CN105663109A - Application of triglyceride compound in preparation of medicine for treating neurodegenerative diseases - Google Patents

Application of triglyceride compound in preparation of medicine for treating neurodegenerative diseases Download PDF

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Publication number
CN105663109A
CN105663109A CN201511016441.1A CN201511016441A CN105663109A CN 105663109 A CN105663109 A CN 105663109A CN 201511016441 A CN201511016441 A CN 201511016441A CN 105663109 A CN105663109 A CN 105663109A
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formula
group
degenerative diseases
nerve degenerative
compound
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Inventor
易伟
徐华强
段晓群
吴啸川
胡增仁
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Zhejiang Xuchen Pharmaceutical Co Ltd
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Zhejiang Xuchen Pharmaceutical Co Ltd
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Priority to CN201511016441.1A priority Critical patent/CN105663109A/en
Publication of CN105663109A publication Critical patent/CN105663109A/en
Priority to PCT/CN2016/092068 priority patent/WO2017113775A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention discloses an application of a triglyceride compound in preparation of a medicine for treating neurodegenerative diseases. The compound can effectively treat the neurodegenerative diseases with low side effect.

Description

The application of triglyceride level compounds in preparation treatment nerve degenerative diseases medicine
Technical field
The present invention relates to pharmaceutical field, specifically, it relates to the application of triglyceride level compounds in preparation treatment nerve degenerative diseases medicine.
Background technology
Alzheimer's disease (Alzheimerdisease, AD), it it is the nerve degenerative diseases of a kind of chronic progressive, the clinical cognitive function that mainly shows as constantly declines, simultaneously with multiple dystropy, finally cause death, alzheimer's disease (Alzheimerdisease, AD) senile dementia it is again, it is that a kind of central nervous system degeneration is sick, play sick hidden attacking, the course of disease is chronic progressive external, it it is the most common type of senile dementia, mainly show as gradual dysmnesia, cognition dysfunction, the psychoneural symptom such as personality change and aphasis, seriously affect social activity, occupation and vital function. the cause of disease and the pathogenesis of AD are not yet illustrated, and characteristic pathological changes into neurofibrillary tangles in the extracellular senile plaque of amyloid beta formation of deposits and the neurocyte of the excessive phosphorylation formation of Protein tau, and neuron loss companion's glial cells hyperplasia etc. therefore, extremely important to stop memory function to go down further by early prevention senile dementia syndromes.
At present, the types of drugs for control senile dementia is a lot, but also there is various problem, as brought various side effects etc. to the health of patient. Therefore, the product innovation of exploitation control senile dementia is significant.
Triglyceride DDD is mainly derived from the natural products such as Oleum Cocois, belong to the one in medium chain triglyceride, being widely used in the fields such as food, medicine and makeup, but treated the application in nerve degenerative diseases medicine about Triglyceride DDD in preparation, there is not been reported.
Therefore, this area urgently needs to develop the medicine of the treatment nerve degenerative diseases that a kind of side effect is little, cost is low.
Summary of the invention
It is an object of the invention to provide the medicine of the treatment nerve degenerative diseases that a kind of side effect is little, cost is low.
First aspect present invention provides the purposes of a kind of formula I or its pharmacy acceptable salt, for the preparation of composition or the preparation for the treatment of nerve degenerative diseases,
In formula,
R1、R2And R3It is selected from lower group: C independently of one another5、C7、C9、C11Alkyl, C5、C7、C9、C11Alkenyl and C5、C7、C9、C11Alkynyl group.
In another preference, R1、R2And R3It is selected from lower group: C independently of one another7、C9Alkyl, C7、C9Alkenyl and C7、C9Alkynyl group.
In another preference, R1、R2And R3It is selected from lower group: C independently of one another9Alkyl, C9Alkenyl and C9Alkynyl group.
In another preference, R1、R2And R3It is selected from lower group: C independently of one another9Alkyl.
In another preference, R1、R2And R3It is different.
In another preference, R1、R2And R3It is identical.
In another preference, R1、R2And R3It is all C9Alkyl.
In another preference, described formula I is even number chain triglyceride.
In another preference, described formula I is Triglyceride DDD.
In another preference, described composition comprises: pharmaceutical composition, Halth-care composition or food compositions or dietary supplement composition.
In another preference, described composition is pharmaceutical composition.
In another preference, described food compositions comprises drink composition.
In another preference, described pharmaceutical composition contains the compound shown in (a) formula I and (b) pharmaceutically acceptable carrier.
