CN101200488A - Novel biogastrone acid derivatives, preparation method and medical uses thereof - Google Patents
Novel biogastrone acid derivatives, preparation method and medical uses thereof Download PDFInfo
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- CN101200488A CN101200488A CNA2007101789749A CN200710178974A CN101200488A CN 101200488 A CN101200488 A CN 101200488A CN A2007101789749 A CNA2007101789749 A CN A2007101789749A CN 200710178974 A CN200710178974 A CN 200710178974A CN 101200488 A CN101200488 A CN 101200488A
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Abstract
The invention provides a compound with the structure in formula I and the hydrate thereof. The compound can be served as the anti-ulcer medicine, wherein M1 and M2 are the metallic elements including sodium, potassium, zinc, magnesium and bismuth, and M1 and M2 can be same or different.
Description
Technical field
The invention provides the novel Enoxolone derivative of a class, preparation method, medicinal compositions and medicinal use thereof.Belong to medical technical field.
Background technology
Radix Glycyrrhizae belongs to leguminous plants, is distributed in European countries such as China western part and Russia, and widely medicinal in many countries.Its main pharmacological active substance is Potenlini and aglycon glycyrrhetinic acid thereof etc.Radix Glycyrrhizae acids medicine is more clearly in the intravital metabolic process of people, this type of medicine through the hydrochloric acid in gastric juice hydrolysis or in liver GRD beta-glucuronidase be decomposed into glycyrrhetinic acid, again in liver sausage circulation in intestines the bacterium agency part generate 3-table-glycyrrhetinic acid and a small amount of 3-dehydrogenation glycyrrhetinic acid and pharmaceutical activity take place.So the effect of Radix Glycyrrhizae acids medicine comes down to the effectiveness of glycyrrhetinic acid performance.
Modern medicine study shows, glycyrrhetinic acid and derivative thereof have many-sided effect such as anti-inflammatory, antiulcer agent, antiviral (hepatitis virus, virus of AIDS, SARS virus etc.), antitumor, antianaphylaxis, treat multiple inflammation and tetter as antiphlogiston.But such medicine is taken for a long time and can be caused the class aldosteronism, it is characterized in that sodium retention, potassium drainage increase, thereby cause oedema, hypertension, tetraplegia and hypokalemia etc.In addition, also there is the report glycyrrhetinic acid can cause that animal Tiroidina moderate suppresses, and has the effect that reduces basal metabolic rate(BMR).
In order to reduce above-mentioned toxic side effect and to improve solvability, absorptivity of glycyrrhetinic acid etc., scientists is carried out chemically modified and structure of modification from its precursor structure staff both at home and abroad, many effective Enoxolone derivatives have been synthesized in design, mainly are that 3 hydroxyls and 30 carboxyls to glycyrrhetinic acid carry out structural modification.Wherein, the derivative that 3 hydroxyls of glycyrrhetinic acid are carried out obtaining after the hemisuccinic acid esterification can directly contact with the epithelial cell of ulcer spot, and the mucus secretion that increases gastric mucosa also increases its viscosity, reduces coming off of gastric epithelial cell; In stomach, can combine simultaneously with stomach en-, the vigor of inhibitory enzyme, thus the protection ulcer surface promotes tissue regeneration and healing.Can be used for the remorse diseases of stomach such as stomach ulcer, duodenal ulcer clinically.
Modern pharmacological research proves that some metal ions are to gastrointestinal tract disease, and especially ulcer class disease has special effect.For example, zine ion can promote mucosa regeneration, quickens ulcer healing, and the cytoprotection of similar prostaglandin(PG) is arranged.Zinc is to absorb in duodenum and proximal small bowel, and the main excretion pathway of human body zinc is an enteron aisle, therefore takes the change that does not cause main organs trace element in the body for a long time, does not also cause accumulating of zinc.Bismuth ion can promote the mucous secretion, can promote ulcer healing to a certain extent, simultaneously because bismuth and bacteria cell wall and wall slurry film formation on every side complex body, can suppress the generation of some enzymes of helicobacter pylori, as urease, catalase and lipase etc., these endonuclease capables influence little growing environment of bacterium, therefore also have the effect of killing helicobacter pylori.Magnesium ion has the catharsis effect, can prevent the constipation symptom that some anti-ulcerative drug causes, magnesium also has the effect of spasmolysis, calmness simultaneously, can alleviate ulcer patient's pain.
