CN1318425C - Cough and phlegm removing purple bergenia element analog and its pharmaceutical composition - Google Patents
Cough and phlegm removing purple bergenia element analog and its pharmaceutical composition Download PDFInfo
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- CN1318425C CN1318425C CNB2005100213085A CN200510021308A CN1318425C CN 1318425 C CN1318425 C CN 1318425C CN B2005100213085 A CNB2005100213085 A CN B2005100213085A CN 200510021308 A CN200510021308 A CN 200510021308A CN 1318425 C CN1318425 C CN 1318425C
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- bergeninum
- kobadrin
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Abstract
The present invention relates to a bergenin compound with the activity of relieving cough and eliminating phlegm, and the structure of the bergenin compound is disclosed in the formula (I), wherein R1 is in an ester structure, an ether structure or an alkyl structure; the ester structure comprises a benzoic acid ester, cinnamate ester or corresponding substituted aromatic acid ester, or ester corresponding to acid with physiological activity; the ether structure comprises aromatic ether or corresponding ether formed from alcohol or phenol, which has physiological activity; the alkyl structure comprises piperazine or a derivative thereof; R2 is H or methyl. Compared with an activated monomer compound (bergenin) extracted from purple bergenia belonging to saxifragaceae plants, an oral administration and/or an injection medical preparation prepared from the compound as an active medical component, which is disclosed in the formula (I), and other pharmaceutically acceptable components has ideal effect in the aspects of therapeutic effect and bioavailability.
Description
Technical field
The present invention relates to a kind of active Bergeninum compounds of kobadrin that has, and can be used for the pharmaceutical composition of respiratory system disease control with this compound as the active drug composition.
Background technology
Bergeninum is a vegetable active monomeric compound that is obtained by extraction in the saxifragaceae plant Rhizome or herb of Purple Bergenia, and its structure is suc as formula shown in (A):
Remove the natural extract beyond the region of objective existence of formula (A) structure formation, naturally occurring Rhizome or herb of Purple Bergenia analog derivative also includes:
(E)R
1＝gall，R
2＝R
3＝R
4＝H，R
5＝Me
(F)R
1＝R
2＝R
4＝H，R
3＝gall，R
5＝Me
(G)R
1＝gall，R
2＝R
3＝R
4＝R
5＝H
(H)R
1＝R
2＝R
3＝R
4＝H，R
5＝Me
(I)R
1＝R
2＝R
3＝H，R
4＝R
5＝Me
(J)R
1＝R
2＝H，R
3＝R
4＝R
5＝Me
(K)R
1＝R
3＝H，R
2＝R
4＝R
5＝Me
(L)R
2＝R
3＝H，R
1＝R
4＝R
5＝Me
(M)R
1＝R
2＝R
3＝R
4＝R
5＝Me
(N)R
1＝gall(Me)
3，R
2＝H，R
3＝R
4＝R
5＝Me
Bergeninum has Antitussive and Expectorant Effect, can be used for chronic bronchitis, has been included in 2005 editions " in the Chinese pharmacopoeia (an one).About existing many reports such as the new medicinal use of Bergeninum, structural analysis, extraction and separation process, detection method and preparation research.For example, " a kind of antibechic system is breathed heavily oral preparation " of CN 94100146 reports, " containing the makeup of Bergeninum extract and the extracting method of this extract " of reports such as CN03107475 and JP 8059452, " the new purposes in Bergeninum treatment chronic prostatitis and the anti-proliferative disease " of CN 02159198 report, " containing soft capsule of Bergeninum and preparation method thereof " of CN 200410078846 reports, " compound bergenin pills and the method for making thereof " of CN200410040660 report, " the anoretic composition " of US 6531162 and JP 2004091464 reports, " hepatoprotective " of JP 11209282 reports, and Xie Jingxi etc. " chemical structure of herbal medicine Japanese Ardisia Herb cough-relieving composition and synthetic " (" Acta Pharmaceutica Sinica) " 1981,16[6]); Gong Jianfu " novel process of extraction Bergeninum from Herba astilbes chinensis " (" Chinese materia medica Leader, Hunan ", 1997,3[3]); Chen Wendou etc. " high performance liquid chromatography of Bergeninum in Herba astilbes chinensis and the scorching calamus " (" Acta Pharmaceutica Sinica " 1988,23[80]); Liu Nvnian " existence and the assay of Bergeninum in Chinese Ardisa plant " (" Shanghai Medical Univ's journal " 1992,20[1]); Zhou Qinghua etc. " Bergeninum Study on extraction in the Root of Chinese Astilbe " (" Heilungkiang medicine ", 1997,10[2]); Zhang Zhengxian " research of Bergeninum Chinese People's Anti-Japanese Military and Political College mouse experiment type ulcer " (" herbal medicine ", 1999,30[supplementary issue]); A Yasi. visit mountain one hundred " Immunoenhancing Action of Bergenin " (" Xinjiang Medical College journal ", 1998, [3]) etc.