In another preference, described component (a) accounts for the 0.1-99.9wt% of described pharmaceutical composition gross weight, it is preferred that 10-99.9wt%, more preferably 70%-99.9wt%.
In another preference, described component (a) accounts for the 60.0%-99.5wt% of described pharmaceutical composition gross weight, it is preferred that 70.0-99.5wt%, more preferably 80.0%-99.5wt%.
In another preference, described pharmaceutical composition is liquid, solid or semisolid.
In another preference, the formulation of described pharmaceutical composition comprises tablet, granule, capsule, oral liquid or injection.
In another preference, described composition or preparation also improve the expression of PPAR γ albumen in mammalian tissues for (i); (ii) expression of A amyloid beta in mammalian tissues is reduced; And/or (iii) reduces the expression of NF-κ B, iNOS and IL-1 β in mammalian tissues.
In another preference, described Mammals comprises people or non-human mammal.
In another preference, described non-human mammal comprises rodent, such as rat, mouse.
In another preference, described Mammals comprises the Mammals suffering from nerve degenerative diseases.
In another preference, described tissue comprises cerebral tissue.
In another preference, described composition is oral preparations.
In another preference, described composition (such as pharmaceutical composition) is applied to Mammals in the following manner: oral, intravenous injection or local injection.
In another preference, described nerve degenerative diseases is selected from lower group: alzheimer's disease (AD), parkinsonism (PD), gram refined Er Shi disease, cerebral atrophy, amyotrophic lateral sclerosis, Huntington Chorea (HD) or its combination.
Second aspect present invention provides a kind of pharmaceutical composition, comprising:
(a1) the first activeconstituents being used for the treatment of nerve degenerative diseases, described first activeconstituents is formula I or its acceptable salt; With
(a2) the 2nd activeconstituents being used for the treatment of nerve degenerative diseases, described 2nd activeconstituents is selected from: levodopa compound or its acceptable salt.
(b) pharmaceutically acceptable carrier,
The definition of its compounds of formula I is as described in the first aspect of the invention.
In another preference, the weight ratio of described first activeconstituents and the 2nd activeconstituents is 1:100 to 100:1, it is preferred that be 1:10 to 10:1.
Third aspect present invention provides a kind of method of drug candidate screening treatment nerve degenerative diseases, and described method comprises step:
A () provides a testing compound and positive reference compound, described positive reference compound is formula I or its pharmacy acceptable salt;
B () is in test group, detect described testing compound to the impact of the A amyloid beta of non-human animal model and/or NF-κ B, iNOS, IL-1 β, and the experimental result corresponding to positive controls and negative control group compares, wherein, in positive controls, detection positive reference compound is on the impact of A amyloid beta and/or NF-κ B, iNOS, IL-1 β;
Wherein, if the reduction degree of the A amyloid beta of non-human animal model and/or NF-κ B, iNOS, IL-1 β is significantly higher than negative control group by described testing compound, then described testing compound is pointed out to be the drug candidate treating nerve degenerative diseases.
In another preference, in step (b), by test group compared with positive controls, and compare the ratio of V1 and V2, wherein V1 is that described testing compound is to the reduction amplitude V1 of the amyloid beta of non-human animal model and/or NF-κ B, iNOS, IL-1 β, and V2 is that positive reference compound is to the reduction amplitude of the amyloid beta of non-human animal model and/or NF-κ B, iNOS, IL-1 β, if V1/V2 >=80%, then described testing compound is pointed out to be the drug candidate treating nerve degenerative diseases.
In another preference, described method also comprises step (c): to the testing compound filtered out in step (b), measures it further to the result for the treatment of of nerve degenerative diseases.
In another preference, described " being significantly higher than " refers to V1/V0 >=2, it is preferred that >=3, more preferably >=4,
Wherein, V1 is that described testing compound is to the reduction amplitude of the amyloid beta of non-human animal model and/or NF-κ B, iNOS, IL-1 β; And V0 is the amyloid beta of people's animal model in negative control group (or model group) and/or the reduction amplitude of NF-κ B, iNOS, IL-1 β.
In another preference, described method is non-diagnostic and non-therapeutic.
Fourth aspect present invention provides a kind of method treating nerve degenerative diseases, comprising: administration formula I or its acceptable salt giving needs, its compounds of formula I is as described in the first aspect of the invention.
In another preference, described formula I is Triglyceride DDD.
In another preference, described Mammals comprises the Mammals suffering from nerve degenerative diseases.
