CN105273031A - Novel triterpene compound and application thereof - Google Patents
Novel triterpene compound and application thereof Download PDFInfo
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- CN105273031A CN105273031A CN201410252758.4A CN201410252758A CN105273031A CN 105273031 A CN105273031 A CN 105273031A CN 201410252758 A CN201410252758 A CN 201410252758A CN 105273031 A CN105273031 A CN 105273031A
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Abstract
The invention discloses a novel triterpene compound and application thereof to treat or prevent kidney diseases. The disclosed novel triterpene compound is capable of reducing biochemical indexes (such as content of urea nitrogen (BUN) or creatinine (CRE) in serum) related to kidney inflammation and improving glomerulus filtration rate (GFR), therefore the novel triterpene compound can be used to manufacture medicines capable of treating or preventing kidney diseases.
Description
Technical field
This disclosure relates to triterpenoid of a kind of novelty and uses thereof, and it can be used to prepare a kind of medicine in order to treat kidney disease (such as acute renal infringement and chronic kidney disease).
Background technology
Acute renal infringement (acutekidneyinjury, AKI), also known as acute renal failure (acutekidneyfailure), Zhao Yin is destroyed rapidly in kidney filtration function, accelerated accumulation in blood to cause the metabolite (as urea or creatinine) of nitrogenous substances in body, thus make the symptoms such as individual appearance is tired, appetite decline, headache, n or V, and reduce with amount of urine.AKI is prevailing in sufferer of being in hospital, particularly severe case.Cause the reason of AKI a lot, such as, after tissue ischemia re perfusion, severe injury, nephropathy or renal transplantation.But there is no clearly single-minded curable substance AKI clinically at present, the therefore supportive treatment of many employings (such as, dialysis) take mitigation symptoms as main purpose.If patient can rehabilitation from above-mentioned disease, often also can develop into long-term, Patients with Chronic Kidney Disease, need to rely on and wash kidney for a long time, the patient be in a bad way, even needs renal transplantation.
The coincident with severity degree of condition being used at present judging AKI patient and the index that whether may be in progress into CKD are glomerular filtration rate (glomerularfiltrationrate, GFR).GFR value declines often with blood urea nitrogen (bloodurinenitrogen, BUN) with serum creatinine acid (serumcreatinine, CRE) amount increases, therefore, if the combination of a compound or multiple compound effectively can improve GFR, suppress BUN and CRE, will be that potential can be used to prepares the lead compound treating or prevent kidney disease (comprise acute renal damage and chronic kidney disease) medicine simultaneously.
Summary of the invention
This disclosure is the novel triterpenoid come based on finding a kind of isolated or purifying in the sporophore or mycelium of glossy ganoderma (Ganodermalucidum) and the composition comprising this novel triterpenoid at least partly, and it can reduce with ephritis related biochemical indicator thing content (comprising blood urea nitrogen and serum creatinine acid content) and improve kidney pompon filterability.This finds the novel triterpenoid of this disclosure of hint and comprises the composition of this novel triterpenoid, can be used as the medicine treating or prevent kidney disease (comprising acute renal infringement and chronic kidney disease).
Therefore, first object of this disclosure is to provide the triterpenoid that one has following formula (I) structure,
According to embodiment of the present invention, the triterpenoid of described formula (I) structure itself can reduce and ephritis related biochemical indicator thing content, comprise blood urea nitrogen (bloodurinenitrogen, BUN) with creatinine (serumcreatinine, CRE) content; And improve kidney pompon filterability (glomerularfiltrationrate, GFR), therefore can be used to manufacture the medicine can treating or prevent kidney disease.
Second object of this disclosure is to provide a kind of in order to treatment or the pharmaceutical compositions preventing kidney disease.This pharmaceutical compositions comprises the triterpenoid of above-mentioned formula (I) structure of a pharmacy effective dose, its pharmacy acceptable salt class, ester class or solvate; And its pharmaceutically acceptable carrier.
According to embodiment of the present invention, disclose pharmaceutical compositions and more can comprise at least another kind of triterpenoid, it is selected from the group that is made up of following material: red sesame acid C (lucidenicacidC, LAC), red sesame acid N (lucidenicacidN, LAN), red sesame acid E
2(lucidenicacidE
2, LAE
-2), lucidenic acid A (lucidenicacidA, LAA), red sesame acid B (lucidenicacidB, LAB), red sesame acid D
2(lucidenicacidD
2, LAD
-2) and combination.
According to a better embodiment, disclose triterpenoid and LAA, LAB, LAC, LAD that pharmaceutical compositions comprises above-mentioned formula (I) structure
2, LAE
2with the combination of LAN, and its pharmaceutically acceptable carrier.In addition, in described pharmaceutical compositions, the triterpenoid of formula (I) structure and the amount of LAC are about the 5-15% (% by weight) of triterpenoid total amount respectively; LAA and LAD
2amount be about the 15-30% (% by weight) of triterpenoid total amount respectively; LAE
2amount be about the 8-15% (% by weight) of triterpenoid total amount; The amount of LAN and LAB is about the 5-12% (% by weight) of triterpenoid total amount respectively.
Be applicable to comprising acute renal infringement (acutekidneyinjury, AKI) and chronic kidney disease (chronickidneydisease, CKD) with the kidney disease that described pharmaceutical compositions carries out treating or prevent.In one example, this kidney disease is AKI, such as acute renal inflammation.In another example, this kidney disease is CKD, such as chronic kidney inflammation.
If with pharmaceuticals or pharmaceutical compositions gross weight for benchmark, triterpenoid combination total amount of the present invention accounts for 0.1% to 99% (% by weight) of this pharmaceutical compositions gross weight.In some embodiments, the total amount of triterpenoid of the present invention is at least about 1% of this pharmaceutical compositions gross weight.In certain embodiments, the total amount of triterpenoid of the present invention is at least about 5% of this pharmaceutical compositions gross weight.In other embodiments, the total amount of triterpenoid of the present invention is at least about 10% of this pharmaceutical compositions gross weight.In other embodiment, the total amount of triterpenoid of the present invention is at least about 25% of this pharmaceutical compositions gross weight.
