WO2017113775A1 - 甘油三酯类化合物在制备治疗神经退行性疾病药物中的应用 - Google Patents

甘油三酯类化合物在制备治疗神经退行性疾病药物中的应用 Download PDF

Info

Publication number
WO2017113775A1
WO2017113775A1 PCT/CN2016/092068 CN2016092068W WO2017113775A1 WO 2017113775 A1 WO2017113775 A1 WO 2017113775A1 CN 2016092068 W CN2016092068 W CN 2016092068W WO 2017113775 A1 WO2017113775 A1 WO 2017113775A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
group
formula
neurodegenerative disease
composition
Prior art date
Application number
PCT/CN2016/092068
Other languages
English (en)
French (fr)
Inventor
易伟
徐华强
段小群
吴啸川
胡增仁
Original Assignee
浙江旭晨医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 浙江旭晨医药科技有限公司 filed Critical 浙江旭晨医药科技有限公司
Publication of WO2017113775A1 publication Critical patent/WO2017113775A1/zh

Links

Images

Classifications

    • 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]
    • 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

Definitions

  • the invention relates to the field of medicines, in particular to the use of triglyceride compounds in the preparation of medicaments for treating neurodegenerative diseases.
  • AD Alzheimer disease
  • AD a chronic progressive neurodegenerative disease
  • AD is characterized by a decline in cognitive function, accompanied by multiple behavioral abnormalities that ultimately lead to death, Alzheimer's disease.
  • AD also known as senile dementia
  • senile dementia is a central nervous system degenerative disease, insidious onset, chronic progression, is the most common type of dementia in the elderly, mainly as progressive memory Neuropsychiatric symptoms such as disorders, cognitive dysfunction, personality changes, and language disorders severely affect social, professional, and life functions.
  • the etiology and pathogenesis of AD have not been elucidated.
  • the characteristic pathological changes are extracellular senile plaques formed by amyloid beta deposition and neuronal fibrillation in the neuronal cells formed by hyperphosphorylation of tau, and neuronal loss with gliosis. Wait. Therefore, it is very important to prevent further deterioration of memory function by early prevention of Alzheimer's syndrome.
  • Alzheimer's disease there are many varieties of drugs for preventing and treating Alzheimer's disease, but there are also various problems, such as bringing various side effects to the body of the patient. Therefore, the development of new products to prevent and treat Alzheimer's disease is of great significance.
  • Tridecanoic acid triglyceride is mainly derived from natural products such as coconut oil and belongs to one of medium chain triglycerides. It has been widely used in food, medicine and cosmetics, but it is used in the preparation of therapeutic nerve degeneration. The application of drugs for sexually transmitted diseases has not been reported.
  • a first aspect of the invention provides a use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a composition or formulation for the treatment of a neurodegenerative disease,
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of C 5 , C 7 , C 9 , C 11 alkyl, C 5 , C 7 , C 9 , C 11 alkenyl, and C 5 , C 7 , C 9 , C 11 alkynyl.
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of C 7 , C 9 alkyl, C 7 , C 9 alkenyl, and C 7 , C 9 alkynyl.
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of C 9 alkyl, C 9 alkenyl, and C 9 alkynyl.
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of C 9 alkyl.
  • R 1 , R 2 and R 3 are different.
  • R 1 , R 2 and R 3 are the same.
  • R 1 , R 2 and R 3 are both C 9 alkyl groups.
  • the compound of formula I is an even chain triglyceride.
  • the compound of formula I is capric triglyceride.
  • the composition comprises: a pharmaceutical composition, a nutraceutical composition, or a food composition, or a dietary supplement composition.
  • the composition is a pharmaceutical composition.
  • the food composition comprises a beverage composition.
  • the pharmaceutical composition comprises (a) a compound of formula I and (b) a pharmaceutically acceptable carrier.
  • the component (a) is from 0.1 to 99.9% by weight, preferably from 10 to 99.9% by weight, more preferably from 70% to 99.9% by weight, based on the total weight of the pharmaceutical composition.
  • component (a) comprises from 60.0% to 99.5 wt%, preferably from 70.0 to 99.5 wt%, more preferably from 80.0% to 99.5 wt%, based on the total weight of the pharmaceutical composition.
  • the pharmaceutical composition is a liquid, solid, or semi-solid.