In another preference, described nerve degenerative diseases is selected from lower group: alzheimer's disease (AD), parkinsonism syndromes (PD), gram refined Er Shi disease, cerebral atrophy, amyotrophic lateral sclerosis or its combination.
In another preference, described Mammals comprises people.
In another preference, described Mammals comprises non-human mammal.
In another preference, described Mammals comprises rodent, such as rat, mouse.
In another preference, application dosage is 100-10000mg/kg/ days, it is preferred that, 500-10000mg/kg/ days, more preferably, 1000-10000mg/kg/ days.
In another preference, frequency of administration is 1-5 times/day, it is preferred that 1-2 times/day.
In another preference, using and comprise one or more cycle, each cycle is 2-30 days, it is preferred that 3-7 days.
Fifth aspect present invention provides PPAR γ albumen in the raising mammalian tissues of a kind of external non-therapeutic and/or reduces the method for A amyloid beta level, comprise: to the administration formula I of needs or its acceptable salt, its compounds of formula I is as described in the first aspect of the invention.
In another preference, described formula I is Triglyceride DDD.
In another preference, described Mammals comprises the Mammals suffering from nerve degenerative diseases.
In another preference, described tissue comprises cerebral tissue.
In another preference, described Mammals comprises people.
In another preference, described Mammals comprises non-human mammal.
In another preference, described Mammals comprises rodent, such as rat, mouse.
In another preference, application dosage is 10-10000mg/kg/ days, it is preferred that, 500-10000mg/kg/ days, more preferably, 1000-10000mg/kg/ days.
In another preference, frequency of administration is 1-5 times/day, it is preferred that 1-2 times/day.
In another preference, using and comprise one or more cycle, each cycle is 2-30 days, it is preferred that 3-7 days.
It will be understood that within the scope of the present invention, above-mentioned each technology characteristic sum of the present invention can combine mutually between specifically described each technology feature in below (eg embodiment), thus form new or preferred technical scheme. As space is limited, tired no longer one by one state at this.
Accompanying drawing explanation
Fig. 1 shows the pathologic finding figure (HE dyeing) of embodiment of the present invention blank group mouse, model group mouse, Triglyceride DDD 200mg/kg, 600mg/kg and 1000mg/kg dosage group mouse, in figure, the arrangement of display model group cell is more disorderly, relatively many cells vacuolar degeneration, pyknosis are downright bad, after pharmacological agent, constantly being improved, wherein high dose group cell integrated degree is close to normal group.
It is the impact that D-semi-lactosi is caused PPAR γ genetic expression in Senlie dementia model Mice brain tissues by 200mg/kg, 600mg/kg and 1000mg/kg that Fig. 2 shows blank group mouse, model group mouse and Triglyceride DDD at dosage; Wherein, the expression of model group PPAR γ obviously reduces, and administration group is increasing of dose-dependently with the expressing of increase PPAR γ of dosage.
Fig. 3 shows the histogram of PPAR γ genetic expression content.
It is that D-semi-lactosi is caused the impact that in Senlie dementia model Mice brain tissues, NF-κ 1 B gene is expressed by 200mg/kg, 600mg/kg and 1000mg/kg that Fig. 4 shows blank group mouse, model group mouse and Triglyceride DDD at dosage; Wherein, the expression showed increased of model group NF-κ B, administration group is with the reduction that the expression of the increase NF-κ B of dosage is dose-dependently.
Fig. 5 shows the histogram of NF-κ 1 B gene expression contents.
It is that D-semi-lactosi is caused the impact of iNOS genetic expression in Senlie dementia model Mice brain tissues by 200mg/kg, 600mg/kg and 1000mg/kg at dosage that Fig. 6 shows blank group mouse, model group mouse and Triglyceride DDD, wherein, the expression showed increased of model group iNOS, administration group is with the reduction that the expression of the increase iNOS of dosage is dose-dependently.
Fig. 7 shows the histogram of iNOS gene expression amount.
It is that D-semi-lactosi is caused the impact of aβ protein genetic expression in Senlie dementia model Mice brain tissues by 200mg/kg, 600mg/kg and 1000mg/kg at dosage that Fig. 8 shows blank group mouse, model group mouse and Triglyceride DDD, the expression showed increased of model group A β, administration group is with the reduction that the expression of the increase A β of dosage is dose-dependently.
Fig. 9 shows the histogram of aβ protein gene expression amount.