3rd object of this disclosure is to provide a kind of method for the treatment of kidney disease.Described method comprises the triterpenoid individuality of needs treatment being used to formula (I) structure of a treatment significant quantity; Or above-mentioned pharmaceutical compositions.According to a preferred forms, described pharmaceutical compositions comprises the triterpenoid of this formula (I) structure, its pharmacy acceptable salt class, ester class or solvate, and LAA, LAB, LAC, LAD
2, LAE
2and LAN; With its pharmaceutically acceptable carrier.The kidney disease being applicable to carrying out in the process of the present invention treating comprises AKI and CKD.In one example, this kidney disease is AKI, such as acute renal inflammation.In another example, this kidney disease is CKD, such as chronic kidney inflammation.The individuality being applicable to carrying out in the process of the present invention treating can be Mammals, is preferably the mankind.
These and other feature of this disclosure more can be understood through following detailed description and subsidiary claims.Need know that above general introduction and following detailed description are only illustration, be used for setting forth this disclosure, and be not used to the category limiting this disclosure.
Accompanying drawing explanation
For allowing of the present invention above-mentionedly to become apparent with other object, feature, advantage and embodiment, being described as follows of institute's accompanying drawings:
Figure 1A is the situation of the kidney cell apoptosis that formula (I) compound of foundation shown by an embodiment of the present invention suppresses cis-platinum to bring out;
Figure 1B is the situation of the kidney cell apoptosis that the pharmaceutical compositions YKII-10 of the present invention shown by foundation an embodiment of the present invention suppresses cis-platinum to bring out;
Fig. 2 A is the situation that the serum urea nitrogen content suppressing cis-platinum to bring out in vivo according to the pharmaceutical compositions YKII-10 of the present invention shown by an embodiment of the present invention increases;
Fig. 2 B is the situation that the serum creatinine acid content suppressing cis-platinum to bring out in vivo according to the pharmaceutical compositions YKII-10 of the present invention shown by an embodiment of the present invention increases;
Fig. 3 reduces according to formula (I) compound shown by an embodiment of the present invention and pharmaceutical compositions YKII-10 the situation that blood urea nitrogen that lipopolysaccharides brings out increases in vivo respectively;
Fig. 4 A is the situation that the serum urea nitrogen content suppressing aristolochic acid-I to bring out in vivo according to the pharmaceutical compositions YKII-10 of the present invention shown by an embodiment of the present invention increases;
Fig. 4 B is the situation that the serum creatinine acid content suppressing aristolochic acid-I to bring out in vivo according to the pharmaceutical compositions YKII-10 of the present invention shown by an embodiment of the present invention increases;
Fig. 5 is the situation improving glomerular filtration rate according to the pharmaceutical compositions YKII-10 of the present invention shown by an embodiment of the present invention in vivo; And
Fig. 6 is the situation improving renal function according to the pharmaceutical compositions YKII-10 of the present invention shown by an embodiment of the present invention in vivo.
Embodiment
In order to make describing of this disclosure more detailed and complete, hereafter have been directed to embodiments of the present invention and specific embodiment proposes illustrative description; But this not implements or uses the unique forms of the specific embodiment of the invention.Cover in embodiment multiple specific embodiment feature and in order to construction and these specific embodiments of operation method steps with its sequentially.But, other specific embodiment also can be utilized to reach identical or impartial function and sequence of steps.
Be below the explanation of specific term used in this specification sheets:
In this article, " treatment (treatmentortreating) " word comprises and can cause the preventive of the pharmacy for asking and/or physiologic effect (that is, preventative), healing property or retentivity disposal.This effect is preferably finger and medically partially or completely can cures or prevent kidney cell apoptosis.In addition, " treatment " one word refer to based on the object that partially or completely can alleviate, postpone generation, probability appears in suppression process, one or more symptom of alleviating seriousness and/or reducing a kind of specified disease, exception and/or medical conditions at this, and to tested individuality (or patient), espespecially there is a kind of medical conditions, a kind of symptom of this medical conditions, a kind of disease of causing because of this medical conditions or illness or to the individuality that can make the situation in advance developed towards this medical conditions, use or apply compound or the pharmaceutical compositions of this disclosure.Also can to the individuality of obvious symptom not yet occurring specified disease, exception and/or medical conditions, and/or only the individuality that this specified disease, exception and/or medical conditions produce early stage symptom is treated, to reducing the risk producing the pathology that this specified disease, exception and/or medical conditions are correlated with.In this article, described symptom, disease, exception and/or medical conditions can be acute renal injury (acutekidneyinjury, AKI) or chronic renal disease (chronickidneydisease, CKD).If reducing one or more symptom or clinical indices, namely to represent this treatment be " effectively ".
" prevention (prophylaxis) " refers to the means anti-processed to a kind of future event at this.Based on preventing kidney cell because of poisonous substance or medicine and then hiding the Wen Yi adding those kidney cell apoptosis herein, therefore, can before individuality is exposed to this poisonous substance or medicine, simultaneously or afterwards, implement preventive disposal means as herein described.
" significant quantity (aneffectiveamount) " one word meaning by for treatment kidney disease object, this consumption after during suitable administration, can reach and reduce serum urea nitrogen and creatinine amount, reduce kidney cell apoptosis or improve the objects such as glomerular filtration rate.According to some embodiment, the composition of formula (I) compound or contained (I) compound be a tested individuality be exposed on can cause kidney injury toxicant (as, chemotherapeutics, lipopolysaccharides (lipopolysaccharide, or aristolochic acid-I (AristolochicacidI LPS), AA-I)), be first applied to it tested individuality in prophylactically mode.
The word such as " compound (compound) ", " composition (composition) " " ", " medicament (agent) " or " pharmaceuticals (medicineormedicament) " can be used alternatingly at this, and all refer to when being applied to an individuality (mankind or animal), a kind of compound or the composition of pharmacy and/or the physiological response urgently asked can be brought out through local and/or systemic effect.
A word refers at this and directly uses described compound or composition " to use (administered, administering or, administration) ", or the premedicant (prodrug) using active compound (such as, the ester class of active compound), derivative (derivative) or analogue (analog) etc., and can using in individual body the suitable consumption person forming this active compound.