  • the pharmaceutical composition is in the form of a tablet, granule, capsule, oral solution, or injection.
  • composition or formulation is also used to (i) increase expression of PPAR gamma protein in mammalian tissues; (ii) reduce expression of A beta amyloid in mammalian tissues; and/or (iii) Reduce the expression of NF- ⁇ B, iNOS and IL-1 ⁇ in mammalian tissues.
  • the mammal comprises a human or a non-human mammal.
  • the non-human mammal comprises a rodent such as a rat or a mouse.
  • the mammal comprises a mammal having a neurodegenerative disease.
  • the tissue comprises brain tissue.
  • the composition is an oral preparation.
  • the composition e.g., a pharmaceutical composition
  • the neurodegenerative disease is selected from the group consisting of Alzheimer's disease (AD), Parkinson's syndrome (PD), Creutzfeldt-Jakob disease, cerebellar atrophy, muscle atrophic lateral cord Sclerosis, Huntington's disease (HD), or a combination thereof.
  • AD Alzheimer's disease
  • PD Parkinson's syndrome
  • HD Huntington's disease
  • a second aspect of the invention provides a pharmaceutical composition comprising:
  • (a2) a second active ingredient for treating a neurodegenerative disease, the second active ingredient being selected from the group consisting of: a levodopa compound or an acceptable salt thereof;
  • the weight ratio of the first active ingredient to the second active ingredient is from 1:100 to 100:1, preferably from 1:10 to 10:1.
  • a third aspect of the invention provides a method of screening for a drug candidate for treating a neurodegenerative disease, the method comprising the steps of:
  • test compound is against A ⁇ amyloid and/or NF- ⁇ B in a non-human animal model
  • degree of reduction of iNOS and IL-1 ⁇ was significantly higher than that of the negative control group, suggesting that the test compound is a drug candidate for treating neurodegenerative diseases.
  • step (b) the test group is compared to a positive control group and the ratio of V1 to V2 is compared, wherein V1 is the beta amyloid protein of the test compound to a non-human animal model. And / or NF- ⁇ B, iNOS, IL-1 ⁇ decreased by V1, and V2 is the positive control compound for the reduction of ⁇ amyloid and / or NF- ⁇ B, iNOS, IL-1 ⁇ in non-human animal models, if V1/V2 ⁇ 80%, suggesting that the test compound is a drug candidate for treating a neurodegenerative disease.
  • the method further comprises the step (c) of further determining the therapeutic effect on the neurodegenerative disease by screening the test compound selected in the step (b).
  • said "significantly higher" means V1/V0 ⁇ 2, preferably ⁇ 3, more preferably ⁇ 4,
  • V1 is a decrease in ⁇ amyloid and/or NF- ⁇ B, iNOS, IL-1 ⁇ of the test compound to a non-human animal model; and V0 is a human animal model in a negative control group (or model group) The decrease in amyloid beta and/or NF- ⁇ B, iNOS, IL-1 ⁇ .
  • the method is non-diagnostic and non-therapeutic.
  • a fourth aspect of the invention provides a method of treating a neurodegenerative disease comprising: administering a compound of formula I or a pharmaceutically acceptable salt thereof to a mammal in need thereof, wherein the compound of formula I is as described in the first aspect of the invention.
  • the compound of formula I is capric triglyceride.
  • the mammal comprises a mammal having a neurodegenerative disease.
  • the neurodegenerative disease is selected from the group consisting of Alzheimer's disease (AD), Parkinson's disease syndrome (PD), Creutzfeldt-Jakob disease, cerebellar atrophy, muscle atrophic side Sclerosing, or a combination thereof.
  • AD Alzheimer's disease
  • PD Parkinson's disease syndrome
  • Creutzfeldt-Jakob disease cerebellar atrophy
  • muscle atrophic side Sclerosing or a combination thereof.
  • the mammal comprises a human.
  • the mammal comprises a non-human mammal.
  • the mammal comprises a rodent such as a rat or a mouse.
  • the administration dose is 100-10000 mg/kg/day, preferably 500-10000 mg/kg/day, more preferably 1000-10000 mg/kg/day.
  • the application frequency is 1-5 times/day, preferably 1-2 times/day.
  • the administration comprises one or more cycles, each cycle being from 2 to 30 days, preferably from 3 to 7 days.
  • the fifth aspect of the invention provides a non-therapeutic increase of PPAR ⁇ protein in mammalian tissues in vitro And/or a method of lowering A[beta] amyloid levels, comprising: administering to a mammal in need thereof a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is as described in the first aspect of the invention.
