CN100509840C - Tubeimuside and bile acid derivative and their medicine composition - Google Patents
Tubeimuside and bile acid derivative and their medicine composition Download PDFInfo
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- CN100509840C CN100509840C CNB2006100190270A CN200610019027A CN100509840C CN 100509840 C CN100509840 C CN 100509840C CN B2006100190270 A CNB2006100190270 A CN B2006100190270A CN 200610019027 A CN200610019027 A CN 200610019027A CN 100509840 C CN100509840 C CN 100509840C
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- acid
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Abstract
This invention relates to organic salt formed by verticinone and bile acid( cholic acid, deoxycholic acid, chenodeoxycholic acid, hyodesoxycholic acid and ursodesoxycholic acid and so on), as well as esters ramification synthesizd by above raw materials, and medicine combination combined by verticinone and one kind bile acid of aboves.
Description
Technical field
The present invention relates to medicinal compound, particularly verticinone and bile acide, and they preparation antibechic, eliminate the phlegm and suppressing panting calming medicine aspect application.
Background technology
Cough is a kind of common disease, frequently-occurring disease, and it is a kind of defensive reflex mechanism of body, can remove the secretory product or the foreign matter of respiratory tract by cough.The common cause that causes cough has: respiratory tract acute and chronic infection, respiratory tract foreign body suck, respiratory tract is subjected to oppression as the bronchial lymph nodes enlargement etc.At present, though antitussive medicine developed have a variety of, the generation effect but these medicines generally all pass through neural inhibition, has bigger side effect, use as the morphine compounds can cause habituation, respiration inhibition and constipation, and Dextromethorphane Hbr can bring out psychotic symptoms such as illusion, vain hope.Often many phlegm of cough that cause because of flu or acute/chronic bronchitis, bronchial asthma in addition, if simple use antitussive medicine though cough can alleviate to some extent, is discharged because of sputum and is obstructed, and sputum is except that a large amount of breedings that help bacterium, also may contain and shrink bronchial material, may cause bronchospasm and allergic asthma, cough can be delayed incessantly on the contrary like this, state of an illness aggravation, therefore for this class cough, in antibechic, must reduce phlegm.This just needs research and development toxic side effect little and effectively antibechic, the medicine that eliminates the phlegm and relieving asthma.
Summary of the invention
With respect to the simple antitussive effect of numerous antibechic Western medicine, the effect that Chinese medicine compound prescription possesses antibechic simultaneously mostly, eliminates the phlegm and relieving asthma, and also toxic side effect is less, has special advantages, as snake gall bulb of fritillary class compound preparation.But such compound preparation directly is used as medicine with crude drug on market or only at present, or is used as medicine with the crude extract of medicinal material, is difficult to solve the aspect problem such as thick, big, black of traditional compound preparation, and the patient uses quite inconvenience, and it is also very big to enter the world market difficulty.The inventor considers that the two flavor Chinese medicines of forming such compound preparation have its singularity, as the various bile acides in the bile is that the main effective constituent of the organic acid bulb of fritillary is then for alkaloid, and do not find at present to generate derivative or with the report of certain proportion combination patent medicine, the inventor has carried out such compound preparation basic substance Study of Interaction thus by this two effective constituents reaction.Further pharmacological research is found the salt by the effective constituent reaction generation separately of two flavor Chinese medicines, original relatively single effective constituent demonstrates the function of attenuation synergistic, synthetic route simple and have certain water-soluble, thereby can replace that such compound preparation becomes that activeconstituents is clear, determined curative effect and quality controllable novel drugs.
Purpose of the present invention is intended to overcome existing bigger shortcoming and the thick black difficulty of traditional Chinese medicine compound preparation of antibechic Western medicine toxic side effect and obtains defectives such as international endorsement, provides one or more to derive from having antibechic concurrently, eliminating the phlegm and the novel cpd or the medicinal compositions of antiasthmatic effect of Chinese medicine.
