CN103641841A - Sesquiterpene lactone compounds as well as preparation method and application thereof - Google Patents
Sesquiterpene lactone compounds as well as preparation method and application thereof Download PDFInfo
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- CN103641841A CN103641841A CN201310674639.3A CN201310674639A CN103641841A CN 103641841 A CN103641841 A CN 103641841A CN 201310674639 A CN201310674639 A CN 201310674639A CN 103641841 A CN103641841 A CN 103641841A
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种倍半萜内酯类化合物及其制备方法和应用，所述化合物具有结构式（I）或（II）所示的结构：
The present invention provides a sesquiterpene lactone compound and its preparation method and application. The compound has the structure shown in structural formula (I) or (II):
Description
Technical field
The present invention relates to a kind of sesquiterpene lactones compounds, relate in particular to and a kind ofly can be used in treatment, prevent cachectic sesquiterpene lactones compounds, and its preparation method and application
Background technology
Emaciation is to take many organs syndrome that weight loss, amyotrophy and fatty tissue consumption is feature, often occur together in various chronic diseases, as tumour, tuberculosis, diabetes, chronic obstructive pulmonary disease, chronic kidney disease, heart failure, communicable disease and acquired immune deficiency syndrome, its carrying out property loses weight and muscle tissue atrophy can not be reversed by conventional nutritional support, causes progressive body function obstacle; Clinical manifestation is apocleisis, lose weight, anaemia and amyotrophy, and these cause Quality of Life of Patients decline and significantly shorten lifetime, and have intervened the normal therapeutic program of disease.Epidemiology survey shows emaciation, and in tumour colony, sickness rate is more than 40%, and wherein the solid tumor sickness rate such as gastroenteric tumor, mammary cancer, lung cancer, prostate cancer, carcinoma of the pancreas is higher, and late incidence is even up to 80%; In acquired immunity syndrome patient, sickness rate approximately 35%, Patients with Chronic Obstructive Pulmonary Disease sickness rate approximately 20%, patients with renal failure sickness rate 40%, arthritic's sickness rate approximately 10%, patients with heart failure sickness rate approximately 20%.The sickness rate that emaciation is high and lethality rate receive much concern its clinical treatment drug research.
At present research shows that tumour emaciation genesis mechanism illustrates not yet completely, it is generally acknowledged that cachectic generation is relevant to patient's energy insufficiency of intake, consumption increase, intermediary metabolism disorder, cytokine increase etc., there is theory and mainly contain cytokine theory, muscle mass theory, protein ubiquitination degradation theory, fat acid decomposition theory etc. in it, patient's sense of taste changes, appetite reduces, hypothalamic function is bad, the machine-processed easily apocleisis such as abnormal of appetite stimulator, causes energy insufficiency of intake.Patient is in the chronic wasting disease evolutions such as tumour simultaneously, a large amount of glucose is degraded with glycolysis-form, lactic acid increases, and the susceptibility decline of tumour patient Regular Insulin beta cell receptor to glucose, and so vicious cycle causes the poor efficiency utilization of a large amount of energy expenditures and glucose; The transformation efficiency of glycerine and lipid acid increases, and the body of becoming thin can not be oxidized endogenous lipid acid or blood fat with usual dispatch, when glucose infusion, can not suppress fatty decomposition; Protein in body synthesis rate declines, and proteolysis increases, and causes rest energy expenditure to increase.The intermediate material that simultaneously metabolism disorder produces causes patient physiological function to be affected as lactic acid etc.The immunomodulatory of the early stage participation such as cytokine TNF-a, IL-1, IL-6, INF-r body to tumour cell, but the progress along with the tumour course of disease, these substances produce significant appetite inhibiting effect, cause the uncomfortable reaction of serious body, and TNF-a, INF-r etc. and albumen, steatolysis are relevant, it can suppress lipoprotein lipase activity, activates the protein catabolism approach such as Ubiquitin-proteasome path and causes proteolysis, causes the decomposition of muscle and fatty tissue.