With above-mentioned Bergeninum compound structure is that the report that structural modification is carried out on the basis also comprises as report (" Bioorganic such as HironobuTakahashi; Medicinal Chemistry ", 2003,11[8]), for improving the lipotropism matter oxidation activity of Bergeninum, the new compound structure of introducing longer chain fatty acid has:
4a R
1＝R
2＝R
3＝CH
3
4b R
1＝R
2＝R
3＝(CH
2)
2CH
3
4c R
1＝R
2＝R
3＝(CH
2)
4CH
3
4d R
1＝R
2＝R
3＝(CH
2)
6CH
3
4e R
1＝R
2＝R
3＝(CH
2)
14CH
3
4f R
1＝R
2＝R
3＝(CH
2)
16CH
3
5 R
1＝(CH
2)
4CH
3，R
2＝R
3＝H
6 R
1＝R
3＝H，R
2＝(CH
2)
4CH
3
7 R
1＝R
2＝H，R
3＝(CH
2)
4CH
3
For improving the coronary vasodilation effect and the antiulcer action of Bergeninum, the relevant modifications thing structure of JP 59186988 reports has:
Summary of the invention
According to above-mentioned situation, it is that basic structure is carried out structural modification and had the active Bergeninum compounds of even more ideal kobadrin with the Bergeninum compound of above-mentioned formula (A) form that the present invention at first will provide a class, thereby can be applied to the new medicinal compound of respiratory system disease control.On this basis, the present invention further also will provide with this class new compound and can prevent and treat the pharmaceutical composition that uses for respiratory system disease as effective pharmaceutical cpd.These pharmaceutical compositions can have even more ideal kobadrin effect, can make doctor and/or patient can increase the selection and the scope of application to available medicine at least to the control of respiratory system diseases such as chronic bronchitis the time.
The present invention has the active Bergeninum compounds of kobadrin, and structure is suc as formula shown in (I):
R1 in the formula is ester structure, ether structure or alkyl structure.Wherein said ester structure, can be benzoic ether, laurate or corresponding substituted cinnamic acid ester, 3,4-dimethoxyphenylacetic acid ester, anisic acid ester, 3-chloro-cinnamic acid ester, 2, the aromatic esters of forms such as 4-dimethyl laurate, or for having the corresponding ester of acid of physiologically active, as ferulic acid ester, acetylsalicylate, monomester succinate or its sodium salt, phosphoric acid ester or its sodium salt, amino acid ester etc.; Said ether structure be aromatic oxide or with the corresponding ether that alcohol or phenol became with physiologically active, as methyl-phenoxide, phenyl ethyl ether, 4-anisole methyl ether, 2, replacements such as 4-dichlorobenzene ether or do not have the aromatic oxide of replacement, and as ether corresponding with common alcohol with physiologically active or phenol such as root bark of tree peony phenolic ether, methyl catechol (hydroxyanisole) ether etc.; Said alkyl structure can be piperazine, or as corresponding derivant structure such as methylpiperazine, ethyl piperazidine, styracin piperazine, butyl piperazine.R in the formula
2Can be H or methyl.
The experimental result demonstration, in the compound of above-mentioned formula (I) structure, in the structure formation of the compound that can have better pharmacologically active, R
1Can be preferably a kind of in acetylsalicylate, monomester succinate and sodium salt, pockwood phenolic ether and the bridged piperazine derivatives; R
2Be H or methyl.
When being the said formula of feedstock production the present invention (I) compound, can adopt following mode to obtain respectively to formula (I) compound of different structure form with the Bergeninum of aforementioned formula (A) structure.
R
1Preparation during for the ester class formation:
R
1Preparation during for the ethers structure:
Behind 11 hydroxy halogenos, can adopt Williamson ether synthesis method to obtain ether structure.
R
1Preparation during for the alkyls structure:
Behind 11 hydroxy halogenos, be that alkylating agent can obtain alkyl structure with piperazine and derivative.
R
2Synthetic method during for methyl can methylate with methyl-sulfate earlier, carries out esterification again.
R
2Synthetic method during for H, can be earlier to the reaction of Bergeninum demethylation, benzyl protection phenolic hydroxyl group then, esterification, last catalytic hydrogenation removes benzyl, obtains the ester structure target product.
Route when being appreciated that by foregoing the said formula of the present invention (I) compound adopts above-mentioned synthesis mode to prepare is all very simple, and cost is lower, and the yield of product is higher, can be suitable for industrialization and enlarge the needs of producing.
The experimentation on animals result shows that above-mentioned formula of the present invention (I) compound can have the kobadrin active function of strengthening Bergeninum, strengthens drug effect.Especially succinate, phosphoric acid salt also obviously increase the water-soluble of compound, improve bioavailability, also are the exploitation that the enlarges multiple pharmaceutical dosage form kind condition of providing convenience simultaneously.
According to " new drug preclinical study governing principle " requirement, selected two indexs: ammoniacal liquor causes mouse cough and sulfurous gas causes mouse cough as kobadrin screening active ingredients index, and the parent compound Bergeninum of some formulas (I) compound of the present invention and formula (A) has been carried out the contrast experiment.Experimental technique is according to " herbal pharmacology research methodology ", " new Chinese medicine development technology and method " and new drug preclinical study governing principle " standard formulation.