It is the impact that D-semi-lactosi is caused IL-1 β content in Senlie dementia model mice serum by 200mg/kg, 600mg/kg and 1000mg/kg that Figure 10 shows blank group mouse, model group mouse and Triglyceride DDD at dosage, wherein, model group IL-1 β content obviously increases, and administration group is with the minimizing that the increase group IL-1 β content of dosage is dose-dependently.
Embodiment
The present inventor, through extensive and deep research, finds first surprisingly, and triglyceride level compounds (formula I) or its pharmacy acceptable salt can treat nerve degenerative diseases for (i) effectively;(ii) Mammals cerebral tissue PPAR γ protein level is improved; (iii) expression of A amyloid beta in Mammals cerebral tissue is reduced; And/or (iv) reduces the expression of NF-κ B, iNOS and IL-1 β in Mammals cerebral tissue. On this basis, the present inventor completes the present invention.
Term
Term " C5、C7、C9、C11Alkyl " refer to the straight or branched alkyl of 5,7,9,11 carbon atoms, such as pentane base, heptane base, nonane base, undecyl or similar group.
Term " C5、C7、C9、C11Alkenyl " refer to the alkene base of the straight or branched of 5,7,9,11 carbon atoms, such as pentenyl, heptenyl, nonenyl, hendecene base or similar group.
Term " C5、C7、C9、C11Alkynyl group " refer to the alkynes base of the straight or branched of 5,7,9,11 carbon atoms, such as alkynes base, heptyne base, n-heptylacetylene base, 11 alkynes bases or similar group.
Term " even number chain triglyceride " refers to the triglyceride level containing even-numbered carbon atom (such as 6,8,10,12), such as, and caproic acid triglyceride level, Trivent OCG, Triglyceride DDD, dodecylic acid triglyceride level or similar triglyceride level.
Activeconstituents
In the present invention, triglyceride level compounds is used as activeconstituents, for i) treating nerve degenerative diseases; (ii) Mammals cerebral tissue PPAR γ protein level is improved; (iii) expression of A amyloid beta in Mammals cerebral tissue is reduced; And/or (iv) reduces the expression of NF-κ B, iNOS and IL-1 β in Mammals cerebral tissue.
As used herein, described " activeconstituents of the present invention ", " formula I ", " the triglyceride level compounds of the present invention ", " triglyceride level compounds " can use each other, all refer to the formula I that extracts from natural product (such as Oleum Cocois) or its pharmacy acceptable salt
In formula, the definition of each group is described above.
In formula, R1、R2And R3It is selected from lower group: C independently of one another5、C7、C9、C11Alkyl, C5、C7、C9、C11Alkenyl and C5、C7、C9、C11Alkynyl group.
The one particularly preferred formula I of class is the compound described in embodiment, i.e. Triglyceride DDD.
In the present invention, the pharmacy acceptable salt of formula I is also comprised. Term " pharmacy acceptable salt " refers to the salt being suitable as medicine that the compounds of this invention is formed with acid or alkali. Pharmacy acceptable salt comprises inorganic salt and organic salt. The one preferred salt of class is the salt that the compounds of this invention is formed with acid. The acid being applicable to being formed salt includes, but are not limited to: the mineral acids such as hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid, methylsulfonic acid, benzene methanesulfonic acid, the organic acids such as Phenylsulfonic acid; And the acidic amino acid such as aspartic acid, L-glutamic acid.
A amyloid beta
A amyloid beta molecular weight is about 4kDa, is hydrolyzed by beta-amyloyd precursor protein, by emiocytosis, has very strong neurotoxic effect after cell matrix precipitation is built up.
The deposition of A β is not only relevant with neuronic degeneration, and a series of pathology affair can be activated, comprise the change etc. of the activation of star spongiocyte and microglia, the broken ring of hemato encephalic barrier and microcirculation, it is the unit's sex change of senile plaque peripheral nerve and main causes of death in patient's AD brain.
In the present invention, by detection A amyloid beta expression level, thus judge the validity of formula I (such as Triglyceride DDD) at treatment nerve degenerative diseases.
In one preferred embodiment, when A amyloid beta expression level reduces, show that nerve degenerative diseases is had therapeutic action by formula I (such as Triglyceride DDD).
NF-κ B, iNOS and IL-1 β
Nuclear factor-kappaB (nuclearfactor-kappaB, NF-κ B) be a kind of have many to the protein of transcriptional regulation, extensively it is present in eukaryotic cell, participate in the transcriptional control of several genes, with the hyperplasia of inflammatory reaction, immunne response and cell, transform and the important physiological and pathological process such as die of withering closely related.