In emaciation, conventionally take nutrition treatment and endocrinotherapy, but it can not effectively reverse amyotrophy and weight loss in emaciation process, especially when emaciation is caused by malignant tumour, emaciation is the contraindication of a lot of chemotherapeutics, consequently can make treatment seriously be obstructed, and can worsen malignant tumour on the contrary for alleviating the nutrition treatment arbitrarily of emaciation symptom, (the Murphy KT that likely shortens patient's life-span, Lynch GS.Update on emerging drugs for cancer cachexia.Expert Opin Emerg Drugs.2009, 14 (4): 619-32).And enter, clinical treatment emaciation medicine---progestogen is as megestrol and medroxyprogesterone; although can effective stimulus appetite and putting on weight; but its effect is main, increases fat mass and liquid hold-up rather than preserve body mytolin (Berenstein EG, Ortiz Z.Megestrol acetate for the treatment of anorexia-cachexia syndrome.Cochrane Database Syst Rev.2005.18; (2): CD004310.).
Therefore a kind of alternative prevention need to be provided, alleviate and/or treat cachectic method and medicine, particularly at least in some aspects than the better method of prior art known treatment methods and medicine.
Summary of the invention
For the cachectic method of the good treatment of current shortage and medicine, the application provides a kind of sesquiterpene lactones compounds and the application in treatment emaciation medicine thereof.
First aspect of the present invention is to provide a kind of sesquiterpene lactones compounds, described compound have structural formula (I) or (II) shown in structure:
Wherein:
R
1be selected from substituting group, the NR of H, C1-C22
11r
12, wherein, R
11, R
12respectively independently selected from H and the group that can eliminate at people or Mammals internal metabolism;
R
1' be selected from substituting group, the NR of C1-C22
11', wherein, R
11' group that is selected from H and can eliminates at people or Mammals internal metabolism;
R
2and R
3respectively independently selected from the substituting group of H, halogen, C1-C22.
Wherein, the substituting group of described C1-C22 is selected from branching or straight chain or ring-type, saturated or undersaturated aliphatic group, aryl radical, aliphatic group substituted aroma alkyl, aryl radical substituted fatty hydrocarbon base, main chain containing containing heteroatomic carbocyclic ring on heteroatomic carbochain, ring skeleton.
Described heteroatoms can be to be selected from any one or a few in N, O, S, P, B.
Described heteroatomic quantity can be 1-3, more preferably 1-2.
More preferably, the substituting group that the substituting group of described C1-C22 is C1-C15, the more preferably substituting group of C1-C12.
The substituting group of described C1-C22 can be to be selected from any one or a few in alkyl, aromatic base substituted alkyl, aromatic base, alky-substituted aromatic base, alkoxyalkyl, phenoxyalkyl, alkyl substituted benzene oxygen base alkyl, alkyl amino alkyl.
In foregoing of the present invention, the substituting group of C1-C22 can be: methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, positive decyl, methoxyl group, oxyethyl group, methoxymethyl, methoxy ethyl, ethoxyl methyl, ethoxyethyl group, phenoxymethyl, phenyl, benzyl, styroyl, aminomethyl phenyl, furyl, pyridyl, pyrryl, pyranyl, pyrazinyl, thienyl, indyl, quinolyl, imidazolyl, piperidyl, carbazyl, purine radicals, thiazolyl, pyrimidyl, oxazolyl, benzofuryl, benzothiazolyl, cyclopropyl, cyclopentyl, cyclohexyl, fluorenyl, azepine fluorenyl etc.
In foregoing of the present invention, described halogen atom can be any one in Cl, Br, I, F, more preferably any one in Cl, Br, I, more preferably any one in Cl, Br, more preferably Cl.
In foregoing of the present invention, described " group that can eliminate at people or Mammals internal metabolism " can be to be selected from: any one or a few in triazole and derivative thereof.As phenyl substituted 1,2,4-triazole, benzotriazole, amino substituted 1,2,4-triazole etc.
Second aspect of the present invention is to provide a kind of cachectic medicine that treats and/or prevents, described medicine comprise there is structural formula (I) or (II) shown in the sesquiterpene lactones compounds, pharmacy acceptable salt, its prodrug of structure in any one or a few.