One, ammoniacal liquor causes the mouse cough experiment: get 150 of healthy mices, be divided into 15 groups by body weight and sex stratified random, and 10 every group, each 5 of male and female.Except that positive drug codeine phosphate group is the intraperitoneal injection, all the other respectively organize equal gastric infusion, behind the administration 1h (behind the codeine phosphate group administration 30mm), mouse is put into the 250ml bell glass, open the ultrasonic atomizer that is attached thereto by rubber tubing, spray into strong aqua in the bell glass uniformly, spraying 10s, take out mouse immediately, the cough reaction of observing and writing down mouse (shows with its abdominal muscle and shrinks, mouth magnifies, and can have sometimes to cough sound) latent period (ammoniacal liquor to the mouse that refers to begin spray is taken place by the required time of cough) and 3min in the cough number of times.Cough latent period rate elongation=(administration group cough latent period-blank group cough latent period)/blank group cough latent period; 3min cough number of times inhibiting rate=(administration group cough number of times-blank group cough number of times)/blank group cough number of times.Experimental result is as shown in table 1.
By table 1 as seen, compare with the blank group, Bergeninum derivative I-1～the I-4 of formula of the present invention (I) structure and I-6 are to all there being prolongation effect (P＜0.05 or P＜0.01) in various degree in latent period of the mouse cough due to the ammoniacal liquor, wherein Bergeninum derivative I-2, I-4 effect are stronger, and its high and low dose group mouse cough prolongation of latency rate reaches 85.7%, 60.9% and 94.5%, 59.4% respectively; Bergeninum derivative I-1～I-4, I-6 also have in various degree restraining effect (P＜0.05 or P＜0.01) to mouse cough number of times in the 3min, wherein Bergeninum derivative I-2, I-4 effect are stronger, and cough number of times inhibiting rate reaches 69.1%, 48.5% and 74.1%, 61.6% respectively in the high and low dose group mouse 3min.
Table 1 ammoniacal liquor causes the mouse cough experimental result
| Group | Dosage (mg/kg) | Number of animals (N) | Cough latent period (s) | Rate elongation (%) | Cough number of times in the 3min | Inhibiting rate (%) |
| The blank group | - | 10 | 35.22±6.79 | - | 80.2±12 3 | - |
| Derivative I-1 R 1=benzoyloxy R 2＝H | 120 60 | 10 10 | 52.63±1276 * 41.82±1357 | 49.4 18.7 | 53.8±13.6 ** 65.3±17.2 | 32.9 18.6 |
| Derivative I-2 R 1=carboxylic butyryl acyloxy R 2＝H | 120 60 | 10 10 | 65.39±11.38 ** 56.67±10.07 * | 85.7 60.9 | 24.8±12.7 ** 41.3±15.9 ** | 69.1 48.5 |
| Derivative I-3 R 1=acetyl oxygen benzoyl oxygen R 2＝H | 120 60 | 10 10 | 58.38±9.78 * 47.03±16.64 | 65.8 33.5 | 55.1±17.3 * 69.2±19.8 | 31.3 13.7 |
| Derivative I-4 R 1=methylpiperazine base R 2=methyl | 120 60 | 10 10 | 68.50±15.93 ** 56.16±12 09 ** | 94.5 59.4 | 20.8±13.3 ** 30.8±11.5 ** | 74.1 61.6 |
| Derivative I-5 R 1=phenylallene acyloxy R 2＝H | 120 60 | 10 10 | 45.01±10.95 36.16±12.27 | 27.8 2.7 | 71.5±17.1 76.6±15.8 | 10.8 4.5 |
| Derivative I-6 R 1=o-methoxyphenyl R 2=methyl | 120 60 | 10 10 | 61.76±15.37 * 48.45±12.55 | 75.4 37.6 | 56.3±16.5 * 67.4±20.9 | 29.8 16.0 |
| Bergeninum (A) contrast | 60 | 10 | 49.31±5.52 * | 40.0 | 51.7±16.0 ** | 35.6 |
| The morphine monomethyl ether control group | 30 | 10 | 63.22±15.09 ** | 79.5 | 22.6±14.1 ** | 71.9 |
Annotate: compare with the blank group,
*P＜0.05,
*P＜0.01
Two, sulfurous gas causes the mouse cough experiment: get 150 of healthy mices, be divided into 15 groups by body weight and sex stratified random, and 10 every group, each 5 of male and female.Except that positive drug codeine phosphate group is the intraperitoneal injection, all the other respectively organize equal gastric infusion, behind the administration 1h (behind the codeine phosphate group administration 30min), mouse is put into the wide-necked bottle of 250ml, inject sulfur dioxide gas 8ml, observe the cough number of times in mouse cough latent period (injecting sulfurous gas) and the 3min to the time of coughing first.Cough latent period rate elongation=(administration group cough latent period-blank group cough latent period)/blank group cough latent period; 3min cough number of times inhibiting rate=(administration group cough number of times-blank group cough number of times)/blank group cough number of times.Experimental result sees Table 2.
By table 2 as seen, compare with the blank group, Bergeninum derivative I-1～I-4, the I-6 of formula of the present invention (I) structure is to all there being prolongation effect (P＜0.05 or P＜0.01) in various degree in latent period of the mouse cough due to the sulfurous gas, wherein Bergeninum derivative I-4 effect is stronger, and its high and low dose group mouse cough prolongation of latency rate reaches 65.2%, 45.2% respectively; Bergeninum derivative I-1～I-6 all has in various degree restraining effect (P＜0.05 or P＜0.01) to mouse cough number of times in the 3min due to the sulfurous gas, wherein Bergeninum derivative I-2, I-4 effect are stronger, and cough number of times inhibiting rate reaches 54.3%, 39.2% and 75.8%, 71.5% respectively in its high and low dose group mouse 3min.