Technical solution of the present invention is as follows: with verticinone and any one bile acide is raw material, utilizes the acid-basicity of two class materials and the singularity of two class material side chain substituents, carries out organic salt derivative and ester derivative that building-up reactions obtains.
The verticinone structural formula is:
Molecular formula: C
27H
43NO
3, being the crystallization of colourless fine hair shape, m.p.212 ℃-214 ℃, the N atom is its basic center.
The structure of each bile acide is seen following general formula, and the difference of different bile acides is not the same at 6,7 or 12 bit substituents only.-COOH group is the acid sites of each bile acide.
Each substituting group of cholic acid is respectively: R
1=H; R
2=OH; R
3=OH; Molecular formula is: C
24H
40O
5Be the white powder crystallization, m.p.178 ℃-182 ℃.
Each substituting group of Deoxycholic Acid is respectively: R
1=H; R
2=H; R
3=OH; Molecular formula is: C
24H
40O
4, be the white powder crystallization, m.p.110 ℃-113 ℃.
Each substituting group of Chenodiol is respectively: R
1=H; R
2=OH; R
3=H; Molecular formula is: C
24H
40O
4, be the white powder crystallization, m.p.144 ℃-146 ℃.
Each substituting group of Hyodeoxycholic Acid is respectively: R
1=OH; R
2=H; R
3=H; Molecular formula is: C
24H
40O
4, be the white powder crystallization, m.p.168 ℃-170 ℃.
The structural formula of ursodesoxycholic acid is as follows;
The molecular formula of ursodesoxycholic acid is C
24H
40O
4, be the white powder crystallization, m.p.185 ℃-189 ℃.
The present invention includes the basic center utilized in the verticinone structure and the acid sites in cholic acid, Deoxycholic Acid, Chenodiol, Hyodeoxycholic Acid or the ursodesoxycholic acid structure, it is reacted in inert solvent such as THF generate weak acid and weak base salt.This organic salt not only has more good antibechic, eliminates the phlegm and antiasthmatic effect with respect to bulk drug verticinone and bile acide, and also has certain water-solublely because of it, is convenient to make various formulations.
The present invention also comprises the ester derivative that the hydroxyl that utilizes in the verticinone structure and the carboxyl reaction in cholic acid, Deoxycholic Acid, Chenodiol, Hyodeoxycholic Acid or the ursodesoxycholic acid structure generate, and these ester derivatives antibechic, eliminate the phlegm and relieving asthma aspect effectiveness.
In addition, the present invention also comprises one or more pharmaceutical compositions that combine with certain proportion in verticinone and the bile acide, and these pharmaceutical compositions antibechic, eliminate the phlegm and relieving asthma aspect application.
The active organic salt that has antibechic, eliminates the phlegm and relieving asthma provided by the invention is characterized in that it is to utilize the basic center of verticinone and the acid sites of bile acide to react the salt that forms, and its general structure is as follows:
When being the verticinone cholate, its substituent R
1Be α hydrogen; R
2It is the α hydroxyl; R
3It is the α hydroxyl;
When being the verticinone deoxycholate, its substituent R
1Be α hydrogen; R
2Be α hydrogen; R
3It is the α hydroxyl;
When being the verticinone CDC, its substituent R
1Be α hydrogen; R
2It is the α hydroxyl; R
3Be α hydrogen;
When being verticinone Hyodeoxycholic Acid salt, its substituent R
1It is the α hydroxyl; R
2Be α hydrogen; R
3Be α hydrogen;
When being verticinone ursodeoxycholic hydrochlorate, its substituent R
1Be α hydrogen; R
2It is the β hydroxyl; R
3Be α hydrogen.