Wherein, described sesquiterpene lactones compounds can be to be selected from any one or a few in its racemic mixture and mixture of diastereomers and optical isomer.
Wherein, described medicine can be pharmaceutically acceptable any formulation, as any one or a few in solution, emulsion, suspension, lyophilisate, pill, tablet, particle, powder.
Wherein, described medicine can also be any one or a few in sustained release dosage, control-released agent, targeting preparation.
In a kind of preferred embodiment aspect second of the present invention, described medicine can also comprise that at least one can be used for treating and/or preventing cachectic extra activeconstituents.
Wherein, described extra activeconstituents can be any one or a few in Chinese medical extract, synthetic drugs, biological products.
Wherein, described extra activeconstituents can be to mix with described sesquiterpene lactones compounds, pharmacy acceptable salt or its prodrug, or separate existence.
In a kind of preferred embodiment aspect second of the present invention, described medicine can also comprise pharmaceutically acceptable auxiliary material.
Wherein, described auxiliary material can be to be selected from any one or a few in vehicle (comprise solid carrier, paste carrier, liquid solvent any one or a few), sanitas, lubricant, oxidation inhibitor, emulsifying agent, suspending agent, tackiness agent, stablizer, solubility promoter, dispersion agent, buffer reagent, pH value conditioning agent, frostproofer, correctives, disintegrating agent, weighting agent, tinting material.
Wherein, described emaciation can be any one or a few in cancer cachexia, Tuberculous emaciation, diabetic emaciation, hemopathy-relevant emaciation, endocrinopathy-relevant emaciation, chronic obstructive pulmonary disease-relevant emaciation, chronic kidney disease-relevant emaciation, heart failure-relevant emaciation, communicable disease-relevant emaciation or acquired immune deficiency syndrome-relevant emaciation.
Third aspect of the present invention is to provide a kind of preparation method of above-mentioned sesquiterpene lactones compounds.
Wherein, described preparation method comprises: with Magnoliacea plant Tsoongiodendron odorum (
tsoongiodendron odorum?
chun) stem and/or leaf be raw material, extract, obtain the sesquiterpene lactones compound of following structure:
Wherein, described extraction solvent can be any one or a few in water extraction, ethanol-extracted, supercritical carbon dioxide extraction.And be preferably ethanol-extracted.
Wherein, described alcohol can be any one or a few in methyl alcohol, ethanol, Virahol, butanols or its aqueous solution.As aqueous ethanolic solution, volumetric concentration is preferably 80-99%, more preferably 85-97%, more preferably 90-95%.
Wherein, described ethanol-extracted is preferably under reflux conditions and carries out.
Wherein, be preferably and take the bark of described Magnoliacea plant Tsoongiodendron odorum and/or leaf and extract as raw material.
In a kind of preferred embodiment of preparation method described in third aspect of the present invention, gained sesquiterpene lactones compound carries out chemically modified and obtains the sesquiterpene lactones compounds described in first aspect of the present invention.
Sesquiterpene lactones compounds provided by the present invention, can be used as cachectic medicine for the treatment of people, animal, treats the emaciation relevant to various diseases.Can effectively slow down the weight loss that skeletal muscle atrophy and fat acid decomposition atrophy cause, obviously ameliorate tumor is loaded, arrestin degraded, the level of raising cytokine TNF-a and IL-6.