NF-κ B is a kind of important transcription factor that various inflammatory reactions and immunogene can be regulated to express, a lot of extracellular stimulus thing such as inflammatory cytokine etc. all can activate NF-κ B signal path, and NF-κ B plays keying action after activating in the genetic expression of inflammation-related factor etc. These inflammatory factors can activate again NF-κ B further, and the NF-κ B of activation can produce short antiapoptotic factors such as iNOS, IL-1 β etc. by inducing nerve cell, finally causes Neuron Apoptosis. The abnormal activation of NF-κ B is that body inflammatory reaction is amplified and the Molecular Biology Mechanism continued, therefore NF-κ B is not only Inflammatory Mediators, is also the crucial mediator of Inflammatory response, take part in the pathologic process of the many diseases comprising AD. Big quantity research shows to suppress the activation of NF-κ B signal path anti-apoptotic, inflammatory and immune response and A β can be deposited and play cerebral protection simultaneously. NF-κ B transcription factor regulation and control nitric oxide synthase type (induciblenitricoxidesynthase under pathological state, iNOS) gene promoter, iNOS expresses, continue to produce a large amount of NO, NO is the important signaling molecule of neural system, has mediation neurotoxic effect in AD, closely related with the pathologic process such as the tau peroxophosphoric acid of AD morbidity, A β deposition, also regulate oxidative stress and the microvascular lesions of AD, affect generation and the development of AD.
In the present invention, by detecting the expression level of NF-κ B, iNOS and IL-1 β, thus indirectly judge the validity of formula I (such as Triglyceride DDD) at treatment nerve degenerative diseases.
In one preferred embodiment, when the expression level of NF-κ B, iNOS and IL-1 β reduces, show that nerve degenerative diseases is had therapeutic action by formula I (such as Triglyceride DDD).
Composition and application thereof
The triglyceride level compounds (formula I or its pharmacy acceptable salt) of the present invention and the composition being main active ingredient containing the compounds of this invention can be used for treatment, prevention and alleviate nerve degenerative diseases.
Composition of the present invention comprises (but being not limited to): pharmaceutical composition, food compositions, health composition, dietary supplements, drink composition etc.
The pharmaceutical composition of the present invention comprises the triglyceride level compounds in safe and effective weight range (formula I) or its pharmacologically acceptable salt and the vehicle that pharmacologically can accept or carrier. Wherein " safe and effective amount " refers to: the amount of compound is enough to obviously improve the state of an illness, and is unlikely to produce severe side effect. Usually, pharmaceutical composition contains the compounds/agent of 1-10000mg triglyceride level, more preferably, containing the compounds/agent of 100-8000mg triglyceride level, best containing the compounds/agent of 200-6000mg triglyceride level. Goodly, described " one dose " is a capsule or tablet.
" carrier that pharmaceutically can accept " refers to: one or more biocompatible solid or liquid filler or gelatinous mass, and they are suitable for people and use and it is necessary to have enough purity and enough low toxicity.The compound that " consistency " referred to herein as in composition each component energy and the present invention and they between mutually admix, and the drug effect of not obvious reduction compound. The carrier part example that pharmaceutically can accept have cellulose and its derivates (such as Xylo-Mucine, ethyl cellulose sodium, cellulose ethanoate etc.), gelatin, talcum, solid lubricant (such as stearic acid, Magnesium Stearate), calcium sulfate, vegetables oil (such as soya-bean oil, sesame oil, peanut oil, sweet oil etc.), polyvalent alcohol (such as propylene glycol, glycerine, N.F,USP MANNITOL, sorbyl alcohol etc.), emulsifying agent (as ), wetting agent (such as sodium lauryl sulphate), tinting material, seasonings, stablizer, antioxidant, sanitas, apirogen water etc.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, representative method of application comprises (but being not limited to): oral, rectum, parenteral (intravenously, intramuscular or subcutaneous) and topical, it is preferable that administering mode be oral administration.
Solid dosage for oral administration comprises capsule, tablet, pill, powder and granule. In these solid dosages, active compound inert excipient (or carrier) conventional with at least one mixes, such as Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade, or mix with following compositions: (a) filler or expanding material, such as, starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid; (b) tackiness agent, such as, Walocel MT 20.000PV, alginate, gelatin, Polyvinylpyrolidone (PVP), sucrose and gum arabic; (c) wetting Agent for Printing Inks, such as, glycerine; (d) disintegrating agent, such as, agar, calcium carbonate, yam starch or tapioca (flour), alginic acid, some composition silicate and sodium carbonate; (e) retarding solvent, such as paraffin; F () absorbs accelerator, such as, and quaternary ammonium compound; (g) wetting agent, such as hexadecanol and glyceryl monostearate; (h) sorbent material, such as, kaolin; (i) lubricant, such as, talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate, or its mixture. In capsule, tablet and pill, formulation also can comprise buffer reagent.