Table 2 sulfurous gas causes the mouse cough experimental result
| Group | Dosage (mg/kg) | Number of animals (N) | Cough latent period (s) | Rate elongation (%) | Cough number of times in the 3min | Inhibiting rate (%) |
| The blank group | - | 10 | 37.83±6.79 | - | 81.4±13.6 | - |
| Derivative I-1 | 120 60 | 10 10 | 49.47±16.34 * 43.59±12.73 | 30.8 15.2 | 50.4±15.7 * 64.9±21.6 | 38.1 20.3 |
| Derivative I-2 | 120 60 | 10 10 | 52.67±10.71 * 50.23±8.46 * | 39.2 32.8 | 37.2±11.5 ** 49.5±17.1 * | 54.3 39.2 |
| Derivative I-3 | 120 60 | 10 10 | 49.85±11.32 * 40.09±12.27 | 31.8 6.0 | 46.3±11.3 ** 54.1±13.6 * | 43.1 33.5 |
| Derivative I-4 | 120 60 | 10 10 | 62.50±11.35 ** 54.94±8.43 ** | 65.2 45.2 | 19.7±13.4 ** 23.2±14 5 ** | 75.8 71.5 |
| Derivative I-5 | 120 60 | 10 10 | 45.86±19.10 39.52±13.77 | 21.2 4.5 | 56.7±13.4 * 67.6±17.2 | 30.3 17.0 |
| Derivative I-6 | 120 60 | 10 10 | 50.48±11.16 * 43.54±14.35 | 33.4 15.1 | 51.3±15.7 * 64.9±18.9 | 37.0 20.3 |
| Bergeninum | 60 | 10 | 50.22±9.68 * | 32.8 | 33.7±14.4 ** | 58.6 |
| The morphine monomethyl ether group | 30 | 10 | 64.67±14.07 ** | 70.9 | 20.4±16.2 | 75.0 |
Annotate: compare with the blank group,
*P＜0.05,
*P＜0.01
As the active drug composition,,, can be made for the available medicine that comprises several formulations forms such as oral, injection with above-mentioned formula of the present invention (I) structural compounds according to conventional processing and treating method with acceptable other composition of pharmacy.For example, with above-mentioned formula (I) compound with can be received in oral preparations mix as auxiliary added ingredients commonly used such as disintegrating agent, vehicle, lubricant, tackiness agent, weighting agent after, the respiratory system disease that promptly may be made in tablet, pill, capsule or solid preparation types such as multiple corresponding sustained release dosage, control-released agent is is according to a conventional method prevented and treated medicine; Mix with the tensio-active agents of using always such as solubilizing agent, emulsifying agent, wetting agent, foaming or defoamer, thinner, sanitas, stablizer, correctives, thickening material etc., by corresponding ordinary method, promptly may be made in respiratory system disease control oral pharmaceutical as liquid preparation types such as aqua, syrup; Cooperates with appropriate solvent commonly used in the injection and additives and operate, the respiratory system disease that can also be prepared into corresponding muscle or intravenous form is prevented and treated medicine etc.Change present patient and doctor by situation that can only unique use Bergeninum oral tablet, thereby increased alternative scope and handiness on to the type of preparation and/or the scope of application greatly, and improved result of treatment.
Based on foregoing, under the prerequisite that does not break away from the above-mentioned basic fundamental thought of the present invention,, modification, replacement or the change of various ways can also be arranged to associated viscera according to the ordinary skill knowledge and the customary means of this area.
The embodiment of form is described in further detail foregoing of the present invention again by the following examples, but this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following embodiment.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Embodiment
Embodiment 16, and 7, the preparation of 8-trimethoxy-phenylformic acid-β-C-glycoside-delta-lactone
The Bergeninum of 15 grams (0.046 mole) suc as formula (A) structure is dissolved in 750 ml methanol, adds 60 gram Anhydrous potassium carbonates, 86 milliliters of methyl-sulfates, 50 ℃ were stirred 18 hours down, filtering salt of wormwood, concentrated mother liquor, column chromatography, get white powder, yield 70%, fusing point 194-196 ℃.
1H NMR(400MHz)(CDCl
3)：6.732(1H，s，ph-H)，5.325-5.415(1H，m，CH)，4.451-4.458(1H，m，CH)，3.951-4.010(1H，m，CH)，3.852-3.875(1H，m，CH)，3.722-3.745(9H，s，3CH
3)，3.523-3.626(2H，m，CH
2)，3.201-3.221(1H，m，CH)；
MS：357(M+1)，327，296，265，206，122。
The structure of gained compound is:
Embodiment 26, and 7, the preparation of 8-trihydroxy--phenylformic acid-β-C-glycoside-delta-lactone
100 gram (0.3 mole) Bergeninums are dissolved in 200 milliliters of pyridines, under the room temperature, drip 200 ml acetic anhydride, stirred 24 hours.Pour in the water, ethyl acetate extraction merges organic layer, and dried over mgso concentrates to such an extent that five acetyl Bergeninums 150 restrain.
