 239000002244 precipitate Substances 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 238000009472 formulation Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 abstract 1
- AXNVHPCVMSNXNP-GKTCLTPXSA-N Aescin Natural products O=C(O[C@H]1[C@@H](OC(=O)C)[C@]2(CO)[C@@H](O)C[C@@]3(C)[C@@]4(C)[C@@H]([C@]5(C)[C@H]([C@](CO)(C)[C@@H](O[C@@H]6[C@@H](O[C@H]7[C@@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O7)[C@@H](O)[C@H](O[C@H]7[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O7)[C@@H](C(=O)O)O6)CC5)CC4)CC=C3[C@@H]2CC1(C)C)/C(=C/C)/C AXNVHPCVMSNXNP-GKTCLTPXSA-N 0.000 description 6
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 6
- 239000004472 Lysine Substances 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 238000012545 processing Methods 0.000 description 6
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 6
- 229930182490 saponin Natural products 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 4
- 230000000857 drug effect Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- 206010038743 Restlessness Diseases 0.000 description 2
- 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 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 235000010575 Pueraria lobata Nutrition 0.000 description 1
- 241000219781 Pueraria montana var. lobata Species 0.000 description 1
- 206010061373 Sudden Hearing Loss Diseases 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000000297 inotrophic effect Effects 0.000 description 1
- 235000021374 legumes Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 230000036284 oxygen consumption Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The present invention discloses a water-soluble puerarin salt compound and its preparation method. Said invention also provides its structure formula, and said compound can be made into various dosage forms including injection, tablet, capsule, granules and liniment, etc.
Description
Technical field:
The present invention relates to a kind of water soluble puerarin salt compound, the present invention relates to the preparation method of this compound simultaneously.
Background technology:
Puerarin is to extract in the dry root by legume pueraria lobata PuerariaIobata (Wild) ohwir, separate 8-β-D-glucopyanosyl-4 of obtaining ', the 7-dihydroxy isoflavone.
According to clinical observation and experiment, puerarin can coronary artery dilator, brings high blood pressure down reducing heart rate, reduction myocardial oxygen consumption index and do not have obvious negative inotropic action; But also reducing cholesterol and blood viscosity, microcirculation improvement, protection cardiac muscle.Be used for the treatment of myocardial infarction, stenocardia, retina arteriovenous obstruction, sudden deafness.
Because the puerarin oral bioavailability is relatively poor, be about 30%, the main intravenously administrable that adopts in clinical application, yet puerarin is slightly soluble in water, solubleness is 1.332g/100ml, can not directly be processed into injection, thus present stage clinical used injection liquid all adopt higher concentration propylene glycol as solubility promoter, just can reach the concentration of this drug injection requirement.
Because the puerarin clinical treatment is longer the course of treatment, a large amount of solubility promoter propylene glycol enter in the body, the people are known from experience produce certain toxic side effect, so certainly will produce some untoward reactions.
In order to overcome the above-mentioned defective of puerarin, from solving the water-soluble problem of puerarin, improve drug effect, reducing the toxicity aspect, we have prepared multiple puerarin water-soluble cpds, and its water-soluble requirement that can satisfy direct processing injection is an initiative both at home and abroad for the research of this compounds.
Summary of the invention:
The objective of the invention is to improve the water-soluble of puerarin, the water soluble puerarin salt compound that can satisfy the requirement of direct processing injection is provided, thereby improve drug effect, reduction toxicity.
The present invention relates to a kind of water soluble puerarin salt compound, it is characterized in that the compound of following structural formula (I) expression, the R in the structural formula
1And R
2Be selected from hydrogen, arginine, Methionin, Histidine, ornithine respectively, 2,4-diamino-butanoic and guanidine propylhomoserin, wherein R
1And R
2Can not be hydrogen simultaneously.
The present invention also relates to above-claimed cpd (I) in pharmaceutically formulation, it is characterized in that: described compound can be made into various formulations pharmaceutically, comprises injection, tablet, capsule, granule and liniment.
The preparation method of the compound that the present invention relates to (I), its concrete technology comprise following two kinds of processing routes:
Wherein first kind of processing route is as follows:
With the puerarin organic solvent dissolution, drop in the equimolar basic aminoacids aqueous solution, stirring reaction is to settled solution at a certain temperature, and concentrating under reduced pressure adopts freeze-drying or organic solvent precipitation method, promptly gets product.
Wherein second kind of processing route is as follows:
Puerarin is used and equimolar basic aminoacids mixing, used water dissolution, stirring reaction is to settled solution at a certain temperature, and concentrating under reduced pressure with freeze-drying or organic solvent precipitation method, promptly gets product.