Be used alternatingly the words such as " individual (subject) " or " patient (patient) " herein, it refers to the animal (comprising the mankind) that can accept described compound and/or method treatment." individuality " or " patient " covers male and female two kinds of sexes at this, unless otherwise expressly specified.Therefore " individuality " or " patient " comprises any mammal, includes, but not limited to the mankind, inhuman primates, and as Mammals, dog, cat, horse, sheep, pig, ox etc., it can benefit because utilizing described compound to carry out treating.The animal being applicable to accepting the compounds of this invention and/or method treatment is preferably the mankind.In general, " patient " one word and " individuality " one word can alternating with each otherly use in this article.
Alternate with each otherly can use both " significant quantity (aneffectiveamount) " or " pharmacy effective dose (atherapeuticallyeffectiveamount) ", mean dosage treatment target being used to the medicable compound of a tool or composition.The measurement of curative effect can be objectively (utilizing some tests or mark to weigh) or (treatment target gives its describing effect and sensation) of subjectivity.Above-mentioned compound or the effective dosage ranges of composition can from about 0.1 mgs/kg/day to about 100 mgs/kg/day, and be preferably from 1 mg/kg/day to about 50 mgs/kg/day, better is from 5 mgs/kg/day to about 10 mgs/kg/day.Effective dose also can along with the difference of route of administration and may and other medicament difference and change to some extent.
In this manual, unless separately do contrary just, otherwise " triterpenoid " one word contain triterpenoid and pharmacy acceptable salt class, ester class or solvate.For example, formula (I) compound of this disclosure is a kind of triterpenoid, therefore, when addressing formula (I) compound of this disclosure in specification sheets, the salt of this disclosure formula (I) compound, ester class or solvate is also contained.Herein " salt " one word representative utilize a kind of alkali and one acid (such as, the novel triterpenoid of this disclosure) salt that formed after reaction, the salt obtained from suitable alkali comprises the salt of basic metal (as sodium), alkaline-earth metal (as magnesium), ammonium ion and N (alkyl) 4+." ester class " word represents the ester class of the triterpenoid of this disclosure, and for formula (I) compound, this ester class is by the carboxyl of formula (I) compound and a kind of alcohols (e.g., C of straight or branched
1-6alcohols) to generate after reaction; Or (R-COOH, wherein R is the C of straight or branched by the hydroxyl of formula (I) compound and another kind of organic acid
1-6alkyl) to generate after reaction.Herein " solvate (solvate) " word this representative by a compound (as, formula (I) compound in this disclosure) and solvent molecule (e.g., water, ethanol etc.) interreaction around it after the wrong compound that formed.In one example, the solvate of this triterpenoid is the ethanol solvate of formula (I) structure.
Although be all rough numerical value in order to the numerical range that defines wider range of the present invention and parameter, as far as possible accurately present the correlation values in specific embodiment herein.But any numerical value inevitably contains because of the standard deviation caused by indivedual testing method in essence.Herein, " about " typically refers to actual numerical value within positive and negative 10%, 5%, 1% or 0.5% of a special value or scope.Or, " about " one word represent actual numerical value and drop within the acceptable standard error of mean value, depending on the consideration of those skilled in the art.Except experimental example, or unless otherwise explicitly bright, when can understand all scopes used herein, quantity, numerical value and per-cent (such as in order to describe material usage, time length, temperature, operational condition, quantitative proportion and other similar person) all passes through the modification of " about ".Therefore, unless otherwise contrary explanation, the numerical parameter that this specification sheets and subsidiary claims disclose is all rough numerical value, and visual demand and changing.At least these numerical parameters should be interpreted as pointed significant digit and apply mechanically the numerical value that general transfer method obtains.
Unless this specification sheets separately has definition, the implication of science and technology vocabulary used herein and those skilled in the art understand and usual same meaning.In addition, when getting along well context conflict, this specification sheets singular noun used contains the complex number type of this noun; And during plural noun used, also contain the odd number type of this noun.
This disclosure has at least a part isolatedly to develop out from Ganoderma sporophore or mycelial novel triterpenoid based on a kind of, described novel triterpenoid and the pharmaceutical compositions comprising this novel triterpenoid, have the characteristic that can reduce serum urea nitrogen and creatinine level and raising kidney pompon filterability.Therefore, this novel triterpenoid is that potential can be used to manufactures the medicament treating or prevent kidney disease with the pharmaceutical compositions comprising this novel triterpenoid.
Therefore, first aspect of this disclosure is to provide the triterpenoid that one has formula (I) structure,
According to particular implementation of the present invention, disclose this triterpenoid with formula (I) structure itself namely have reduce by medicine (as, cis-platinum or aristolochic acid-I) ability that raises of the serum urea nitrogen that causes or creatinine, or recover because of the kidney cell apoptosis phenomenon caused by medicine (e.g., cis-platinum or aristolochic acid-I).
Inventor also finds a kind of triterpenoid combination of novelty, wherein each triterpenoid is all isolated from Ganoderma sporophore or mycelium, and the combination of the triterpenoid of this novelty is the same with above-mentioned formula (I) compound, have can reduce by medicine (as, cis-platinum or aristolochic acid-I) ability that raises of the serum urea nitrogen that causes or creatinine, or recover because of the caused kidney cell apoptosis phenomenon of medicine (e.g., cis-platinum or aristolochic acid-I).
Based on this, second object of this disclosure is to provide a kind of in order to treatment or the pharmaceutical compositions preventing kidney disease.This pharmaceutical compositions at least comprises the triterpenoid of above-mentioned formula (I) structure of a pharmacy effective dose; And its pharmaceutically acceptable carrier.
According to embodiment of the present invention, disclose pharmaceutical compositions and more can comprise at least another kind of triterpenoid, it is selected from the group that is made up of following material: red sesame acid C (lucidenicacidC, LAC), red sesame acid N (lucidenicacidN, LAN), red sesame acid E
2(lucidenicacidE
2, LAE
-2), lucidenic acid A (lucidenicacidA, LAA), red sesame acid B (lucidenicacidB, LAB), red sesame acid D
2(lucidenicacidD
2, LAD
-2) and combination.