40 gram (0.08 mole) five acetyl Bergeninums are dissolved in 500 milliliters of methylene dichloride, add 120 milliliters of boron trichlorides (0.12 mole), 0 ℃ was reacted 1 hour, reaction is 24 hours under the room temperature, pour in the frozen water, steam and remove methylene dichloride, add 10% solution of potassium carbonate and stirred 1 hour, use hcl acidifying again, concentrate, column chromatography gets product, white powder, yield 62%, 250 ℃ of fusing points.
1H NMR(400MHz)(C
5D
5N)：6.782(1H，s，ph-H)，5.335-5.415(1H，m，CH)，4.441-4.458(1H，m，CH)，3.981-4.010(1H，m，CH)，3.852-3.875(1H，m，CH)，3.553-3.626(2H，m，CH2)，3.201-3.221(1H，m，CH)；
MS：315(M+1)，286，235，206，122。
The structure of gained compound is:
Embodiment 36, and 7, the preparation of 8-three benzyloxies-phenylformic acid-β-C-glycoside-delta-lactone
With 0.5 gram (0.002 mole) 6,7,8-trihydroxy--phenylformic acid-β-C-glycoside-delta-lactone is dissolved in the mixed solution of 6 milliliters of dimethyl formamides and 6 milliliters of acetone, add 1.3 gram salt of wormwood, 0 ℃ drips 1 milliliter of benzyl bromine, stirring at room 24 hours down, pour in the water, ethyl acetate extraction is separated organic layer, dry, concentrate, column chromatography gets white powder, yield 70%, fusing point 158-160 ℃.
1H NMR(400MHz)(DMSO)：7.212-7.250(15H，m，ph-H)，6.782(1H，s，ph-H)，5.335-5.415(1H，m，CH)，5.121-5.132(6H，m，3CH
2)，4.441-4.458(1H，m，CH)，3.981-4.010(1H，m，CH)，3.852-3.875(1H，m，CH)，3.553-3.626(2H，m，CH
2)，3.201-3.221(1H，m，CH)；
MS：586(M+1)，557，448，238，208，123。
The structure of gained compound is:
Embodiment 46, and 7, the preparation of 8-trimethoxy-phenylformic acid-14-carboxylic butyryl acyloxy-β-C-glycoside-delta-lactone
With 0.5 gram (0.001 mole) 6,7,8-trimethoxy-phenylformic acid-β-C-glycoside-delta-lactone is dissolved in 20 milliliters of pyridines, adds 0.15 gram (0.0015 mole) Succinic Acid, 0.5 gram DCC and 0.3 gram DMAP, stirring at room 24 hours, steaming desolventizes, and column chromatography gets white powder, yield 30%, fusing point 177-175 ℃.
Ultimate analysis: C:52.60 (calculated value 52.63), H:5.56 (calculated value 530);
1H NMR(400MHz)(DMSO)：6.792(1H，s，ph-H)，5.365-5.415(1H，m，CH)，4.455-4.458(1H，m，CH)，4.125-4.158(2H，m，CH
2)，3.855-3.875(2H，m，2CH)，3.722-3.745(9H，s，3CH
3)，3.201-3.221(1H，m，CH)，633-2.645(4H，m，2CH
2)；
MS：457(M+1)，341，328，235，206，121。
The structure of gained target compound is:
Embodiment 56, and 7, the preparation of 8-trihydroxy--phenylformic acid-14-carboxylic butyryl acyloxy-β-C-glycoside-delta-lactone
With 0.5 gram (0.001 mole) 6,7,8-three benzyloxies-phenylformic acid-β-C-glycoside-delta-lactone is dissolved in 20 milliliters of pyridines, add 0.15 gram (0.0015 mole) Succinic Acid, 0.5 gram DCC and 0.3 gram DMAP, stirring at room 24 hours, steaming desolventizes, column chromatography gets white powder, yield 32%.
Above-mentioned product is dissolved in 10 milliliters of ethanol and the methylene dichloride mixed solution, feeds hydrogen, add 10 milligrams of 10%Pd/C, under the room temperature constant pressure, reacted 24 hours, filtering Pd/C, steaming desolventizes, and column chromatography gets product, yield 45%, fusing point 182-185 ℃.
Ultimate analysis: C:49.02 (calculated value 49.28), H:4.45 (calculated value 4.38);
1H NMR(400MHz)(DMSO)：6.722(1H，s，ph-H)，5.335-5.415(1H，m，CH)，4.441-4.458(1H，m，CH)，3.981-4.010(1H，m，CH)，3.852-3.875(1H，m，CH)，3.553-3.626(2H，m，CH
2)，3.201-3.221(1H，m，CH)，2.633-2.645(4H，m，2CH
2)；
MS：415(M+1)，299，286，238，204，122。
The structure of gained target compound is:
Embodiment 66, and 7, the preparation of 8-trimethoxy-phenylformic acid-14-benzoyloxy-β-C-glycoside-delta-lactone
With 0.5 gram (0.001 mole) 6,7,8-trimethoxy-phenylformic acid-β-C-glycoside-delta-lactone is dissolved in 20 milliliters of pyridines, adds 0.15 gram (0.0012 mole) phenylformic acid, 0.5 gram DCC and 0.3 gram DMAP, stirring at room 24 hours, steaming desolventizes, and column chromatography gets white powder, yield 33%, fusing point 182-185 ℃.