  • the compound of formula I is capric triglyceride.
  • the mammal comprises a mammal having a neurodegenerative disease.
  • the tissue comprises brain tissue.
  • the mammal comprises a human.
  • the mammal comprises a non-human mammal.
  • the mammal comprises a rodent such as a rat or a mouse.
  • the administration dose is 10-10000 mg/kg/day, preferably 500-10000 mg/kg/day, more preferably 1000-10000 mg/kg/day.
  • the application frequency is 1-5 times/day, preferably 1-2 times/day.
  • the administration comprises one or more cycles, each cycle being from 2 to 30 days, preferably from 3 to 7 days.
  • FIG. 1 shows a pathological examination map (HE staining) of a blank group mouse, a model group mouse, and a citrate triglyceride 200 mg/kg, 600 mg/kg, and 1000 mg/kg group of mice in the present invention, which shows The cells in the model group were more disorderly arranged, and more cell vacuolar degeneration, pyknosis and necrosis were obtained. After drug treatment, the cells were continuously improved. The cell integrity of the high dose group was close to the normal group.
  • HE staining HE staining
  • Figure 2 shows the expression of PPAR ⁇ gene in the brain tissue of mice with D-galactose-induced Alzheimer's disease at a dose of 200 mg/kg, 600 mg/kg and 1000 mg/kg in blank group mice, model group mice and citrate triglyceride at doses of 200 mg/kg, 600 mg/kg and 1000 mg/kg.
  • the effect of PPAR ⁇ was significantly decreased in the model group, and the expression of PPAR ⁇ increased in a dose-dependent manner with increasing dose.
  • Figure 3 shows a histogram of the expression level of the PPAR ⁇ gene.
  • Figure 4 shows NF- ⁇ B in brain tissue of D-galactose-induced Alzheimer's disease model mice at a dose of 200 mg/kg, 600 mg/kg, and 1000 mg/kg in a blank group of mice, a model group of mice, and citrate triglyceride.
  • the expression of NF- ⁇ B was decreased in a dose-dependent manner.
  • Figure 5 shows a histogram of the expression level of NF- ⁇ B gene.
  • Figure 6 shows the expression of iNOS gene in brain tissue of mice with D-galactose-induced Alzheimer's disease at a dose of 200 mg/kg, 600 mg/kg and 1000 mg/kg in blank group mice, model group mice and citrate triglyceride at doses of 200 mg/kg, 600 mg/kg and 1000 mg/kg.
  • the effect of iNOS expression in the model group was significantly increased, and the expression of iNOS decreased in a dose-dependent manner with increasing dose.
  • Figure 7 shows a histogram of the amount of iNOS gene expression.
  • Figure 8 shows the A ⁇ protein gene in the brain tissue of mice with D-galactose-induced Alzheimer's disease at a dose of 200 mg/kg, 600 mg/kg and 1000 mg/kg in blank group mice, model group mice and citrate triglyceride at doses of 200 mg/kg, 600 mg/kg and 1000 mg/kg.
  • the expression of A ⁇ was significantly increased in the model group, and the expression of A ⁇ was decreased in a dose-dependent manner with increasing dose.
  • Figure 9 shows a histogram of the amount of A ⁇ protein gene expression.
  • Figure 10 shows the IL-1 ⁇ content in the serum of the D-galactose-induced Alzheimer's disease model mice in the blank group, the model group, and the citrate triglyceride at doses of 200 mg/kg, 600 mg/kg, and 1000 mg/kg.
  • the effect of IL-1 ⁇ was significantly increased in the model group, and the IL-1 ⁇ content was decreased in a dose-dependent manner in the drug-administered group.
  • a triglyceride compound (a compound of formula I) or a pharmaceutically acceptable salt thereof can be effectively used for (i) treating a neurodegenerative disease; (ii) Increasing the level of PPAR ⁇ protein in mammalian brain tissue; (iii) reducing the expression of A ⁇ amyloid in mammalian brain tissue; and/or (iv) reducing the expression of NF- ⁇ B, iNOS and IL-1 ⁇ in mammalian brain tissue.
  • the inventors completed the present invention.
  • C 5 , C 7 , C 9 , C 11 alkyl refers to a straight or branched alkyl group of 5 , 7 , 9 , 11 carbon atoms, such as pentylene, heptyl, decyl, ten A monoalkyl group, or a similar group.
  • C 5 , C 7 , C 9 , C 11 alkenyl refers to a straight or branched alkenyl group of 5 , 7 , 9 , 11 carbon atoms, such as a pentenyl, heptenyl, nonenyl group. , undecenyl, or the like.
  • C 5 , C 7 , C 9 , C 11 alkynyl refers to a straight or branched alkynyl group of 5 , 7 , 9 , 11 carbon atoms, such as alkynyl, heptynyl, decynyl, Undecynyl, or a similar group.
  • even chain triglyceride refers to a triglyceride containing an even number of carbon atoms (eg, 6, 8, 10, 12), for example, caproic acid triglyceride, caprylic acid triglyceride, capric acid triglyceride, dodecane Acid triglycerides, or similar triglycerides.