The ester that is formed by the reaction of verticinone and bile acide provided by the invention is characterized in that utilizing 3 hydroxyls in the verticinone structure and the carboxyl in the bile acide to react the ester that forms, and general structure is as follows:
When being the verticinone cholate, its substituent R
1Be α hydrogen; R
2It is the α hydroxyl; R
3It is the α hydroxyl;
When being verticinone Deoxycholic Acid ester, its substituent R
1Be α hydrogen; R
2Be α hydrogen; R
3It is the α hydroxyl;
When being the verticinone chenodeoxycholic acid ester, its substituent R
1Be α hydrogen; R
2It is the α hydroxyl; R
3Be α hydrogen;
When being verticinone Hyodeoxycholic Acid ester, its substituent R
1It is the α hydroxyl; R
2Be α hydrogen; R
3Be α hydrogen;
When being verticinone ursodeoxycholic acid esters, its substituent R
1Be α hydrogen; R
2It is the β hydroxyl; R
3Be α hydrogen.
Antibechic provided by the invention, eliminate the phlegm, the suppressing panting calming medicine composition, be to be formed by verticinone and the bile acide mixed by weight 2:1 to 1:2, described bile acide is that cholic acid, Deoxycholic Acid, Chenodiol, Hyodeoxycholic Acid are or/and ursodesoxycholic acid.
Description of drawings
Fig. 1 represents the antibechic effect of verticinone cholate (being called for short CA salt), verticinone CDC (being called for short CDCA salt), verticinone cholate (being called for short the CA ester) and verticinone cholic acid composition (abbreviation composition) gastric infusion, positive control drug is that codeine phosphate (is irritated stomach, 10mg/kg), but the antibechic effect all represent to cough rate (%).
The height (4.5mg/kg) of Fig. 1-1 expression two salt, in (3mg/kg), the different antibechic effect of low (2mg/kg) three dosage.With negative control * P＜0.05, * * P＜0.01.
Fig. 1-2 is the amount effect relation curve of CA salt and CDCA salt.
Under Fig. 1-3 expression Isodose (dosage is 2mg/kg), verticinone cholate, verticinone CDC, verticinone cholate and verticinone cholic acid composition and the comparison of raw material gastric infusion antitussive effect size separately.The antitussive effect of three kinds of raw materials with verticinone for the strongest, the antibechic effect of CA salt, CDCA salt, CA ester and composition is all strong than verticinone, all have significant difference,, and wherein be better than ester and composition with the antibechic effect of two salt with verticinone * P＜0.05 relatively.
Fig. 2 represents the expectorant activity of verticinone cholate, verticinone CDC, verticinone cholate and verticinone cholic acid composition gastric infusion, and the positive control medicine is that guaiacol glycerol ether (is irritated stomach, 200mg/kg).Dosage is 2.5mg/kg, with negative control * P＜0.05, and * * P＜0.01.Show also among the figure that the verticinone cholate demonstrates the expectorant activity stronger than verticinone.
Fig. 3 represents the antiasthmatic activity of verticinone cholate, verticinone CDC, verticinone cholate and verticinone cholic acid composition gastric infusion, and positive control is that aminophylline (is irritated stomach, 125mg/kg).Dosage is 4mg/kg, with negative control * P＜0.05, and * * P＜0.01.Show among the figure that wherein CA salt, CDCA salt will demonstrate the antiasthmatic activity stronger than verticinone.
Embodiment
Following examples are intended to further specify the present invention, scope of the present invention are not limited.
The monomeric separation preparation of embodiment 1 verticinone
With Hupeh Fritillary Bulb in 60 ℃ of baking ovens after dry 12 hours, pulverized 10 order medicines sieve the Hupeh Fritillary Bulb medicinal powder, the Hupeh Fritillary Bulb medicinal powder is extracted for several times with the aqueous ethanol thermal backflow, filter, collect and also merge ethanol extract, reclaim ethanol and get concentrated solution; Concentrated solution fully stirs with after an amount of 2% aqueous hydrochloric acid and diatomite mix, and filters, and collects filtrate and residue.Residue continues to filter with a certain amount of 2% aqueous hydrochloric acid washing for several times, collects filtrate; Merge above filtrate, filtrate is alkalized to certain pH value with 5%NaOH, adopts the macroporous adsorbent resin separation and purification, comprising steps such as washing removal of impurities, low-concentration ethanol removal of impurities and high concentration ethanol wash-outs, collects the high concentration ethanol elutriant; The high concentration ethanol elutriant gets fluid extract behind decompression recycling ethanol, place 40 ℃ of vacuum drying ovens can obtain flaxen Hupeh Fritillary Bulb total alkaloids finished product after a few hours fluid extract; Again with silica gel H post on the Hupeh Fritillary Bulb total alkaloids, after carrying out gradient elution and carry out recrystallization with sherwood oil and ethyl acetate with ethyl acetate, white needle, be accredited as the verticinone monomer through TLC, reference substance is provided by this teaching and research room.