In some embodiments, the described triterpenoid of pharmaceutical compositions Chinese style (I) structure and the amount of LAC are about the 5-15% (% by weight) of total triterpenoids content respectively, such as about 5,5.5,6,6.5,7,7.5,8,8.5,9,9.5,10,10.5,11,11.5,12,12.5,13,13.5,14,14.5 or 15% (% by weight), this is used as 100% calculating with the total amount of triterpenoid contained in composition and obtains.In a preferred embodiments, the triterpenoid of this formula (I) structure and the amount of LAC are about 10% of triterpenoid total amount respectively.
In other embodiments, LAA and LAD in described pharmaceutical compositions
2amount be about the 15-30% (% by weight) of triterpenoid total amount respectively; Such as about 15,15.5,16,16.5,17,17.5,18,18.5,19,19.5,20,20.5,21,21.5,22,22.5,23,23.5,24,24.525,25.5,26,26.5,27,27.5,28,28.5,29,29.5 or 30% (% by weight), this is used as 100% calculating with the total amount of triterpenoid contained in composition and obtains.In one example, LAA and LAD
2amount be about 25% of triterpenoid total amount in composition respectively.
In other embodiments, LAE in described pharmaceutical compositions
2amount be about the 8-15% (% by weight) of triterpenoid total amount; Such as about 8,8.5,9,9.5,10,10.5,11,11.5,12,12.5,13,13.5,14,14.5 or 15% (% by weight), this is be used as 100% calculating with the total amount of triterpenoid contained in composition and obtain.In one example, LAE
2amount be about 12% (% by weight) of triterpenoid total amount in this pharmaceutical compositions.
In some embodiments, in described pharmaceutical compositions, the amount of this LAN and LAB is about the 5-12% (% by weight) of total triterpenoids content respectively, such as about 5,5.5,6,6.5,7,7.5,8,8.5,9,9.5,10,10.5,11,11.5 or 12% (% by weight), this is used as 100% calculating with the total amount of triterpenoid contained in composition and obtains.In a preferred embodiments, the amount of this LAN and LAB is about 8.5% (% by weight) of triterpenoid total amount in this pharmaceutical compositions respectively.
According to a preferred forms, disclose triterpenoid, LAC, LAN, LAE that pharmaceutical compositions comprises above-mentioned formula (I) structure
2, LAA, LAB and LAD
2, and its pharmaceutically acceptable carrier; And the wherein triterpenoid of above-mentioned formula (I) structure and LAC, LAN, LAE
2, LAA, LAB and LAD
2amount be about about 10%, 10%, 8.5%, 15%, 25% and 25% (% by weight) of total triterpenoids content respectively.
Triterpenoid of the present invention, comprises triterpenoid and LAC, LAN, LAE of above-mentioned formula (I) structure
2, LAA, LAB and LAD
2all can be separated by Ganoderma mushroom according to embodiment 1 revealing method, such as, be isolated by the sporophore of red sesame (Ganodermalucidum) or mycelium.No matter raw material is from Ganoderma sporophore or mycelium, separation purification method used is all generally with solvent (being preferably alcohol solution), extract at temperatures greater than room temperature, then extract is carried out col-umn chromatography, it includes but not limited to the liquid chromatography (HPLC) of high-level efficiency and the liquid chromatography (ReversePhaseLiquidChromatograpy) of anti-phase etc., and concentrated, drying and other steps, until obtain the dried powder of this ganoderma active compound.
Be applicable to comprising acute renal infringement (acutekidneyinjury, AKI) and chronic kidney disease (chronickidneydisease, CKD) with the kidney disease that described pharmaceutical compositions carries out treating or prevent.In one example, this kidney disease is AKI, such as acute renal inflammation.In another example, this kidney disease is CKD, such as chronic kidney inflammation.
In general, if with pharmaceuticals or pharmaceutical compositions gross weight for benchmark, triterpenoid total amount of the present invention accounts for 0.1% to 99% (% by weight) of this pharmaceutical compositions gross weight.In some embodiments, the total amount of triterpenoid of the present invention is at least about 1% of this pharmaceutical compositions gross weight.In certain embodiments, the total amount of triterpenoid of the present invention is at least about 5% of this pharmaceutical compositions gross weight.In other embodiments, the total amount of triterpenoid of the present invention is at least about 10% of this pharmaceutical compositions gross weight.In other embodiment, the total amount of triterpenoid of the present invention is at least about 25% of this pharmaceutical compositions gross weight.
The kidney disease being applicable to carrying out in the process of the present invention treating comprises AKI and CKD.In one example, this kidney disease is AKI, such as acute renal inflammation.In another example, this kidney disease is CKD, such as chronic kidney inflammation.The individuality being applicable to carrying out in the process of the present invention treating can be Mammals, is preferably the mankind.
The pharmacy preparation method that can accept according to crowd prepares said medicine or pharmaceutical compositions, as Remington ' sPharmaceuticalSciences (17thedition, ed.AlfonosoR.Gennaro, MackPublishingCompany, Easton, Pa (1985)) preparation method that discloses in a book.Pharmaceutically acceptable excipient refer to can with other composition in pharmaceutical formulations compatible and with organism compatibility person.
According to disclosed embodiment, disclosed medicine or pharmaceutical compositions can be used via any suitable route of administration, such as, through the capsule of orally administer, suspension or lozenge, or to use without intestines and stomach mode.Method of application without intestines and stomach comprises the systemic administration modes such as such as intramuscular injection, vein blood vessel injection, subcutaneous injection or intraperitoneal injection.Or, also can pass through and wear epithelium mode and use, as local skin is smeared or imbedibility (e.g., in segmental bronchus, in nasal cavity, oral cavity or nose drops etc.); Or internal rectum mode is used.Can be individually dosed or and assistant agent administration together can be accepted with known pharmacy when using.In better embodiment, via oral way (e.g., through food), the compounds of this invention can be cast individuality.