Ultimate analysis: C:59.88 (calculated value 60.00), H:5.48 (calculated value 5.25);
1H NMR(400MHz)(DMSO)：7.332-7.885(5H，m，ph-H)，6.792(1H，s，ph-H)，5.365-5.415(1H，m，CH)，4.423-4.438(1H，m，CH)，4.125-4.158(2H，m，CH2)，3.855-3.875(2H，m，2CH)，3.745-3.768(9H，s，3CH3)，3.212-3.233(1H，m，CH)；
MS：461(M+1)，354，235，207，122。
The structure of gained target compound is:
Embodiment 76, and 7, the preparation of 8-trihydroxy--phenylformic acid-14-benzoyloxy-β-C-glycoside-delta-lactone
With 0.5 gram (0.001 mole) 6,7,8-three benzyloxies-phenylformic acid-β-C-glycoside-delta-lactone is dissolved in 20 milliliters of pyridines, add 0.15 gram (0.0012 mole) phenylformic acid, 0.5 gram DCC and 0.3 gram DMAP, stirring at room 24 hours, steaming desolventizes, column chromatography gets white powder, yield 35%.
Above-mentioned product is dissolved in 10 milliliters of ethanol and the methylene dichloride mixed solution, feeds hydrogen, add 10 milligrams of 10%Pd/C, under the room temperature constant pressure, reacted 24 hours, filtering Pd/C, steaming desolventizes, and column chromatography gets product, yield 43%, fusing point 188-190 ℃.
Ultimate analysis: C:57.19 (calculated value 57.42), H:4.48 (calculated value 4.34);
1H NMR(400MHz)(DMSO)：7.332-7.885(5H，m，ph-H)，6.722(1H，s，ph-H)，5.389-5.415(1H，m，CH)，4.445-4.458(1H，m，CH)，3.971-4.010(1H，m，CH)，3.852-3.875(1H，m，CH)，3.553-3.626(2H，m，CH2)，3.201-3.221(1H，m，CH)；
MS：419(M+1)，299，238，204，122。
The structure of gained target compound is:
Embodiment 86, and 7, the preparation of 8-trihydroxy--phenylformic acid-14-acetyl oxygen benzoyloxy-β-C-glycoside-delta-lactone
With 0.5 gram (0.001 mole) 6,7,8-three benzyloxies-phenylformic acid-β-C-glycoside-delta-lactone is dissolved in 20 milliliters of pyridines, add 0.25 gram (0.001 5 mole) acetylsalicylic acid, 0.5 gram DCC and 0.3 gram DMAP, stirring at room 24 hours, steaming desolventizes, column chromatography gets white powder, yield 35%.
Above-mentioned product is dissolved in 10 milliliters of ethanol and the methylene dichloride mixed solution, feeds hydrogen, add 10 milligrams of 10%Pd/C, under the room temperature constant pressure, reacted 24 hours, filtering Pd/C, steaming desolventizes, and column chromatography gets product, yield 48%, fusing point 168-170 ℃.
Ultimate analysis: C:55.36 (calculated value 55.47), H:4.50 (calculated value 4.23);
1H NMR(400MHz)(DMSO)：7.252-7.756(4H，m，ph-H)6.722(1H，s，ph-H)，5.335-5.415(1H，m，CH)，4.441-4.458(1H，m，CH)，4.423-4.455(2H，m，CH
2)，3.981-4.010(1H，m，CH)，3.852-3.875(1H，m，CH)，3.201-3.221(1H，m，CH)，2.223(3H，s，CH
3)；
MS：477(M+1)，435，420，315，285，120。
The structure of gained target compound is:
Embodiment 96, and 7, the preparation of 8-trihydroxy--phenylformic acid-14-phenylallene acyloxy-β-C-glycoside-delta-lactone
With 0.5 gram (0.001 mole) 6,7,8-three benzyloxies-phenylformic acid-β-C-glycoside-delta-lactone is dissolved in 20 milliliters of pyridines, add 0.20 gram (0.0015 mole) styracin, 0.5 gram DCC and 0.3 gram DMAP, stirring at room 24 hours, steaming desolventizes, column chromatography gets white powder, yield 36%.
Above-mentioned product is dissolved in 10 milliliters of ethanol and the methylene dichloride mixed solution, feeds hydrogen, add 10 milligrams of 10%Pd/C, under the room temperature constant pressure, reacted 24 hours, filtering Pd/C, steaming desolventizes, and column chromatography gets product, yield 46%, fusing point 165-168 ℃.