The preparation of embodiment 2 verticinone cholates
The structural formula of verticinone cholate is as follows:
The preparation method of verticinone cholate is: moles such as verticinone and cholic acid are dissolved among the inert organic solvents THF, at room temperature react, stir after 12 hours, on Rotary Evaporators, reclaim solvent and vacuum-drying, the gained material filters with dissolved in distilled water and carries out purifying, removes on Rotary Evaporators and anhydrates, and obtains target compound verticinone cholate, be the white powder solid, its solubleness in distilled water can reach 1mg/ml; Fusing point: 137.3 ℃-139.2 ℃;
1H-NMR (D
2O, 400MHZ): δ 0.55 (s, 3H), δ 0.58 (s, 3H), δ 0.75 (s, 3H), δ 0.82 (d, 3H), δ 0.94 (d, 3H), δ 1.06 (s, 3H), δ 3.45-3.49 (m, 3H), δ 3.72 (s, 1H), δ 3.89 (s, 1H).
The preparation of embodiment 3 verticinone CDCs
The structural formula of verticinone CDC is as follows:
The preparation method of verticinone CDC is: moles such as verticinone and Chenodiol are dissolved among the inert organic solvents THF, at room temperature react, stir after 12 hours, on Rotary Evaporators, reclaim solvent and vacuum-drying, the gained material filters with dissolved in distilled water and carries out purifying, removes on Rotary Evaporators and anhydrates, and obtains target compound verticinone CDC, be the white powder solid, it is slightly soluble in distilled water; Fusing point: 132.0 ℃-134.5 ℃.
The preparation of embodiment 4 verticinone cholates
The structural formula of verticinone cholate is as follows:
The preparation method of verticinone cholate is: add DMF (dimethyl formamide) in the dry round-bottomed flask of band magnetic agitation and reflux, moles such as verticinone and cholic acid are dissolved in wherein, stirring and dissolving is to the solution becomes clarification, add equimolar DCC (carbodiimide) and a spot of DMAP (Dimethylamino pyridine) again, ice bath to 4 ℃, stir after 2 hours, followed the tracks of and continue under the room temperature stirring reaction 48 hours with TLC, filter the white precipitate of generation, use dissolve with methanol behind the filtrate evaporate to dryness, on the silica gel H post, carry out gradient elution, obtain newly-generated material, to its recrystallization, getting highly finished product is the white needle that aggregates into the chrysanthemum shape with dehydrated alcohol, promptly make target product verticinone cholate, yield is 19%; Fusing point: 125.6 ℃-128.4 ℃;
1H-NMR (CDCL
3, 400MHZ): δ 0.64 (s, 3H), δ 0.85 (s, 3H), δ 0.9-0.95 (d, 3H), δ 1.19 (s, 3H), δ 1.21 (s, 3H), δ 1.23 (s, 3H), δ 3.63 (s, 1H), and δ 3.65 (s, 1H), δ 3.81 (s, 1H), δ 3.93 (s, 1H); Mass m/z (FAB): 820 (M+1).
The mensuration of embodiment 5 verticinone cholates, verticinone CDC, verticinone cholate and verticinone cholic acid composition (weight ratio of verticinone and cholic acid is 2:1 to 1:2) antitussive activity
Adopt the spraying of cavy Citric Acid to draw the method for coughing, with the single synthetic glass chamber that places sealed transparent of cavy (in 16cm * 16cm * 16cm), use 402AI type ultrasonic nebulizer, spray into 17.5% Citric Acid with constant speed, spray time is 1min, and the cough number of times of the interior cavy of record 5min also carries out preliminary election, the cough of cavy is clear loud, to hear the counting of sound, the cough number of times is less than person's reject 10 times, filters out qualified cavy.