If use with oral way, triterpenoid of the present invention or its novel combination formula can be become and include various assistant agent (e.g., Microcrystalline Cellulose, calcium carbonate, Si Liaodengji dicalcium phosphate feed grade and glycine); Various disintegrating agent (as starch, alginic acid and specific silicon hydrochlorate); And the lozenge of particle tamanori (e.g., polyvinylpyrrolidone, sucrose, gelatin and Australian gum (acacia)).In addition, the lubricant of such as Magnesium Stearate, sodium lauryl sulphate and talcum etc. can also be comprised.Preferred materials related to this comprises sugar in lactose or milk and high molecular weight polyethylene glycol.Above-mentioned solid dosage also can optionally comprise coating or shell, such as Enteric coatings, and is used for improving the coating of arbitrary active constituents of medicine rate of release.The example of this type coating is well known to those skilled in the art.In one example, described pharmaceutical compositions is filled a prescription and is become lozenge.In another example, described pharmaceutical compositions is become by filling a prescription and is filled in soft or hard gelatin capsule or the particle be encapsulated in the cartridge bag of bioerodible.When use-pattern be suspension for oral use and/or specific remedy (elixirs) time, activeconstituents capable of being combined is filled a prescription together with various sweeting agent or flavour agent, tinting material or dyestuff, also emulsifying agent and/or suspension agent can be added when needing, and the thinner such as such as water, alcohol, propylene glycol, glycerine.In some embodiments, pharmaceutical compositions of the present invention is become applicable oral liquid dosage form by filling a prescription.This type of liquid-mixing more can comprise the damping fluid for maintaining pH value.Also this liquid formulations can be filled in soft capsule.This liquid dosage form can be a kind of solution, suspension, emulsion, microemulsion, precipitates or can carry any liquid medium of the compounds of this invention, its pharmaceutically acceptable derivates, isomer, metabolite, salt or solvate.This liquid can be designed to improve its solubleness of pharmaceutically-acceptable salts class of the compounds of this invention, to form a kind of emulsion containing medicine or dispersion liquid.When using this formulation, be that active compound and the pharmaceutically acceptable adjuvant of at least one (including, but not limited to above-mentioned adjuvant) are mixed together rear formation.
If use in parenteral (parenterally) mode, triterpenoid of the present invention or its novel combination formula can be become liquid pharmaceutical compositions, it can be the sterile solution or suspension that can use in modes such as intravenous injection, intramuscular injection, subcutaneous injection or peritoneal injections.The thinner that can be used to manufacture above-mentioned aseptic injectable solution or suspension includes, but not limited to 1,3 butylene glycol, N.F,USP MANNITOL, water, Ringer's solution, isotonicity sodium chloride solution.Also can use lipid acid (e.g., oleic acid) and glyceride derivative, or the acceptable oil of natural pharmacy (e.g., sweet oil or rapeseed oil) manufacture can the solution of injection or suspension.Also can comprise in this kind of oily solution or suspension for the alcohols of dilution or carboxymethyl cellulose or similar dispersion agent.Also can use other conventional tensio-active agent (e.g., Tweens or Spans series) or emulsifying agent, or be commonly used to the medicament strengthening bioavailability during pharmaceutical field manufacture formula.
Also above-mentioned for the present invention pharmaceuticals or pharmaceutical compositions can be made the multiple formulation being applicable to mucosal drug delivery (mucosalapplication), as through cheek (buccal) and/or sublingual (sublingual) pharmaceutical dosage unit, with delivering drugs through oral mucosa.Multiple biodegradable can be used and the acceptable polymer assistant agent of pharmacy, this kind of assistant agent can make pharmaceutical compositions have acceptable adsorption effect and desired drug release pattern, and can and contained for using activeconstituents or other composition is compatible in cheek and/or sublingual medications dosage form units.In general, above-mentioned polymer assistant agent comprises hydrophilic polymer, and it can be adhered to the wetted surface of oral mucosa.The embodiment of polymer assistant agent includes but not limited to acrylate copolymer and multipolymer (acrylicacidpolymersandcopolymers); Hydrolyzed polyvinyl alcohol (hydrolyzedpolyvinylalcohol); Polyethylene oxide (polyethyleneoxides); Polyacrylic ester (polyacrylates); Ethene polymers and multipolymer (vinylpolymersandcopolymers); Polyvinylpyrrolidine; Glucose (dextran); Melon glue (guargum); Pectin (pectins); Starch; And cellulose polymer compound (cellulosicpolymers).
When understanding, the dosage of triterpenoid of the present invention or its novel combination can be different because of individual, this is not only because the difference of the factors such as institute's wish reaction that specific compound used or composition, route of administration, compound (separately or together with one or more medicine) cause in patient body, also may be subject to other factors impact, such as: for morbid state or the severity for the treatment of symptom; The healthy state of age of patient, sex or body weight, patient; And for the severity of pathological state for the treatment of, patient in other medical treatment or the special diet content of carrying out simultaneously; And the other factors that those skilled in the art can expect; And the healthcare givers being responsible for taking care of finally can judge suitable dosage based on these factors.Adjustable administration dosage and form are to provide preferably therapeutic response.Also the toxicity caused by compound or composition or harmful effect too late treatment interests brought in it are referred to the while for the treatment of significant quantity.In preferably situation, triterpenoid of the present invention be combined in dispensing time, suitable dosage should be adopted and continue for some time, to reduce the number of times and/or severity that occur symptom.
When the triterpenoid of formula (I) structure or pharmaceutical compositions of the present invention be administered to an individuality with it time, the effective level used is about between 0.1-100 mg/kg of/day whose body weight.The consumption that can be applied to this individuality pharmaceutical compositions with it every day is about 0.1,0.5,1,2,5,7,9,10,12,15,17,19,20,22,25,27,29,30,32,35,37,39,40,42,45,47,49,50,52,55,57,59,60,62,65,67,69,70,72,75,77,79,80,82,85,87,89,90,92,95,97,99 or 100 mg/kg of body weight; Be preferably about 1-50 mg/kg body weight, such as about 1,2,5,7,8,9,10,12,15,17,19,20,22,25,27,29,30,32,35,37,39,40,42,45,47,49,50 mg/kg of body weight; Better is about 5-10 mg/kg body weight, such as about 5,7,8,9 or 10 mgs/kg of body weight.These dosage can single administration or be divided into repeatedly be used in one day.