Summary of the invention
The derivative of glycyrrhetinic acid and these special metal ions are combined, collaborative or summation action can be arranged ulcer class disease.Just be based on this, we have designed and synthesized the novel Enoxolone derivative of a class.This compounds has following general formula (I):
M wherein
1, M
2Be metallic element, comprise sodium, potassium, zinc, magnesium, bismuth, M
1And M
2Can be identical, also can be inequality.
The preferred compound of the present invention is:
Glycyrrhetinic acid hemisuccinic acid ester zinc salt (I
1)
Glycyrrhetinic acid hemisuccinic acid ester bismuth salt (I
2)
Glycyrrhetinic acid hemisuccinic acid ester magnesium salts (I
3)
The present invention also provides the preparation method of these derivatives.By glycyrrhetinic acid as starting raw material, with succinic acid derivative (comprising succsinic acid, succinyl oxide etc.) esterification, last salify and getting.
The present invention also provides the pharmaceutical composition of these derivatives, and said composition contains the medicine acceptable carrier in case of necessity.Composition of the present invention, can make any pharmaceutically useful formulation when making medicament, these formulations comprise: tablet, sugar coated tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, suck agent, granule, electuary, pill, powder, paste, sublimed preparation, suspensoid, solution, injection, suppository, ointment, plaster, creme, sprays, drops, patch.Preparation of the present invention, oral dosage form preferably, as: capsule, tablet, oral liquid, granule, pill, powder, sublimed preparation, paste etc., more preferably capsule, tablet.
Can add the medicine acceptable carrier when being prepared into medicament, described medicine acceptable carrier can be: starch, sucrose, lactose, mannitol, silicon derivative, Mierocrystalline cellulose and derivative thereof, alginate, gelatin, polyvinylpyrrolidone, glycerine, soil temperature 80, agar, lime carbonate, Calcium hydrogen carbonate, tensio-active agent, polyoxyethylene glycol, cyclodextrin, beta-cyclodextrin, phospholipid material, kaolin, talcum powder, calcium stearate, Magnesium Stearate etc.
Pharmaceutical preparation of the present invention is determined usage and dosage according to patient's situation in use, but oral three times of every day, each 1～2 dose, as: 1～2 or sheet.
Pharmaceutical composition of the present invention, when making medicament, the medicament of unitary dose can contain compound 10～100mg of the present invention, and all the other are pharmaceutically acceptable carrier.Pharmaceutically acceptable carrier can be 0.1～99.9% of total formulation weight amount by weight.
Embodiment
Can further describe the present invention by the following examples, yet invention of the present invention is not limited to the following examples, the scope that these embodiment do not limit the present invention in any way.Some change that those skilled in the art has done within the scope of the claims and adjust also should be thought and belongs to scope of the present invention.
Embodiment 1 glycyrrhetinic acid hemisuccinic acid ester zinc salt (I
1)
100 gram glycyrrhetinic acids are dissolved in the 250ml dry pyridine, stir, and drip the solution of 26g succinyl oxide-120ml dry pyridine, add the 130ml triethylamine then, 100 ℃ of reacting by heating 10h pour reaction mixture in the mixture of dilute hydrochloric acid and ice then, filter washing, chloroform dissolving, the dilute hydrochloric acid washing, washing, anhydrous sodium sulfate drying, it is dense dried to filter the back, resistates recrystallizing methanol, activated carbon decolorizing, white, needle-shaped crystals 112g, yield 92%, mp292～294 ℃.