Solid dosage can adopt dressing and the preparation of shell material such as tablet, sugar-pill, capsule, pill and granule, such as casing and other material well known in the art. They can comprise opacifying agent, and, in this kind of composition, the release of active compound or compound can release in the part of certain in digestive tube in a delayed fashion. The example of the embedding component that can adopt is polymeric material and Wax. If desired, active compound also can with in above-mentioned vehicle one or more formed microencapsulation form.
Liquid dosage form for oral administration comprises pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture. Except active ingredient beyond the region of objective existence, liquid dosage form can comprise the conventional inert diluent adopted in this area, such as water or other solvent, solubilizing agent and emulsifying agent, example is known, the mixture etc. of ethanol, Virahol, ethyl-carbonate, ethyl acetate, propylene glycol, 1,3 butylene glycol, dimethyl formamide and oil, particularly Oleum Gossypii semen, peanut oil, maize germ, sweet oil, Viscotrol C and sesame oil or these materials.
Except these inert diluents, composition also can comprise auxiliary agent, such as wetting agent, emulsifying agent and suspension agent, sweeting agent, tender taste agent and spices.
Except active ingredient beyond the region of objective existence, suspension can comprise suspension agent, such as, and the mixture etc. of ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and Isosorbide Dinitrate, Microcrystalline Cellulose, aluminum methylate and agar or these materials.
Composition for parenteral injection can comprise physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, suspension or emulsion, and for being again dissolved into aseptic Injectable solution or the sterilized powder of dispersion liquid. Moisture and the nonaqueous carrier, thinner, solvent or the vehicle that are suitable for comprise water, ethanol, polyvalent alcohol and suitable mixture thereof.
Formulation for the compounds of this invention of topical comprises ointment, powder, patch, propellant and inhalation. Activeconstituents aseptically with physiologically acceptable carrier and any sanitas, buffer reagent, or the propelling agent that may need if desired is mixed together.
The compounds of this invention can be individually dosed, or with other pharmaceutically acceptable compound Combined Preparation (such as levodopa or its pharmacy acceptable salt etc.).
When making pharmaceutical composition, it it is the Mammals (such as people) that the compounds of this invention of safe and effective amount is applicable to need treatment, when wherein using, dosage is the effective dosage pharmaceutically thought, for the people of 60kg body weight, day dosage is generally 1～10000mg, preferably 100～8000mg, it is more preferable to be 200-6000mg. Certainly, concrete dosage also should consider the factor such as route of administration, patient health situation, and these are all within skilled practitioners skill.
The major advantage of the present invention comprises:
(1) Late Cambrian triglyceride level compounds (formula I) of the present invention has the activity for the treatment of nerve degenerative diseases.
(2) Late Cambrian triglyceride level compounds (formula I) of the present invention has following feature: (i) treats nerve degenerative diseases; (ii) Mammals cerebral tissue PPAR γ protein level is improved; (iii) expression of A amyloid beta in Mammals cerebral tissue is reduced; And/or (iv) reduces the expression of NF-κ B, iNOS and IL-1 β in Mammals cerebral tissue.
(3) triglyceride level compounds (formula I) derives from natural product (such as Oleum Cocois), has the advantages that side effect is little, cost is low, security is good.
Below in conjunction with specific embodiment, set forth the present invention further. Limit the scope of the invention it will be understood that these embodiments are only not used in for illustration of the present invention. The experimental technique of unreceipted concrete condition in the following example, usually conveniently condition, or according to the condition that manufacturer advises. Unless otherwise indicated, otherwise per-cent and part number are weight percent and weight part number. Following examples statistically all with the blank group of * P < 0.05, * * p < 0.01vs, < 0.01vs model group is considered as significant difference for #p < 0.05, ##p.
Embodiment
1. material
1.1 animal
Animal SPF level KM female mice 50, body weight 20 ± 2g, is provided by Hunan Si Laike company.
1.2 medicines and reagent
Triglyceride DDD is purchased from sigma-aldrich company.