Among the preparation method who the present invention relates to: described organic solvent is selected from methyl alcohol, ethanol, acetonitrile and acetone.
Among the preparation method who the present invention relates to: described temperature is 10～80 ℃.
Among the preparation method who the present invention relates to: described basic aminoacids is selected from arginine, Methionin, Histidine, ornithine, guanidine propylhomoserin and 2,4-diamino-butanoic.
Among the preparation method who the present invention relates to: described organic solvent precipitation method is meant:
In the preparation method of compound (I), behind the concentrating under reduced pressure, in residue, add acetone, grind to such an extent that off-white color precipitates, filter, a small amount of organic solvent washing of solid places 80 ℃ of environment drying under reduced pressure, gets product.
The compound that the present invention relates to has improved the water-soluble of puerarin, can satisfy the requirement of direct processing injection, can improve drug effect, reduce toxicity.
Embodiment
Embodiment 1:
In reaction flask, add Aescine 65.6g (0.05mol), 0.05mol amino acid and 500ml distilled water successively, at 60 ℃ of stirring reactions to clear liquor, the evaporated under reduced pressure solvent, in residue, add 500ml acetone, grind to such an extent that off-white color precipitates, filter, solid washs 2 times with small amount of acetone, place 80 ℃ of environment drying under reduced pressure, get product, test-results sees the following form:
| Sequence number | The name of an article | Yield | Content |
| ??1 | Lysine aescin saponin | ??85.2％ | ??98.7％ |
| ??2 | The Histidine Aescine | ??83.5％ | ??99.3％ |
| ??3 | The ornithine Aescine | ??87.9％ | ??100.2％ |
| ??4 | Guanidine propylhomoserin Aescine | ??81.9％ | ??98.9％ |
| ??5 | The 2,4-diamino-butanoic Aescine | ??90.3％ | ??98.1％ |
Embodiment 2:
Get Aescine 65.6g (0.05mol), use the 200ml dissolve with methanol, get 0.05mol amino acid again, use the 500ml dissolved in distilled water, the Aescine methanol solution dropped in the amino acid solution, at 40 ℃ of stirring reactions to clear liquor, the evaporated under reduced pressure solvent, in residue, add 500ml acetone, grind to such an extent that off-white color precipitates, filter, solid washs 2 times with small amount of acetone, place 80 ℃ of environment drying under reduced pressure, get product, test-results sees the following form:
| Sequence number | The name of an article | Yield | Content |
| ??1 | Lysine aescin saponin | ??84.9％ | ??99.1％ |
| ??2 | The Histidine Aescine | ??83.5％ | ??99.6％ |
| ??3 | The ornithine Aescine | ??86.7％ | ??98.7％ |
| ??4 | Guanidine propylhomoserin Aescine | ??80.3％ | ??99.4％ |
| ??5 | The 2,4-diamino-butanoic Aescine | ??88.6％ | ??98.5％ |
Embodiment 3:
In reaction flask, add Aescine 65.6g (0.05mol), 0.05mol amino acid and 500ml distilled water successively, at 60 ℃ of stirring reactions to clear liquor, the evaporated under reduced pressure solvent, lyophilize, product, test-results sees the following form:
| Sequence number | The name of an article | Yield | Content |
| ??1 | Lysine aescin saponin | ??99.1％ | ??99.1％ |
| ??2 | The Histidine Aescine | ??99.2％ | ??99.0％ |
| ??3 | The ornithine Aescine | ??99.0％ | ??99.7％ |
| ??4 | Guanidine propylhomoserin Aescine | ??99.5％ | ??99.0％ |
| ??5 | The 2,4-diamino-butanoic Aescine | ??99.2％ | ??99.5％ |
Embodiment 4:
Get Aescine 65.6g (0.05mol), use the 200ml dissolve with methanol, get 0.05mol amino acid again, use the 500ml dissolved in distilled water, the Aescine methanol solution is dropped in the amino acid solution, at 40 ℃ of stirring reactions to clear liquor, the evaporated under reduced pressure solvent, at 60 ℃ of stirring reactions to clear liquor, the evaporated under reduced pressure solvent, lyophilize gets product, and test-results sees the following form:
| Sequence number | The name of an article | Yield | Content |
| ??1 | Lysine aescin saponin | ??99.6％ | ??99.6％ |
| ??2 | The Histidine Aescine | ??99.1％ | ??99.3％ |
| ??3 | The ornithine Aescine | ??99.3％ | ??98.2％ |
| ??4 | Guanidine propylhomoserin Aescine | ??99.5％ | ??99.6％ |
| ??5 | The 2,4-diamino-butanoic Aescine | ??99.6％ | ??99.5％ |
Embodiment 5:
Use the Aescine salt of different concns respectively, intravenous administration is measured the LD of various Aescine salt
50, test-results sees the following form:
| Sequence number | The name of an article | ??LD 50(P＝0.95) |
| ??1 | Aescine | ??16.3±5.3mg/kg |
| ??2 | The arginine Aescine | ??30.6±6.0mg/kg |
| ??3 | Lysine aescin saponin | ??27.1±5.5mg/kg |
| ??4 | The Histidine Aescine | ??25.4±5.9mg/kg |
| ??5 | The ornithine Aescine | ??39.6±5.2mg/kg |
| ??6 | Guanidine propylhomoserin Aescine | ??48.5±4.3mg/kg |
| ??7 | The 2,4-diamino-butanoic Aescine | ??30.3±4.9mg/kg |
Embodiment 6:
During rat tail vein instillation different pharmaceutical, pain can cause the uneasiness of rat and restless, adopts rat tail vein to stimulate and causes the restless recording unit of rat, investigates the vein irritating test of various Aescine salt.