  • a triglyceride compound is used as an active ingredient for i) treating a neurodegenerative disease; (ii) increasing a PPAR ⁇ protein level in a mammalian brain tissue; and (iii) reducing an A ⁇ amyloid in a mammalian brain tissue. Expression of the protein; and/or (iv) reduced expression of NF- ⁇ B, iNOS and IL-1 ⁇ in mammalian brain tissue.
  • the "active ingredient of the present invention”, “the compound of the formula I”, the “triglyceride compound of the present invention”, and the “triglyceride compound” may be used interchangeably, and both refer to a natural product (such as a compound of formula I or a pharmaceutically acceptable salt thereof, extracted from coconut oil),
  • each group is as defined above.
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of C 5 , C 7 , C 9 , C 11 alkyl, C 5 , C 7 , C 9 , C 11 alkenyl and C 5 , C 7 , C 9 , C 11 alkynyl.
  • a particularly preferred class of compounds of formula I are the compounds described in the examples, namely capric triglycerides.
  • pharmaceutically acceptable salts of the compounds of formula I are also included in the invention.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention which is formed with an acid or a base and which is suitable for use as a medicament.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzoic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,
  • Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid,
  • a ⁇ amyloid has a molecular weight of about 4 kDa, which is hydrolyzed by beta amyloid precursor protein and secreted by cells. It has a strong neurotoxic effect after the accumulation of cell matrix.
  • a ⁇ is not only related to the degenerative lesions of neurons, but also activates a series of pathological events, including activation of astrocytes and microglia, disruption of the blood-brain barrier, and changes in microcirculation.
  • the effectiveness of a compound of the formula I (such as citric acid triglyceride) in the treatment of a neurodegenerative disease is judged by detecting the level of A ⁇ amyloid expression.
  • a compound of formula I such as triglyceride, has a therapeutic effect on a neurodegenerative disease.
  • Nuclear factor-kappa B is a multi-directional transcriptional regulatory protein widely distributed in eukaryotic cells, involved in the transcriptional regulation of various genes, and in response to inflammation and immunity. Responses and important physiological and pathological processes such as cell proliferation, transformation and apoptosis are closely related.
  • NF- ⁇ B is an important transcription factor that regulates various inflammatory responses and immune gene expression.
  • Many extracellular stimuli such as inflammatory cytokines activate NF- ⁇ B signaling pathway, and NF- ⁇ B activates inflammation-related factors. Gene expression plays a key role. These inflammatory factors can further activate NF- ⁇ B, and activated NF- ⁇ B can induce neuronal production of pro-apoptotic factors such as iNOS, IL-1 ⁇ , etc., and finally lead to neuronal apoptosis.
  • Abnormal activation of NF- ⁇ B is a molecular and biological mechanism for the amplification and persistence of inflammatory response in the body. Therefore, NF- ⁇ B is not only an inflammatory marker, but also a key transmitter of inflammatory response.
  • NF- ⁇ B transcription factor regulates the initiation of inducible nitric oxide synthase (i NOS) gene, iNOS expression, and continues to produce a large number of NO.
  • NO is an important signaling molecule in the nervous system.
  • the neurotoxicity is closely related to the pathological processes such as tau hyperphosphorylation and A ⁇ deposition in AD. It also regulates oxidative stress and microvascular injury of AD, affecting the occurrence and development of AD.
  • the effectiveness of a compound of the formula I is indirectly determined by detecting the expression levels of NF- ⁇ B, iNOS and IL-1 ⁇ .
  • a compound of formula I such as triglyceride, has a therapeutic effect on a neurodegenerative disease.
  • the triglyceride compound of the present invention (the compound of the formula I or a pharmaceutically acceptable salt thereof) and the composition containing the compound of the present invention as a main active ingredient can be used for the treatment, prevention and alleviation of neurodegenerative diseases.
  • compositions of the invention include, but are not limited to, pharmaceutical compositions, food compositions, health care compositions, dietary supplements, beverage compositions, and the like.