Accompanying drawing explanation
Fig. 1 is the embodiment of the present invention 1 sesquiterpene lactones compounds and the intervention effect contrast of control group to emaciation animal pattern;
Fig. 2 is the intervention effect of the embodiment of the present invention 1 sesquiterpene lactones compounds to emaciation animal pattern body weight, and wherein, Fig. 2 A is body weight graphic representation over time, and Fig. 2 B is the body weight comparison diagram after 20 days;
Fig. 3 is the intervention effect contrast that the embodiment of the present invention 1 sesquiterpene lactones compounds and control group are heavy to emaciation animal pattern knurl, and wherein, Fig. 3 A is the heavy graphic representation over time of knurl, and Fig. 3 B is the heavy comparison diagram of the knurl after 20 days;
Fig. 4 is that the embodiment of the present invention 1 sesquiterpene lactones compounds promotes cytokine effect, and wherein, Fig. 4 A is the contrast of IL-6 level, and Fig. 4 B is the contrast of TNF-a level;
Fig. 5 is the embodiment of the present invention 1 sesquiterpene lactones compounds arrestin degradation effect; Wherein, Fig. 5 A is the protein expression intervention effect to myoglobulin heavy chain (MHC), and Fig. 5 B is albumen ubiquitination degeneration system E3 part MuRF1 and Atrogin-1/MAFbx(Fbx32) the intervention effect of protein expression;
In above-mentioned accompanying drawing, a represents relatively have remarkable significant difference (p≤0.05) with control group; B represents relatively have remarkable significant difference (p≤0.05) with lotus knurl emaciation.
Embodiment
embodiment 1
sesquiterpene lactones compounds in the present embodiment (being called PZ-1 in the present embodiment) molecular structure is as follows:
the synthetic method of the compounds of sesquiterpene lactones described in the present embodiment is as follows:
After 10kg Tsoongiodendron odorum leaf is dry, with the ethanol (moisture 5%) of volumetric concentration 95%, carry out refluxing extraction twice, each 2 hours, extracting solution is merged.Concentrated, remove ethanol.
Enriched material petroleum ether extraction, discards petroleum ether extraction liquid; Residue enriched material is extracted with ethyl acetate, and combined ethyl acetate extraction liquid is removed ethyl acetate, obtains Tsoongiodendron odorum lactone PZ-1.By column chromatography (chloroform/methanol mixed solvent carries out wash-out), refine again.
prevention emaciation Mouse Weight alleviates
Material: the PZ-1 that in the present embodiment prepared by separation and purification, purity >=98%, get respectively 37.57mg and 190.61mg PZ-1, add 0.5ml dimethyl sulfoxide (DMSO), be settled to again in 30ml deionized water and 50ml deionized water, the storing solution (P-L, P-H) that obtains two kinds of concentration, storing solution is kept in refrigerator, in one month, finishes using.
Animal: male balb/c mouse (20.60+0.87g) is purchased from Shanghai western pul-Bi Kai laboratory animal company, license licensed licenser licence SCXK(Shanghai) 2008-0016.According to the requirement of laboratory animal working specification, subcutaneous in animal right fore back upper place with the fragment of trochar inoculation CT26 colorectal carcinoma glandular epithelium tumour, animal ad lib and drinking-water, carry out decrement method mensuration to food-intake.
Grouping administration: after animal lotus knurl, divide into groups to give medicine and placebo treatment next day, and administering mode is abdominal injection, every injected in mice 0.2ml, and contrast with normal mouse (control group).
Result: every group of 10 animals, since the 10th day, lotus knurl treated animal body weight started to decline, and there were significant differences for the 14th day lotus knurl treated animal and intact animal body weight, and as shown in Figure 1, PZ-1 can obviously alleviate the weight loss of emaciation mouse.Table 1 is listed the impact that PZ-1 forms emaciation mouse body, and as can be seen from the table, PZ-1 slows down emaciation, and to cause weight loss be mainly by reducing skeletal muscle (gastrocnemius muscle and tibialis anterior muscle are representative) atrophy and fat acid decomposition atrophy.
Table 1, the intervention effect of PZ-1 to emaciation animal pattern
a: relatively there is remarkable significant difference (p≤0.05) with control group;
b: relatively there is remarkable significant difference (p≤0.05) with lotus knurl emaciation;
high dosage PZ-1 treatment emaciation Mouse Weight alleviates
PZ-1 is suspended in the suspension containing 1%CMC-Na, according to two dosages of height (P-H, P-L), gives balb/c mouse, and every day, abdominal injection 0.2ml, recorded Mouse Weight, knurl is long, knurl is wide and food ration.Animal is put to death in anesthesia in the 20th day, gets blood system determination of serum cytokine, core liver spleen lung nephridial tissue, tibialis anterior muscle, gastrocnemius muscle and epididymal adipose tissues weigh, and be placed in liquid nitrogen cryopreservation.