Qualified cavy through 24 hours recovery after, random packet, six every group, draw and cough preceding 1 hour gastric infusion: the high, normal, basic dosage of two salt is respectively 4.5mg/kg, 3mg/kg and 2mg/kg; The dosage of cholate, composition and bulk drug verticinone, cholic acid and Chenodiol is the relatively variation of administration front and back guinea pig cough's number of times C of 2mg/kg., but the antibechic effect is to cough rate=((C
Before the administration-C
After the administration)/C
Before the administration) * 100% is represented.
The result shows: 1, when the Isodose gastric infusion, CDCA salt, CA salt, CA ester, composition and the remarkable antitussive effect of the equal tool of bulk drug verticinone are referring to accompanying drawing 1-1 and accompanying drawing 1-3.The antibechic effect of CA and CDCA two raw materials is then not obvious.2, under the Isodose, CDCA salt, CA salt, CA ester and composition and bulk drug verticinone relatively all demonstrate the antibechic effect stronger than verticinone, referring to accompanying drawing 1-3.Wherein be better than CA ester and composition with the effect of CDCA salt, CA salt again
The mensuration of embodiment 6 verticinone cholates, verticinone CDC, verticinone cholate and verticinone cholic acid composition (weight ratio of verticinone and cholic acid is 2:1 to 1:2) and verticinone expectorant activity
Adopt the phenol red method of mouse of improvement, select the male mice in kunming of 22 ± 2 grams for use, random packet, every group 10, water 12h is can't help in fasting before the experiment, behind the gastric infusion 30 minutes, inject 5% phenol red normal saline solution with the dosage of 500mg/kg to mouse peritoneal again, put to death mouse after 30 minutes, do not damage tracheae as far as possible, face upward the position and be fixed on the operation plate, cut off neck center skin, separate tracheae, reject the tracheae surrounding tissue carefully, the clip thyroid cartilage behind the taking-up tracheae, is put into the test tube that fills physiological saline 2.00ml to the tracheae section of tracheae crotch then, shook 30 minutes, the NaOH solution that adds the 1mol/L of 0.20ml with 4000 rev/mins rotating speed centrifugal 30 minutes, is drawn centrifugate is measured each elutant in 558nm wavelength place absorbancy, according to phenol red typical curve, calculate phenol red excretion amount, draw the expectorant activity of each compound thus, referring to accompanying drawing 2.
The result shows: 1, verticinone cholate, verticinone CDC, verticinone cholate and verticinone cholic acid composition (weight ratio of verticinone and cholic acid is 2:1 to 1:2) and verticinone all demonstrate certain expectorant activity, and wherein with the verticinone cholate for the strongest.2, can find out that from accompanying drawing 2 the verticinone cholate demonstrates the expectorant activity of being eager to excel than verticinone.
The mensuration of embodiment 7 verticinone cholates, verticinone CDC, verticinone cholate and verticinone cholic acid composition (weight ratio of verticinone and cholic acid is 2:1 to 1:2) and verticinone antiasthmatic activity
Get the cavy of 150-200 gram, male and female are regardless of, and measure to draw one by one and breathe heavily latent period, select eligible.Cavy is put into 402 type ultrasonic atomizatio instrument, spray into the equivalent mixed liquor 15 seconds of 2% Ovisot and 0.1% histamine phosphate with constant rate of speed, observe promptly to draw in latent period that the tic of panting property appears in cavy within 6 minutes and breathe heavily latent period, as see that cavy falls immediately with its taking-up, in order to avoid dead.And record draws and breathes heavily latent period, draws to breathe heavily and then thinks defective greater than 120 seconds latent period and will not select for use.Next day, 8 every group, it is an amount of that precision takes by weighing each sample, is configured to 10ml solution with qualified cavy random packet, and cavy gastric infusion, dosage are 4mg/kg, and administration is after 1 hour, draws with similarity condition and breathe heavily and measure to draw and breathe heavily latent period.Relatively draw before and after the administration and breathe heavily preclinical variation, observe the antiasthmatic activity of each sample, referring to accompanying drawing 3.