Ultimate analysis: C:59.22 (calculated value 59.46), H:4.75 (calculated value 4.54);
1H NMR(400MHz)(DMSO)：7.665(1H，s，CH＝)，7.152-7.356(5H，m，ph-H)，6.732(1H，s，ph-H)，6.232(1H，s，＝CH)，5.335-5.415(1H，m，CH)，4.441-4.458(1H，m，CH)，4.423-4.445(2H，m，CH
2)，3.981-4.010(1H，m，CH)，3.852-3.875(1H，m，CH)，.201-3.221(1H，m，CH)；
MS：445(M+1)，315，286，235，206，122。
The structure of gained target compound is:
Embodiment 10 6, and 7, the preparation of 8-trimethoxy-phenylformic acid-14-bromo-β-C-glycoside-delta-lactone
With 10 gram (0.02 moles) 6,7,8-trimethoxy-phenylformic acid-3-C-glycoside-delta-lactone is dissolved in 135 milliliters of anhydrous pyridines, under 0 ℃, drips 6.4 gram (0.03 mole) Tosyl chlorides, stirring at room 16 hours.10% hcl acidifying, ethyl acetate extraction is separated organic layer, and dried over mgso is filtered, and concentrates, and gets product 10.4 grams.
Above-mentioned product is dissolved in methylene dichloride, adding 8 gram Sodium Bromides, back flow reaction 2 hours is poured in the water, and ethyl acetate extraction is separated organic layer, and drying is filtered, and concentrates, and gets product, yield 80%.
1H NMR(400MHz)(DMSO)：6.752(1H，s，ph-H)，5.325-5.415(1H，m，CH)，4.451-4.458(1H，m，CH)，3.951-4.010(1H，m，CH)，3.852-3.875(1H，m，CH)，3.722-3.745(9H，s，3CH
3)，3.523-3.626(2H，m，CH
2)，3.201-3.221(1H，m，CH)；
MS：418(M-1)，327，296，265，206，122。
The structure of gained compound is:
Embodiment 11 6, and 7, the preparation of 8-trimethoxy-phenylformic acid-14-methylpiperazine base-β-C-glycoside-delta-lactone
With 0.5 gram (0.001 mole) 6,7,8-trimethoxy-phenylformic acid-14-bromo-β-C-glycoside-delta-lactone (going up routine product), 0.2 gram (0.002 mole) methylpiperazine are dissolved in 10 milliliters of pyridines, back flow reaction 10 hours, pour in the water, ethyl acetate extraction is separated organic layer, dry, filter, concentrate, column chromatography gets product, yield 70%, 165 ℃-168 ℃ of fusing points.
Ultimate analysis: C:57.48 (calculated value 57.52), H:7.02 (calculated value 6.90), N:6.26 (calculated value 6.39);
1H NMR(400MHz)(DMSO)：6.752(1H，s，ph-H)，5.325-5.415(1H，m，CH)，4.451-4.458(1H，m，CH)，3.951-4.010(1H，m，CH)，3.852-3.875(1H，m，CH)，3.722-3.745(9H，s，3CH
3)，3.201-3.221(1H，m，CH)，2.332-2.356(2H，m，CH
2)，2.562-2.658(8H，m，4CH
2)，2.302(3H，s，CH
3)；
MS：437(M-1)，424，341，328，236，122。
The structure of gained target compound is:
Embodiment 12 6, and 7, the preparation of 8-trimethoxy-phenylformic acid-14-O-methoxy phenoxy group-β-C-glycoside-delta-lactone
With 0.5 gram (0.001 mole) 6,7,8-trimethoxy-phenylformic acid-14-bromo-β-C-glycoside-delta-lactone (embodiment 10 products), 0.25 gram (0.002 mole) hydroxyanisole, 2 gram yellow soda ash are dissolved in 10 milliliters of pyridines, back flow reaction 10 hours, pour in the water, ethyl acetate extraction is separated organic layer, dry, filter, concentrate, column chromatography gets product, yield 50%, fusing point 185-188 ℃.
Ultimate analysis: C:59.68 (calculated value 59.74), H:5.75 (calculated value 5.67);
1H NMR(400MHz)(DMSO)：6.752(1H，s，ph-H)，6.725-6.778(4H，m，ph-H)，5.325-5.415(1H，m，CH)，4.451-4.458(1H，m，CH)，3.951-4.010(1H，m，CH)，3.892-3.925(1H，m，CH)，3.722-3.745(12H，s，4CH
3)，3.523-3.626(2H，m，CH
2)，3.201-3.221(1H，m，CH)；
MS：463(M+1)，433，358，325，296，205，122。
The structure of gained target compound is:
The Bergeninum compounds that embodiment 13 obtains with above-mentioned each example is the preparation of the oral tablet of effective medicinal ingredients
With any and Microcrystalline Cellulose in above-mentioned each the routine Bergeninum compounds of powdered and starch with weight ratio 0.01: (1.6-2): (0.5-1.4) mix, cross the 60-80 mesh sieve, tablet processing mode routinely adds an amount of ethanol, mixture is made softwood, cross 22 mesh sieves, make particle, add again and account for the dry starch of film-making particle weight 3-4% and the talcum powder of 1-2%, mix, on tabletting machine, be pressed into tablet, the bag film-coat is made the every tablet form oral preparations that to contain corresponding Bergeninum compounds effective constituent be 100mg.Usage and consumption: oral, one time 1,3 times on the one.