Result: with the result of embodiment 1, lotus knurl treated animal body weight declined since the 9th day, there were significant differences for the 13rd day lotus knurl treated animal and intact animal body weight, and as shown in Figure 2, PZ-1 can obviously alleviate the weight loss of emaciation mouse.Under high dosage, reduce heart, skeletal muscle (gastrocnemius muscle and tibialis anterior muscle are representative) atrophy and fat acid decomposition atrophy are more obvious.And relatively knurl is retransmitted now, PZ-1 can alleviate tumor-bearing mice tumor load significantly, as shown in Figure 3.
the anti-emaciation mouse cytokine of PZ-1 rises
High dosage PZ-1 treatment emaciation Mouse Weight alleviates after off-test, and mouse is condemned to death, and research Cytokine of Serum TNF-a and IL-6 level, the results are shown in Figure 4.
Result shows that the present embodiment compound PZ-1 has not only preserved the lean mass of animal (take gastrocnemius muscle and tibialis anterior muscle as representative) relatively, and the cytokine TNF-a that can reduce due to tumour chronic stimulation rises, under high dosage (P-H) condition, the rising of cytokine IL-6 level is also suppressed.Existing document shows, in emaciation process, lean tissue mass of collective Quality Down is mainly because the nuclear factor due to cytokine-kappaB raises, and then activates ubiquitin protein degeneration system, protein in body is decomposed and accelerate, cause negative nitrogen balance, amyotrophy and weight loss.
the atrophy of the anti-emaciation mouse muscle of PZ-1
High dosage PZ-1 treatment emaciation Mouse Weight alleviates after off-test, mouse is condemned to death, gastrocnemius muscle and tibialis anterior muscle liquid nitrogen cryopreservation, muscle tissue is done histopathological examination and Western Blot experimental study muscle form and mytolin constituent myoglobulin heavy chain (MHC) after taking out, and the expression amount of E3 ubiquitin protein introduction system part Atrogin-1/MAFbx and MuRF1.As shown in Figure 5, PZ-1 myoglobulin I Ib's experimental result that obviously the antagonism emaciation of dose-dependently causes degrades as can be seen from Figure 5, and its mechanism may be to suppress MuRF1 in ubiquitin protein degeneration system, and then arrestin degraded.
sesquiterpene lactones compounds in the present embodiment (being called PZ-2 in the present embodiment) molecular structure is as follows:
Wherein, Bn is benzyl.
the synthetic method of the compounds of sesquiterpene lactones described in the present embodiment is as follows:
R in PZ-1
3(methyl) carries out halo, then reacts with BnONa, obtains PZ-2.Reaction formula is as follows:
sesquiterpene lactones compounds in the present embodiment (being called PZ-3 in the present embodiment) molecular structure is as follows:
the synthetic method of the compounds of sesquiterpene lactones described in the present embodiment is as follows:
embodiment 4
sesquiterpene lactones compounds in the present embodiment (being called PZ-4 in the present embodiment) molecular structure is as follows:
the synthetic method of the compounds of sesquiterpene lactones described in the present embodiment is as follows:
PZ-1 Yu Geshi reagent C H
2=CH-(CH
2)
3-BrMg carries out coupling, and then shortening obtains PZ-4, and reaction formula is as follows:
sesquiterpene lactones compounds in the present embodiment (being called PZ-5 in the present embodiment)
In the present embodiment, PZ-5 is the mixture that comprises PZ-1, and preparation method is as follows:
10kg Tsoongiodendron odorum bark is pulverized, and the post-drying that is soaked in water, then under reflux conditions extracts 3 times with the ethanol of volumetric concentration 95%, and each 2 hours, united extraction liquid.Concentrated, removal ethanol.
Petroleum ether extraction enriched material, discards petroleum ether extraction liquid, and residue enriched material is extracted with ethyl acetate, combined ethyl acetate extract, the concentrated rear dry PZ-5 that obtains.In gained PZ-5, contain PZ-1, parithenolide and Tsoongiodendron odorum lactone.