Give and to be used certain density Aescine salt respectively, intravenous administration is measured the LD of various Aescine salt
50, test-results sees the following form:
| Sequence number | The name of an article | Concentration | Turn round the body number of times |
| ??1 | Physiological saline | ??---------- | ??7±5 |
| ??2 | Aescine | ??0.2mg/ml | ??19±7 |
| ??3 | The arginine Aescine | ??0.2mg/ml | ??13±6 |
| ??4 | Lysine aescin saponin | ??0.2mg/ml | ??15±5 |
| ??5 | The Histidine Aescine | ??0.2mg/ml | ??17±7 |
| ??6 | The ornithine Aescine | ??0.2mg/ml | ??10±5 |
| ??7 | Guanidine propylhomoserin Aescine | ??0.2mg/ml | ??11±8 |
| ??8 | The 2,4-diamino-butanoic Aescine | ??0.2mg/ml | ??13±7 |
Claims (7)
1, a kind of water soluble puerarin salt compound is characterized in that the compound (I) that following structural formula is represented, the R in the structural formula
1And R
2Be selected from hydrogen, arginine, Methionin, Histidine, ornithine, guanidine propylhomoserin and 2,4-diamino-butanoic, wherein R respectively
1And R
2Can not be hydrogen simultaneously.
2, can be made into pharmaceutically various formulations according to the described compound of claim 1 (I), comprise injection, tablet, capsule, granule and liniment.
3,, it is characterized in that with following method preparation according to the preparation method of the described compound of claim 1 (I):
(1), with the puerarin organic solvent dissolution, drop in the equimolar basic aminoacids aqueous solution, stirring reaction is to settled solution at a certain temperature, concentrating under reduced pressure adopts freeze-drying or organic solvent precipitation method, product.
Or (2), with puerarin with and equimolar basic aminoacids mixing, use water dissolution, stirring reaction is to settled solution at a certain temperature, concentrating under reduced pressure adopts freeze-drying or organic solvent precipitation method, must product.
4, organic solvent according to claim 3 is selected from methyl alcohol, ethanol, acetonitrile and acetone.
5, temperature according to claim 3 is 10～80 ℃.
6, basic aminoacids according to claim 3 is selected from arginine, Methionin, Histidine, ornithine, guanidine propylhomoserin and 2,4-diamino-butanoic.
7, organic solvent precipitation method according to claim 3 is meant:
Preparation method according to claim 3 behind the concentrating under reduced pressure, adds acetone in residue, grind to such an extent that off-white color precipitates, and filters, and a small amount of organic solvent washing of solid places 80 ℃ of environment drying under reduced pressure, gets product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510020570 CN1687051A (en) | 2005-03-24 | 2005-03-24 | Water soluble puerarin salt compound and preparing process thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510020570 CN1687051A (en) | 2005-03-24 | 2005-03-24 | Water soluble puerarin salt compound and preparing process thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1687051A true CN1687051A (en) | 2005-10-26 |
Family
ID=35305093
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200510020570 Pending CN1687051A (en) | 2005-03-24 | 2005-03-24 | Water soluble puerarin salt compound and preparing process thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1687051A (en) |
-
2005
- 2005-03-24 CN CN 200510020570 patent/CN1687051A/en active Pending
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