3rd object of this disclosure is to provide a kind of method for the treatment of kidney disease.Described method comprises uses to the individuality of needs treatment medicine or the composition that can treat kidney disease.When this medicine or composition be administered to need treatment badly mammalian subject (being preferably the mankind) with it time, triterpenoid or the pharmaceutical compositions of the invention described above of formula (I) structure of significant quantity can be passed out.This medicine can by suitable approach, such as per os, intranasal, through lung, through passive type transfer mode administrations such as skins, or carrys out administration via modes such as intravenous injection, intramuscular injection, subcutaneous injection, internal rectum, intraoculars.
Following examples are used to illustrate this disclosure ad hoc fashion, and help those skilled in the art to understand and implement this disclosure.But this disclosure category is not limited in these embodiments.
Embodiment
Materials and methods
Cell culture
This research uses the strain of MDCK dog kidney cell, with 1.5x10
5the density of individual cell/dish is seeded in the culture plate in 96-hole, and cultivate the EagleShi substratum improved through DulbeccoShi (Dulbecco ' smodifiedEagle ' smedium, DMEM) in, and all add 10% foetal calf serum (fetalcalfserum in the medium, the penicillin of FCS), 100 units/ml, the Streptomycin sulphate (Invitrogen of 100ng/ml, Carlsbad, CA), 2mML-L-glutamic acid and non-essential amino acid and Sodium.alpha.-ketopropionate, and (5%CO under maintaining the wet environment of 37 DEG C
2and 95% air).
Laboratory animal
This experiment uses BLb/c mouse, and raise without under the environment of pathogenic bacteria, room temperature is maintained at 22 ± 3 DEG C, and relative humidity is held in 50 ± 20%, and day and night the cycle maintains 12/12 hour, and freely can take and drink water and food.Animal-feed use experimental mouse feed 5001 (LaboratoryRodentDiet5001) (purchased from
nutritionInternational, Inc., MO, USA).Drinking water for animals then uses the tap water boiled.All experimentation on animals operations, all follow the specification of " management of laboratory animal and the instruction manual " that Chinese laboratory animal association publishes.
Embodiment 1 the compounds of this invention and pharmaceutical compositions
1.1 are separated and purifying formula (I) compound
By dry weight be the ganoderma lucidum sporocarp of 50g cracked with disintegrating machine after, red sesame powder is placed in concussion extraction plant, and adds ethanol, its ratio is ganoderma lucidum sporocarp powder dry measure: alcohol by volume=1:24, then concentrates after one day with 37 DEG C of digestions.Continuous several repeats aforementioned extraction step, the extraction liquid of gained after filtration, merge and after concentrating under reduced pressure drains, obtain the molten thick extraction thing of 5 grams of ganoderma lucidum sporocarp alcohol of productive rate about 10%.By molten for the ganoderma lucidum sporocarp alcohol of above-mentioned gained thick extraction thing, remove residual solvent with the vacuum drying system of 40 DEG C of constant temperature suction filtration overnight.
At the molten thick extraction thing of dry weight 5.0 grams of ganoderma lucidum sporocarp alcohol of above-mentioned gained, the ethyl acetate (ethylacetate) added containing equal-volume water extracts, obtain another water layer solution and extraction into ethyl acetate layer solution, after this extraction into ethyl acetate layer solution concentrate drying, remove residual solvent with the vacuum drying system of 40 DEG C of constant temperature suction filtration overnight, the ganoderma lucidum sporocarp acetic acid ethyl ester extract that productive rate accounts for the molten thick extraction thing dry weight 40% (2 grams) of total ganoderma lucidum sporocarp alcohol can be obtained.
By the red sesame acetic acid ethyl ester extract of above-mentioned gained drying, after dissolving with alcohol, be separated with half preparation scale HPLC, movement is cyanogen methane/2% acetic acid (1/2 ~ 1/4) mutually, can obtain formula (I) compound (8mg), its productive rate is 0.4%.
Formula (I) compound
13c,
1it is as follows that H and heteronuclear multiple-bond tie cognation nuclear-magnetism frequency spectrum (HeteronuclearMultipleBondCorrelation, HMBC) data:
MS(EI,20eV),m/z(rel.int.):460[M+](53.56),442(22.56),339(16.46),322(100),304(46.41)；
HRMSm/z=460.2834 (C
27h
40o
6calculating molecular weight: 460.2819)
IR
max3445,1736,1707,1661cm
-1
UV(MeOH)
max252nm
Fusing point: 124-1260C
The 1.2 pharmaceutical compositions YKII-10s of preparation containing formula (I) compound
In this disclosure, specific pharmaceutical compositions YKII-10 system for the treatment of kidney disease fills a prescription according to shown in following table 2, formula (I) compound of novelty embodiment 1.1 be separated and other known triterpenoid are obtained after being mixed into a uniform mixture, those triterpene compound systems can according to any published isolated or purified method, isolated or purified in Ganoderma sporophore or mycelium and obtaining.
Each component content in table 2 pharmaceutical compositions YKII-10
The kidney inflammation that cis-platinum is induced can effectively be alleviated or improve to embodiment 2 formula (I) compound and YKII-10 pharmaceutical compositions
In the present embodiment, bring out in vitro with cis-platinum (cisplatin) or in vivo kidney cell apoptosis, then impose formula (I) compound or YKII-10 composition again, to assess effect of its treatment kidney disease.
The kidney cell apoptosis that 2.1 cis-platinums are induced
With 1 × 10
5the density of individual cell/culture hole, MDCK dog kidney cell is inoculated in 6 flat hole culture plates, in incubator, overnight incubation is after cell attachment, cell is anticipated 4 hours with the cis-platinum of 50 μMs (Cisplatin), add the YKII-10 pharmaceutical compositions (25-100 μ g/mL) of formula (I) compound (50 μ g/mL or 100 μ g/mL) or embodiment 1 more respectively to process cell, the DiOC6 stain directly adding 50nM after 24 hours in nutrient solution carries out mitochondrial membrane potential dyeing, react 30 minutes at 37 DEG C, cell is cleaned twice again with PBS, use the situation of handstand fluorescence microscope mitochondrial membrane potential dyeing and Taking Pictures recording, the kidney cell of apoptosis cannot be dyeed by DioC6, whether assess apoptosis by this.Result is shown in 1A and Figure 1B.