1.3 instrument
TLL-C tabletop refrigerated centrifuge, purchased from Fourth Ring, Beijing scientific instrument factory;
AU600 full-automatic biochemical detector, is produced by Olympus;
752 type spectrophotometers, purchased from Shanghai the 3rd analytical instrument factory;
O1ymPusBX51 microscope, is produced by Olympus;
BS1105 electronic balance, purchased from sartorius company of Germany.
2. method
2.1 grouping and model are set up
Experiment grouping: 1. blank group (normal group) 2. model group 3. Triglyceride DDD (GT) 200mg/kg 4. Triglyceride DDD (GT) 600mg/kg 5. Triglyceride DDD (GT) 100mg/kg dosage group.
Model is set up: get SD mouse 50, and wherein 10 mouse are blank group, and 10 mouse are model group, and 30 mouse are administration group. Wherein model group and administration group adopt subcutaneous D-gal50mg/kg/d method to carry out modeling, every day 1 time, altogether 40d
Giving pharmacological agent in modeling, medicine GT is dissolved in peanut oil by 200mg/kg, 600mg/kg and 1000mg/kg dosage simultaneously, every day gavage once, once a day; Model group and blank group give blank solvent simultaneously.
2.2 Testing index
Protein immunoblotting method measures the expression of each group of Mice brain tissues A β, IL-1 β, iNOS, NF-κ B, PPAR γ albumen; Measure its ability of learning and memory with water maze laboratory method simultaneously; Pathological observation, gets each mouse brain same position tissue, fixes with 10% neutral formalin, dehydration, embedding, section, dewaxing, does conventional H E dyeing, envelope sheet. Microscopic observation analyzes histopathology situation.
2.3 data processing
Statistical analysis is carried out with SPSS13.0 software. Testing data mean value ± standard is missed (mean ± SE) and is represented, the comparison all counted between each group adopts one-way analysis of variance (one-wayANOVEA), Dunnett-t is adopted to check again, using P < 0.05 as significant difference standard.
3. result
3.1 Triglyceride DDDs are on the impact of senile dementia learning and memory.
By the Spatial memory ability of Morris determined with Morris water mouse, each group mouse detects after modeling and drug intervention terminate.
Result is as shown in table 1. Result shows, compared with blank group (normal group), model group significantly reduced in the residence time of platform quadrant, showed that its memory obviously weakens; And GT administration group increases memory with dosage is further improved. Compared with model group, the platform quadrant residence time of GT administration group obviously raises, close to blank group level.
D-semi-lactosi is caused the impact (Mean ± S.E.M) of Senlie dementia model mouse Spatial memory ability by table 1 Triglyceride DDD
D-semi-lactosi is caused the pathological examination of Senlie dementia model mouse by 3.2 Triglyceride DDDs
Result is as shown in Figure 1. Result shows, and normal mouse hippocampus CA3 district pyramidal cell arrangement is still neat, rarely seen cell vacuolar degeneration and Necrosis Model group mouse CA1 pyramidal cell at hippocampus arrangement disorder, a large amount of cell vacuolar degeneration, pyknosis necrosis. Cones arrangement in GT low dose group hippocampus CA1 district is more disorderly, and relatively many cells vacuolar degeneration, pyknosis are downright bad; In GT, the arrangement of dosage group CA1 pyramidal cell at hippocampus is relatively neat, a small amount of cell vacuolar degeneration but have no downright bad; GT high dose group CA1 pyramidal cell at hippocampus integrated degree is close to normal group.
Result shows, Triglyceride DDD can significantly improve the senile dementia symptom of model mice.
D-semi-lactosi is caused the impact of PPAR γ in Senlie dementia model Mice brain tissues by 3.3 Triglyceride DDDs
Result is as shown in table 2 and Fig. 2-3. Result shows, compared with blank group (normal group), the expression of the PPAR γ of model group reduces 37%, and compared with model group, the expression of the PPAR γ of GT1000mg/kg mouse significantly improves 253%.
Table 2.
D-semi-lactosi is caused the impact of NF-κ B in Senlie dementia model Mice brain tissues by 3.4 Triglyceride DDDs
Result is as shown in table 3 and Fig. 4-5. Result shows, compared with blank group (normal group), the level of model group NF-κ B increases 20%, and compared with model group, the level of the NF-κ B of GT1000mg/kg mouse reduces 36.7%.
Table 3.
D-semi-lactosi is caused the impact of iNOS in Senlie dementia model Mice brain tissues by 3.5 Triglyceride DDDs
Result is as shown in table 4 and Fig. 6-7. Result shows, compared with blank group (normal group), the level of model group iNOS raises 13%, and compared with model group, the level of the iNOS of GT1000mg/kg mouse reduces 49.5%.