The result shows: 1, five samples all demonstrate certain antiasthmatic activity, wherein with the verticinone cholate for the strongest, under low tens times than aminophylline dosage, the two effect of relievining asthma is similar, with feminine gender P＜0.01 relatively; 2, can find out also that by accompanying drawing 3 antiasthmatic activity with two salt is eager to excel in whatever one does than verticinone in these samples.
The LD of embodiment 8 verticinone cholates, verticinone CDC, verticinone cholate and verticinone
50Mensuration
Get 50 of body weight 20 ± 2g healthy mices, be divided into 5 groups at random, 10 every group, male and female half and half.Mouse was fed three in 25 ℃ of environment, and it is fully adapted to, and began experiment on 4th, and water 12h is can't help in the mouse fasting before the experiment, the toxicity symptom behind the disposable gastric infusion of observation mouse, and death time and mortality calculate LD with the Bliss method
50And 95% fiducial limit.
Record verticinone cholate LD
50=16.2706mg/kg, 95% the credible 15.0882mg/kg～17.5457mg/kg that is limited to; Verticinone CDC LD
50=18.4166mg/kg, 95% the credible 11.0767mg/kg～30.6202mg/kg that is limited to; Verticinone cholate LD
50=10.2567mg/kg, 95% the credible 9.0176mg/kg～11.3207mg/kg that is limited to; And bulk drug verticinone LD
50=5.2208mg/kg, 95% the credible 4.5251mg/kg～6.0234mg/kg that is limited to, show that by the acute toxicity result verticinone is with the bile acide salify or after becoming ester, toxicity significantly reduces, especially the salt that is become, toxicity only is 1/3 of verticinone, in conjunction with the embodiments 5 and the experimental result of embodiment 8, two embodiment explanation verticinone with the bile acide salify or the derivative after becoming ester antibechic, eliminate the phlegm and relieving asthma aspect the effect of tool efficacy enhancing and toxicity reducing.
Claims (4)
1. have with the following formula (I) or (II) salt of structure
In the formula (II):
R
1＝H R
2＝OH R
3＝OH；
Or
R
1＝H R
2＝H R
3＝OH；
Or
R
1＝H R
2＝OH R
3＝H；
Or
R
1＝OH R
2＝H R
3＝H。
2, the application of the described salt of claim 1 in the preparation antitussive medicine.
3, the application of the described salt of claim 1 in the preparation expelling phlegm drugs.
4, the application of the described salt of claim 1 in the preparation suppressing panting calming medicine.
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| CN101643493B (en) * | 2008-08-07 | 2012-07-11 | 华中科技大学 | Peininine bile acid ester, method for preparing same and application thereof |
| CN102342946B (en) * | 2011-07-20 | 2013-06-05 | 华中农业大学 | Application of bile acid peiminine ester and its derivative in preparation of antitumor medicines |
| JP6917144B2 (en) | 2014-07-29 | 2021-08-11 | シンセン ハイタイド バイオファーマシューティカル リミテッド | Berberine salt, ursodeoxycholic acid salt and combination, preparation and application method thereof |
| CN105061331A (en) * | 2015-09-21 | 2015-11-18 | 董瑞兰 | Pharmaceutical composition for eliminating phlegm for children |
| CN115420825B (en) * | 2022-08-31 | 2023-12-22 | 北京大学第三医院（北京大学第三临床医学院） | Method for detecting bile acid and bile acid derivative |
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Non-Patent Citations (2)
| Title |
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| 湖北贝母生物碱单体的镇咳、祛痰和平喘作用. 张勇慧等.中草药，第36卷第8期. 2005 |
| 湖北贝母生物碱单体的镇咳、祛痰和平喘作用. 张勇慧等.中草药，第36卷第8期. 2005 * |
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