  • compositions of the present invention comprise a triglyceride compound (compound of formula I) or a pharmacologically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier in a safe and effective amount.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-1000 mg of a triglyceride/agent, more preferably 100-8000 mg of a triglyceride/agent, and most preferably 200-6000 mg of a triglyceride/agent.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as Tween ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • vegetable oil such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyol such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifier such as Tween
  • a wetting agent such as sodium lauryl sulfate
  • a coloring agent such as a flavoring agent, a stabilizer, an antioxidant, a preservative
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration, preferably The mode of administration is oral administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., levodopa or a pharmaceutically acceptable salt thereof, etc.).
  • pharmaceutically acceptable compounds e.g., levodopa or a pharmaceutically acceptable salt thereof, etc.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually from 1 to 10,000 mg, preferably from 100 to 8000 mg, more preferably from 200 to 6000 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the present invention has found for the first time that a triglyceride compound (a compound of the formula I) has an activity for treating a neurodegenerative disease.
  • triglyceride compounds have the following characteristics: (i) treatment of neurodegenerative diseases; (ii) increase of PPAR ⁇ protein levels in mammalian brain tissue; and (iii) reduction of mammalian brain tissue Expression of A ⁇ amyloid; and/or (iv) reduction of expression of NF- ⁇ B, iNOS and IL-1 ⁇ in mammalian brain tissue.
  • Triglyceride compounds are derived from natural products (such as coconut oil) and have the characteristics of small side effects, low cost, and good safety.
  • Citric acid triglyceride was purchased from sigma-aldrich.
  • TLL-C desktop refrigerated centrifuge purchased from Beijing Sihuan Scientific Instrument Factory;
  • the 752 spectrophotometer was purchased from Shanghai No. 3 Analytical Instrument Factory;
  • Experimental group 1 blank group (normal group) 2 model group 3 citrate triglyceride (GT) 200 mg / kg 4 citrate triglyceride (GT) 600 mg / kg 5 citrate triglyceride (GT) 100 mg / kg dose group.
  • Model establishment 50 SD mice were taken, of which 10 mice were blank, 10 mice were model group, and 30 mice were administered.
  • the model group and the drug-administered group were modeled by subcutaneous D-gal 50 mg/kg/d method, once a day for 40 days.
  • the drug was treated at the same time of modeling.
  • the drug GT was dissolved in peanut oil at a dose of 200 mg/kg, 600 mg/kg and 1000 mg/kg, once a day, once a day; the model group and the blank group were simultaneously given a blank solvent.
  • Western blotting was used to determine the expression of A ⁇ , IL-1 ⁇ , iNOS, NF- ⁇ B and PPAR ⁇ protein in brain tissue of each group.
  • the learning and memory ability was determined by water maze test.
  • Pathological observation was taken. The same part of the tissue, fixed with 10% neutral formalin, dehydrated, embedded, sliced, dewaxed, routine HE staining, sealing. Microscopic observation and analysis of brain tissue pathology.
  • mice The spatial learning and memory ability of the mice was detected by Morris water maze. The mice in each group were tested after modeling and drug intervention.
  • the vertebral cells in the hippocampal CA1 area of the GT low-dose group were disordered, with more cell vacuolar degeneration, pyknosis and necrosis; the pyramidal cells in the hippocampal CA1 area of the GT medium dose group were arranged neatly, and a few cells were vacuolar degeneration but no necrosis; GT The degree of pyramidal cell integrity in the hippocampal CA1 region of the high-dose group was close to that of the normal group.
  • citrate triglyceride significantly improved the symptoms of Alzheimer's disease in model mice.
  • citrate triglyceride has a good therapeutic effect on neurodegenerative diseases; citrate triglyceride can up-regulate the expression of PPAR ⁇ protein in brain tissue, reduce the expression level of A ⁇ amyloid protein, and reduce brain tissue.
  • the expression levels of NF- ⁇ B, iNOS, and IL-1 ⁇ improve the memory of senile dementia.