As the display of Figure 1A histogram, be used alone formula (I) compound (50 μ g/mL), can have efficient recovery cis-platinum induce the renal tubular cell membrane potential of generation to decline, when concentration brings up to 100 μ g/mL, then reversible membrane potential decrease beyond 8 one-tenth, makes the membrane potential being tending towards control group.Similar, if use the YKII-10 pharmaceutical compositions (25-100mg/Kg) of various dose, equally also effectively can recover renal tubular cell membrane potential to decline, and its recovery extent increases along with YKII-10 pharmaceutical compositions dosage and increases (Figure 1B).It can thus be appreciated that the pharmaceutical compositions YKII-10 of formula (I) compound or contained (I) compound effectively can reverse rat tubular cell apoptosis, therefore can be used to alleviate or treatment nephritis.
The mouse kidney inflammation that 2.2 cis-platinums are induced
In the present embodiment, select 6 weeks large dC57BL/6 mouse, experimental group gives the YKII-10 pharmaceutical compositions (10mL/Kg) of embodiment 1.2 every day with oral way, continuous 5 days, control group mice then gives distilled water, all animals gave test mice cis-platinum (15mg/kg at the 2nd day in abdominal injection mode, i.p.) once, mouse blood is gathered after 3 days, blood obtains after serum through centrifuging and taking and utilizes Biochemical Analyzer (TOSHIBA, TBA-40FR) serum urea nitrogen (bloodurinenitrogen is measured, BUN), serum creatinine acid (creatinine, the numerical value such as CRE), to assess Mouse Kidney function situation.The results are shown in the 2nd figure.
As Fig. 2 A and Fig. 2 B shows, the Biochemical Indices In Serum relevant to inflammation can be effectively reduced to the YKII-10 pharmaceutical compositions (10mL/Kg) that laboratory animal uses the embodiment of the present invention 1.2 with oral way, comprise BUN and CRE, make it close to control group, represent that the pharmaceutical compositions of the present invention of contained (I) compound can effectively be used for alleviating or treatment nephritis.
The ephritis that in vivo lipopolysaccharides is induced can effectively be alleviated or improve to the YKII-10 pharmaceutical compositions of embodiment 3 formula (I) compound and embodiment 1
In the present embodiment, with lipopolysaccharides (lipopolysaccharide, LPS) mouse kidney inflammation (kidneyinflammation) is brought out, then formula (I) compound or YKII-10 composition is imposed again, to assess effect of its treatment kidney inflammation.
The BLb/c mouse in 6 week age of this test use, test the day before yesterday, divides into groups animal according to body weight, and between confirming each group after grouping, body weight is without statistically significant difference.After on-test, every day, injection 5 days continuously, produced inflammation to bring out mouse kidney by abdominal injection LPS (2.5mg/Kg) in Mice Body.Simultaneously, and formula (I) compound (100mg/Kg) or the YKII-10 composition of embodiment 1.2 (dosage is for 250mg/Kg) of experimental mice embodiment 1.1 is given once a day with oral way), control group mouse then gives distilled water.Within the 5th day and the 10th day after on-test, gather animals urine respectively, and with ARKRAY Urine Analyzer mensuration urine protein content wherein, to assess the renal function of mouse.The results are shown in Fig. 3.
As the display of Fig. 3 histogram, for the mouse kidney inflammation that LPS induction produces, be no matter the formula of being used alone (I) compound (100mg/Kg) or with other known triterpenoid and with (as, give the YKII-10 pharmaceutical compositions (250mg/Kg) of embodiment 1.2), all effectively can reduce the protein content in laboratory animal urine, represent that formula (I) compound or the pharmaceutical compositions YKII-10 of contained (I) compound can effectively be alleviated or treat nephritis.
The infringement of live body acute renal can effectively be alleviated or improve to the YKII-10 pharmaceutical compositions of embodiment 4 embodiment 1
In the present embodiment, with aristolochic acid-I (AristolochicacidI, AA-I) bring out mouse and produce acute renal infringement (acutekidneyinjury), then the YKII-10 pharmaceutical compositions of the embodiment of the present invention 1.2 is imposed again, to assess effect of its treatment acute renal infringement.
4.1AA-I induces renal function injury zootype
Select 6 weeks large Balb/c mouse, every day gives mouse AA-I (2.5mg/kg) continuous 5 days with oral way, experimental mice in on-test namely with the YKII-10 pharmaceutical compositions (300mg/kg) of oral way administration embodiment 1.2 once a day, give 12 continuously, control group then gives distilled water.Mouse blood is gathered in the 12nd day, obtain after serum through centrifuging and taking and utilize Biochemical Analyzer (TOSHIBA, TBA-40FR) numerical value such as blood urea nitrogen (BUN), creatinine (Creatinine, CRE) are measured, to assess Mouse Kidney function.The results are shown in 4A and 4B figure.
Shown by the 4th figure result, the YKII-10 pharmaceutical compositions of the embodiment of the present invention 1.2 effectively can reduce BUN and CRE that AAI institute brings out generation, represents that the pharmaceutical compositions YKII-10 of the embodiment of the present invention 1.2 can effectively be alleviated or treat acute renal and damage.
4.2 glomerular filtration rate (glomerularfiltrationrate, GFR) tests
In the present embodiment, utilizing with kidney pompon is the fluorescent mark synanthrin (Inulin) of unique excretion pathway, is injected in Mice Body, by living body fluorescent image detecting instrument monitoring fluorescence dissipation rate so that reflect kidney pompon filtration efficiency.
Select 6 weeks large Balb/c mouse, YKII-10+AAI experimental mice gives medicine (dosage is 300mg/Kg)) continuous 8 days, in abdominal injection AA-I (2.5mg/kg) continuous 5 days on the 4th; YKII-10 experimental mice gives medicine (300mg/kg) continuous 8 days; AA-I experimental mice gave distilled water after 3 days, and in abdominal injection AA-I (2.5mg/kg) continuous 5 days on the 4th, control group was then given and distilled water.After test carries out 8 days, by fluorescent mark synanthrin (GFR-Vivo680) (2x10
-9mole) squeeze in Mice Body, by PerkinElmer living body fluorescent image detecting instrument (FMT4000) the 1st, 5,15,30,45 minute detecting fluoroscopic image after injection, calculate fluorescent mark synanthrin (Inulin) concentration residual in Mice Body, and then calculate kidney pompon filtration curve, compare the glomerular filtration efficiency of four groups of mouse.The results are shown in Fig. 5.