The Bergeninum compounds that embodiment 14 obtains with above-mentioned each example is the preparation of the injection of effective medicinal ingredients
Get the water for injection of cumulative volume 50% and put dense joining in the cylinder, the 0.025% Bergeninum succsinic acid sodium salt that adds cumulative volume is as effective medicinal ingredients, be heated to about 70 ℃ of stirrings and make it dissolving and mixing, the usual manner of pressing the injection preparation adds 0.025% (w/v) needle-use activated carbon, stir, adsorbed about 15 minutes, pump pressure filtering decarbonization then, concentrated wiring liquid pumps into rare cylinder of joining, with the dense cylinder of joining of water for injection washing of recipe quantity about 10%, washing lotion pumps into rare joining in the cylinder after filtering, and adds the injection water to the full dose of writing out a prescription, stir evenly, after the coarse filtration, extremely clear and bright with the smart filter of 0.65 μ m millipore filtration again, carry out the inspection of semifinished product, the pH value is 4～9, after content was qualified, embedding was in ampoule, 115 ℃ of following heat sterilizations 30 minutes, after the assay was approved, obtain every milliliter of vein or intramuscular injection type preparation that to contain above-mentioned Bergeninum compounds active drug component cpd be 20mg.Usage and consumption: quiet notes or intramuscular administration, a 20mg, once-a-day.
Claims (10)
1. have the active Bergeninum compounds of kobadrin, structure is suc as formula shown in (I):
R in the formula
1Be ester structure, ether structure or alkyl structure, ester structure wherein is benzoic ether, laurate or corresponding substituted cinnamic acid ester, 3,4-dimethoxyphenylacetic acid ester, anisic acid ester, 3-chloro-cinnamic acid ester, 2, the aromatic esters of 4-dimethyl laurate form, or ester with acid correspondence of physiologically active; Ether structure be aromatic oxide or with the corresponding ether that alcohol or phenol became with physiologically active; Alkyl structure is piperazine and the derivative thereof that connects with alkyl bond; R
2Be H or methyl.
2. as claimed in claim 1 have an active Bergeninum compounds of kobadrin, it is characterized in that the said corresponding ester of acid with physiologically active is a kind of in ferulic acid ester, acetylsalicylate, monomester succinate or its sodium salt, phosphoric acid ester or its sodium salt, the amino acid ester.
3. as claimed in claim 1 have an active Bergeninum compounds of kobadrin, it is characterized in that said aromatic oxide is a kind of in methyl-phenoxide, phenyl ethyl ether, 4-anisole methyl ether, the 2,4 dichloro benzene ether.
4. as claimed in claim 1 have an active Bergeninum compounds of kobadrin, it is characterized in that the said ether corresponding with alcohol with physiologically active or phenol is root bark of tree peony phenolic ether, pockwood phenolic ether.
5. as claimed in claim 1 have an active Bergeninum compounds of kobadrin, it is characterized in that said alkyl structure is piperazine or its alkyl derivative.
6. as claimed in claim 1 have an active Bergeninum compounds of kobadrin, it is characterized in that said piperazine alkyl derivative is a kind of in methylpiperazine, ethyl piperazidine, styracin piperazine, the butyl piperazine.
7. have an active Bergeninum compounds of kobadrin as one of claim 1 to 6 is described, it is characterized in that said R
1A kind of in acetylsalicylate, monomester succinate and sodium salt, phosphoric acid ester and sodium salt, pockwood phenolic ether, piperazine or the bridged piperazine derivatives.
8. have the active pharmaceutical composition of kobadrin, it is characterized in that the compound with formula (I) structure is the active drug composition, form jointly with acceptable other composition of pharmacy.
9. as claimed in claim 8 have an active pharmaceutical composition of kobadrin, it is characterized in that medicine is the oral type preparation.
10. as claimed in claim 8 have an active pharmaceutical composition of kobadrin, it is characterized in that medicine is the injection-type preparation.
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| CN1318425C (en) * | 2005-07-21 | 2007-05-30 | 四川滇虹医药开发有限公司 | Cough and phlegm removing purple bergenia element analog and its pharmaceutical composition |
| CN104725393B (en) * | 2015-02-02 | 2017-02-22 | 新乡医学院 | Bergenin derivative as well as preparation method and application thereof |
| CN106432259B (en) * | 2016-07-28 | 2018-12-04 | 广州科技职业技术学院 | A kind of Bergenin analog derivative and its synthetic method and application |
| CN106632379B (en) * | 2016-12-31 | 2019-06-04 | 西安泰科迈医药科技股份有限公司 | A kind of Bergenin azepine cinnamate derivative compound and its synthetic method having anti-tumor activity |
| CN108314689B (en) * | 2018-05-03 | 2021-03-26 | 安阳工学院 | Synthesis method of 4, 11-diacyl bergenin derivative |
| CN108997379B (en) * | 2018-06-22 | 2021-02-12 | 陕西科技大学 | Sulfur-containing bergenin derivative with antioxidant activity and synthesis method thereof |
| CN109718233A (en) * | 2019-02-28 | 2019-05-07 | 天津国际生物医药联合研究院 | Bergenin is in preparation for treating the application in pulmonary fibrosis disease drug |
| CN111171042B (en) * | 2020-01-15 | 2021-05-28 | 中国科学院西北高原生物研究所 | Separation preparation process and application of natural free radical scavenger in saxifrage |
| CN113214262B (en) * | 2020-02-05 | 2023-07-07 | 华创合成制药股份有限公司 | Compound containing guanidine group, and preparation method and application thereof |
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