Get previous step product 10 and restrain, be suspended in the 200ml water, stir, add 1.4 gram zinc oxide, 60 ℃ of reactions are clarified substantially until reaction solution, are cooled to room temperature, filter, and filtrate decompression is concentrated into dried, get off-white color solid 10.4 grams.
1H-NMR(DMSO-d6，δppm)：0.80(s，3H)，0.84(s，3H)，1.00(s，3H)，1.13(s，3H)，1.15(s，3H)，1.24(s，3H)，1.38(s，3H)，2.42(m，4H)，2.48(s，1H)，5.65(s，1H)。
Embodiment 2 glycyrrhetinic acid hemisuccinic acid ester bismuth salt (I
2)
Extracting liquorice hypo acid hemisuccinic acid ester 10 restrains, and is suspended in the 200ml water, stirs, and adds 3.0 gram bismuth hydroxides, and 60 ℃ of reactions are clarified substantially until reaction solution, are cooled to room temperature, filter, and filtrate decompression is concentrated into dried, gets off-white color solid 11.6 grams.
1H-NMR(DMSO-d6，δppm)：0.81(s，3H)，0.84(s，3H)，1.01(s，3H)，1.14(s，3H)，1.17(s，3H)，1.24(s，3H)，1.40(s，3H)，2.43(m，4H)，2.48(s，1H)，5.59(s，1H)。
Embodiment 3 glycyrrhetinic acid hemisuccinic acid ester magnesium salts (I
3)
Extracting liquorice hypo acid hemisuccinic acid ester 10 restrains, and is suspended in the 200ml water, stirs, and adds 0.7 gram magnesium oxide, and 60 ℃ of reactions are clarified substantially until reaction solution, are cooled to room temperature, filter, and filtrate decompression is concentrated into dried, gets off-white color solid 10.2 grams.
1H-NMR(DMSO-d6，δppm)：0.80(s，3H)，0.85(s，3H)，0.99(s，3H)，1.13(s，3H)，1.17(s，3H)，1.24(s，3H)，1.42(s，3H)，2.41(m，4H)，2.48(s，1H)，5.60(s，1H)。
The tablet of embodiment 4 preparation glycyrrhetinic acid novel derivatives
Prepare every tablet of tablet that contains 50 milligrams of glycyrrhetinic acid hemisuccinic acid esters as follows:
Prescription: glycyrrhetinic acid novel derivative (amounting to glycyrrhetinic acid hemisuccinic acid ester 50 grams), Microcrystalline Cellulose 100 grams, lactose 40 grams, polyvinylpolypyrrolidone 8 grams, silicon-dioxide 2 grams
Method: above-mentioned main materials and auxiliary materials is crossed 80 mesh sieves respectively, take by weighing respectively by recipe quantity; By the equivalent incremental method main ingredient and auxiliary material are mixed; Granule content is measured in the inspection of semifinished product, determines that average sheet is heavy; With the little recessed punch die compressing tablet of 8 Φ millimeters.
Claims (8)
1. the present invention is structure compound shown by formula I or its hydrate:
It is characterized in that, wherein M
1, M
2Be metallic element, comprise sodium, potassium, zinc, magnesium, bismuth, M
1And M
2Can be identical, also can be inequality.
2. the described compound of claim 1 or its hydrate is characterized in that, preferred compound is glycyrrhetinic acid hemisuccinic acid ester zinc salt (I
1).
3. the described compound of claim 1 or its hydrate is characterized in that, preferred compound is glycyrrhetinic acid hemisuccinic acid ester bismuth salt (I
2).
4. the described compound of claim 1 or its hydrate is characterized in that, preferred compound is glycyrrhetinic acid hemisuccinic acid ester magnesium salts (I
3).
5. the described compound of claim 1～4 or its hydrate is characterized in that, compound or its hydrate can be made compound oral administration preparation with the medicine acceptable carrier.
6. the described oral preparations of claim 5 is characterized in that, containing the described compound of claim 1～4 or its hydrate is 10～100 milligrams.