Table 4.
D-semi-lactosi is caused the impact that in Senlie dementia model Mice brain tissues, aβ protein is expressed by 3.6 Triglyceride DDDs
Result is as shown in table 5 and Fig. 8-9. Result shows, compared with blank group (normal group), the level that model group aβ protein is expressed raises 68%, and compared with model group, the aβ protein expression level of GT1000mg/kg mouse reduces 48.8%.
Table 5.
D-semi-lactosi is caused the impact of IL-1 β content in Senlie dementia model mice serum by 3.7 Triglyceride DDDs
Result is as shown in table 6 and Figure 10. Result shows, compared with blank group (normal group), the content of model group IL-1 β raises 99.8%, and compared with model group, the content of the IL-1 β of GT1000mg/kg mouse reduces 48.7%, close to blank group level.
Table 6.
To sum up, result shows, nerve degenerative diseases is had good therapeutic action by Triglyceride DDD; Triglyceride DDD can raise the expression of PPAR γ albumen in cerebral tissue, reduces A amyloid beta expression level, reduces the expression level of NF-κ B, iNOS, IL-1 β in cerebral tissue simultaneously, improves the memory of senile dementia.
The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document. In addition it will be understood that after the above-mentioned teachings having read the present invention, the present invention can be made various changes or modifications by those skilled in the art, these equivalent form of values fall within the application's appended claims limited range equally.

Claims (10)

1. a purposes for formula I or its pharmacy acceptable salt, for the preparation of composition or the preparation for the treatment of nerve degenerative diseases,
In formula,
R1、R2And R3It is selected from lower group: C independently of one another5、C7、C9、C11Alkyl, C5、C7、C9、C11Alkenyl and C5、C7、C9、C11Alkynyl group.
2. purposes as claimed in claim 1, it is characterised in that, R1、R2And R3It is selected from lower group: C independently of one another7、C9Alkyl, C7、C9Alkenyl and C7、C9Alkynyl group.
3. purposes as claimed in claim 1, it is characterised in that, described composition comprises: pharmaceutical composition, Halth-care composition or food compositions or dietary supplement composition.
4. purposes as claimed in claim 1, it is characterised in that, described composition or preparation also improve the expression of PPAR γ albumen in mammalian tissues for (i); (ii) expression of A amyloid beta in mammalian tissues is reduced; And/or (iii) reduces the expression of NF-κ B, iNOS and IL-1 β in mammalian tissues.
5. a pharmaceutical composition, comprising:
(a1) the first activeconstituents being used for the treatment of nerve degenerative diseases, described first activeconstituents is formula I or its acceptable salt; With
(a2) the 2nd activeconstituents being used for the treatment of nerve degenerative diseases, described 2nd activeconstituents is selected from: levodopa compound or its acceptable salt.
(b) pharmaceutically acceptable carrier,
The definition of its compounds of formula I is as claimed in claim 1.
6. pharmaceutical composition as claimed in claim 5, it is characterised in that, the weight ratio of described first activeconstituents and the 2nd activeconstituents is 1:100 to 100:1, it is preferred that be 1:10 to 10:1.
7. screening a method for the drug candidate for the treatment of nerve degenerative diseases, described method comprises step:
A () provides a testing compound and positive reference compound, described positive reference compound is formula I or its pharmacy acceptable salt;
B () is in test group, detect described testing compound to the impact of the A amyloid beta of non-human animal model and/or NF-κ B, iNOS, IL-1 β, and the experimental result corresponding to positive controls and negative control group compares, wherein, in positive controls, detection positive reference compound is on the impact of A amyloid beta and/or NF-κ B, iNOS, IL-1 β;
Wherein, if the reduction degree of the A amyloid beta of non-human animal model and/or NF-κ B, iNOS, IL-1 β is significantly higher than negative control group by described testing compound, then described testing compound is pointed out to be the drug candidate treating nerve degenerative diseases.
8. method as claimed in claim 7, it is characterised in that, described method also comprises step (c): to the testing compound filtered out in step (b), measures it further to the result for the treatment of of nerve degenerative diseases.
9. treat a method for nerve degenerative diseases, comprising: to the administration formula I of needs or its acceptable salt, its compounds of formula I is as claimed in claim 1.
10. in the raising mammalian tissues of an external non-therapeutic PPAR γ albumen and/or reduce A amyloid beta level method, comprise: to the administration formula I of needs or its acceptable salt, its compounds of formula I is as claimed in claim 1.
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