The display of Fig. 5 histogram is under mouse is exposed on AAI process, kidney pompon filterability (GFR) is from original normal value (about 250 μ L/ minute) rapid drawdown 10 times to about 25 μ L/ minute, if treat with pharmaceutical compositions YKII-10, though the acute renal infringement that AAI causes cannot be reversed completely, but still effectively can promote GFR about about 4 times, to about 100 μ L/ minute.
Live body chronic kidney disease can effectively be alleviated or be improved to the YKII-10 pharmaceutical compositions of embodiment 5 embodiment 1
In the present embodiment, by excision laboratory animal part kidney, its renal function is made to drop to 1/6 of about intact animal, then the YKII-10 pharmaceutical compositions of the embodiment of the present invention 1.2 is imposed again, to assess effect that it promotes renal function, reflect the YKII-10 pharmaceutical compositions of the embodiment of the present invention 1.2 by this to effect for the treatment of chronic kidney disease.
Select 8 weeks large Adult male rats, be divided into experimental group and control group (often organizing 3 rats) at random, every treated animal is all with excision left kidney 2/3, after allowing animal have a rest one week, excise right kidney again, make experimental animal decreased renal function to 1/6 of about intact animal, to simulate the renal function situation that chronic kidney disease is suffered from.Second postoperative week starts dispensing, test group of animals gives the YKII-10 pharmaceutical compositions of the embodiment 1.2 of 300 mgs/kg of body weight every day, control group then gives water, taken a blood sample by animal afterbody simultaneously, creatinine level in the blood of determination experiment animal, eGFR (estimatedGFR) is converted into, to assess renal function, and not carry out the reference line of the front eGFR of experiment as 100% renal function through following equation:
EGFR (ml/min/1.73 square centimeter)=186x (creatinine numerical value)
-1.154x (30)
-0.203
Then, blood sampling in every two weeks measures creatinine level, and becomes eGFR via same formula scales, the results are shown in Fig. 6
As the display of Fig. 6 result, at the beginning of dispensing, the renal function of experimental animal is about 44% of normal rat, Post operation 6 weeks, the renal function of dispensing group laboratory animal is obviously promoted to 59% of normal rat, about increase by 15%, control group is then unchanged, calculates the 6th week experimental group and control group data there were significant differences to have statistical meaning through T-test.
In sum, the novel triterpenoid (that is, formula (I) compound) of this disclosure and the pharmaceutical compositions of contained (I) compound are that potential can be used to treats medicine that is acute or chronic renal disease.
When understanding above-mentioned embodiment and embodiment is only illustration, and those skilled in the art can carry out various modification to it.The object of specification sheets proposed above, embodiment and data is that the structure making this specification sheets is complete, and as the illustration of implementation the present invention.Although this disclosure discloses as above with embodiment; so itself and be not used to limit this disclosure; any those skilled in the art; not departing from the spirit and scope of this disclosure; when being used for a variety of modifications and variations, therefore the protection domain of this disclosure is when being as the criterion depending on accompanying those as defined in claim.
Claims (8)
1. there is a triterpenoid for following formula (I) structure,
And pharmacy acceptable salt class, ester class or solvate.
2., for slowing down or treat a pharmaceutical compositions for kidney disease, comprise the triterpenoid as claimed in claim 1 of a significant quantity; And pharmaceutically acceptable carrier.
3. pharmaceutical compositions as claimed in claim 2, more comprises another kind of triterpenoid, and it is selected from the group that is made up of following material: red sesame acid C, red sesame acid N, red sesame acid E
2, lucidenic acid A, red sesame acid B, red sesame acid D
2and combination.
4. pharmaceutical compositions as claimed in claim 3, wherein the amount of this formula (I) compound and red sesame acid C is about the 5-15% (% by weight) of triterpenoid total amount in this pharmaceutical compositions respectively.
5. pharmaceutical compositions as claimed in claim 4, wherein lucidenic acid A and red sesame acid D
2amount be about the 15-30% (% by weight) of triterpenoid total amount in this pharmaceutical compositions respectively.
6. pharmaceutical compositions as claimed in claim 4, wherein red sesame acid E
2amount be about the 8-15% (% by weight) of triterpenoid total amount in this pharmaceutical compositions.
7. pharmaceutical compositions as claimed in claim 4, wherein the amount of red sesame acid B and red sesame acid N is about the 5-12% (% by weight) of triterpenoid total amount in this pharmaceutical compositions.
8. pharmaceutical compositions as claimed in claim 3, wherein said kidney disease is acute renal injury or chronic kidney disease.
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| CN201410252758.4A CN105273031B (en) | 2014-06-09 | 2014-06-09 | Novel triterpene compound and application thereof |
| HK16105967.0A HK1217954A1 (en) | 2014-06-09 | 2016-05-25 | A novel triterpenoid and uses thereof |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5631038A (en) * | 1990-06-01 | 1997-05-20 | Bioresearch, Inc. | Specific eatable taste modifiers |
-
2014
- 2014-06-09 CN CN201410252758.4A patent/CN105273031B/en active Active
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2016
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5631038A (en) * | 1990-06-01 | 1997-05-20 | Bioresearch, Inc. | Specific eatable taste modifiers |
Non-Patent Citations (4)
| Title |
|---|
| KENJI IWATSUKI等: "Lucidenic acids P and Q, methyl lucidenate P, and other triterpenoids from the fungus Ganoderma lucidum and their inhibitory effects on Epstein-Barr virus activation", 《J.NAT.PROD》 * |
| NGUYEN THE TUNG等: "Inhibitory effect on NO production of triterpenes from the fruiting bodies of Ganoderma lucidum", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| QING-XI YUE等: "Interaction of ganoderma triterpenes with doxorubicin and proteomic characterization of the possible molecular targets of ganoderma triterpenes", 《CANCER SCI》 * |
| TOSHIHIRO AKIHISA等: "Anti-infalmmatory and anti-tumor-promoting effects of triterpene acids and sterols from the fungus ganoderma lucidum", 《CHEMISTRY&BIODIVERSITY》 * |
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| CN105273031B (en) | 2017-04-12 |
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