Table 2, the intervention effect to emaciation animal pattern under the above embodiment of the present invention compound same dose
By table 2, can find out, the sesquiterpene lactones compounds experimental mice body weight in the above embodiment of the present invention is compared with emaciation group, can effectively suppress tumor load, and the situation that loses weight and decline, all can effectively prevent and treat emaciation.
sesquiterpene lactones compounds in the present embodiment (being called PZ-6 in the present embodiment) molecular structure is as follows:
the synthetic method of the compounds of sesquiterpene lactones described in the present embodiment is as follows:
PZ-1 reacts in methanol solution with piperidines, obtains PZ-6.
embodiment 7
sesquiterpene lactones compounds in the present embodiment (being called PZ-7 in the present embodiment) molecular structure is as follows:
the synthetic method of the compounds of sesquiterpene lactones described in the present embodiment is as follows:
PZ-1 epoxide group reduces and forms two keys, then to R
2group carries out halo, after halo with CH
3-(CH
2)
9-CHO carries out coupling, obtains PZ-7.
Above specific embodiments of the invention be have been described in detail, but it is just as example, the present invention is not restricted to specific embodiment described above.To those skilled in the art, any equivalent modifications that the present invention is carried out and alternative also all among category of the present invention.Therefore, equalization conversion and the modification done without departing from the spirit and scope of the invention, all should contain within the scope of the invention.
Claims (10)
1. a sesquiterpene lactones compounds, is characterized in that, described sesquiterpene lactones compounds have structural formula (I) or (II) shown in structure:
Wherein:
R
1be selected from substituting group, the NR of H, C1-C22
11r
12, wherein, R
11, R
12respectively independently selected from H and the group that can eliminate at people or Mammals internal metabolism;
R
1' be selected from substituting group, the NR of C1-C22
11', wherein, R
11' group that is selected from H and can eliminates at people or Mammals internal metabolism;
R
2and R
3respectively independently selected from the substituting group of H, halogen, C1-C22.
2. sesquiterpene lactones compounds according to claim 1, it is characterized in that, the substituting group of described C1-C22 is selected from branching or straight chain or ring-type, saturated or undersaturated aliphatic group, aryl radical, aliphatic group substituted aroma alkyl, aryl radical substituted fatty hydrocarbon base, main chain containing containing heteroatomic carbocyclic ring on heteroatomic carbochain, ring skeleton.
3. sesquiterpene lactones compounds according to claim 1, is characterized in that, the substituting group that the substituting group of described C1-C22 is C1-C15.
4. treat and/or prevent a cachectic medicine, it is characterized in that, comprise there is structural formula (I) or (II) shown in the sesquiterpene lactones compounds, pharmacy acceptable salt, its prodrug of structure in any one or a few:
Wherein:
R
1be selected from substituting group, the NR of H, C1-C22
11r
12, wherein, R
11, R
12respectively independently selected from H and the group that can eliminate at people or Mammals internal metabolism;
R
1' be selected from substituting group, the NR of C1-C22
11', wherein, R
11' group that is selected from H and can eliminates at people or Mammals internal metabolism;
R
2and R
3respectively independently selected from the substituting group of H, halogen, C1-C22.
5. medicine according to claim 4, is characterized in that, described sesquiterpene lactones compounds is selected from any one or a few in its racemic mixture and mixture of diastereomers and optical isomer.
6. medicine according to claim 4, is characterized in that, also comprises at least one extra activeconstituents.
7. medicine according to claim 4, is characterized in that, also comprises pharmaceutically acceptable auxiliary material.
8. a preparation method for sesquiterpene lactones compounds, is characterized in that, stem and/or the leaf of Magnoliacea plant Tsoongiodendron odorum of take is raw material, extracts, and obtains the sesquiterpene lactones compound of following structure:
9. preparation method according to claim 8, is characterized in that, described in be extracted as under reflux conditions with ethanol or aqueous ethanolic solution and extract.
10. preparation method according to claim 8, is characterized in that, also comprise to extracted sesquiterpene lactones compound carry out chemically modified with obtain structural formula (I) or (II) shown in the step of sesquiterpene lactones compounds of structure.
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