7. the described oral preparations of claim 6, preferred tablet, capsule.
8. the preparation method of the described compound of claim 1 or its hydrate is characterized in that, through following reaction: by glycyrrhetinic acid as starting raw material, with succinic acid derivative (comprising succsinic acid, succinyl oxide etc.) esterification, last salify and getting.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007101789749A CN101200488A (en) | 2007-12-07 | 2007-12-07 | Novel biogastrone acid derivatives, preparation method and medical uses thereof |
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| CNA2007101789749A CN101200488A (en) | 2007-12-07 | 2007-12-07 | Novel biogastrone acid derivatives, preparation method and medical uses thereof |
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| CN101200488A true CN101200488A (en) | 2008-06-18 |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102464699A (en) * | 2010-11-16 | 2012-05-23 | 中国科学院兰州化学物理研究所 | Method for preparing carbenoxolone sodium |
| CN102516350A (en) * | 2011-11-10 | 2012-06-27 | 沈阳化工大学 | Glycyrrhetinic acid modifier with antitumor activity and preparation method thereof |
| CN105713064A (en) * | 2014-12-05 | 2016-06-29 | 中国科学院大连化学物理研究所 | Pentacyclic triterpenoid and application thereof as human intestine carboxylesterase inhibitor |
| CN107281209A (en) * | 2017-07-19 | 2017-10-24 | 本溪国家中成药工程技术研究中心有限公司 | A kind of pharmaceutical composition of anti-gastric-ulcer and preparation method thereof and purposes |
| CN111018938A (en) * | 2019-12-10 | 2020-04-17 | 中国人民解放军第二军医大学 | Pentacyclic triterpenoid glycyrrhetinic acid derivative and preparation method and application thereof |
| CN111519438A (en) * | 2020-05-06 | 2020-08-11 | 江苏金太阳纺织科技股份有限公司 | Antibacterial and antiviral finishing agent and preparation method and use method thereof |
-
2007
- 2007-12-07 CN CNA2007101789749A patent/CN101200488A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102464699A (en) * | 2010-11-16 | 2012-05-23 | 中国科学院兰州化学物理研究所 | Method for preparing carbenoxolone sodium |
| CN102516350A (en) * | 2011-11-10 | 2012-06-27 | 沈阳化工大学 | Glycyrrhetinic acid modifier with antitumor activity and preparation method thereof |
| CN105713064A (en) * | 2014-12-05 | 2016-06-29 | 中国科学院大连化学物理研究所 | Pentacyclic triterpenoid and application thereof as human intestine carboxylesterase inhibitor |
| CN105713064B (en) * | 2014-12-05 | 2017-10-27 | 中国科学院大连化学物理研究所 | Pentacyclic triterpenoid and its application as people's intestines carboxylesterase inhibitor |
| CN107281209A (en) * | 2017-07-19 | 2017-10-24 | 本溪国家中成药工程技术研究中心有限公司 | A kind of pharmaceutical composition of anti-gastric-ulcer and preparation method thereof and purposes |
| CN107281209B (en) * | 2017-07-19 | 2019-05-24 | 本溪国家中成药工程技术研究中心有限公司 | A kind of pharmaceutical composition of anti-gastric-ulcer and preparation method thereof and purposes |
| CN111018938A (en) * | 2019-12-10 | 2020-04-17 | 中国人民解放军第二军医大学 | Pentacyclic triterpenoid glycyrrhetinic acid derivative and preparation method and application thereof |
| CN111018938B (en) * | 2019-12-10 | 2021-05-25 | 中国人民解放军第二军医大学 | Pentacyclic triterpenoid glycyrrhetinic acid derivative and preparation method and application thereof |
| CN111519438A (en) * | 2020-05-06 | 2020-08-11 | 江苏金太阳纺织科技股份有限公司 | Antibacterial and antiviral finishing agent and preparation method and use method thereof |
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Application publication date: 20080618 |