Landscapes

  • 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

本发明提供了甘油三酯类化合物在制备治疗神经退行性疾病的药物中的应用。

Description

甘油三酯类化合物在制备治疗神经退行性疾病药物中的应用 技术领域
本发明涉及药物领域，具体地，涉及甘油三酯类化合物在制备治疗神经退行性疾病药物中的应用。
背景技术
阿尔茨海默病(Alzheimer disease，AD)，是一种慢性渐进性的神经退行性疾病，临床主要表现为认知功能不断下降，同时伴有多种行为异常，最终导致死亡，阿尔茨海默病(Alzheimer disease，AD)又叫老年性痴呆，是一种中枢神经系统变性病，起病隐袭，病程呈慢性进行性，是老年期痴呆最常见的一种类型，主要表现为渐进性记忆障碍、认知功能障碍、人格改变及语言障碍等神经精神症状，严重影响社交、职业与生活功能。AD的病因及发病机制尚未阐明，特征性病理改变为β淀粉样蛋白沉积形成的细胞外老年斑和tau蛋白过度磷酸化形成的神经细胞内神经原纤维缠结，以及神经元丢失伴胶质细胞增生等。因此，通过早期预防老年痴呆综合症以阻止记忆功能进一步减退非常重要。
目前，针对防治老年痴呆的药物品种很多，但也存在各种问题，如给病人的身体带来各种副作用等。因此，开发防治老年痴呆的新产品意义重大。
癸酸甘油三酯主要来源于椰子油等天然产物中，属于中链甘油三酯中的一种，已广泛应用于食品、医药及化妆品等领域，但关于癸酸甘油三酯在制备治疗神经退行性疾病药物中的应用，尚未见报道。
因此，本领域迫切需要开发一种副作用小、成本低的治疗神经退行性疾病的药物。
发明内容
本发明的目的是提供一种副作用小、成本低的治疗神经退行性疾病的药物。
本发明第一方面提供了一种式I化合物或其药学上可接受的盐的用途，用于制备治疗神经退行性疾病的组合物或制剂，
Figure PCTCN2016092068-appb-000001
式中，
R1、R2和R3各自独立地选自下组：C5、C7、C9、C11烷基、C5、C7、C9、C11链烯基、和C5、C7、C9、C11链炔基。
在另一优选例中，R1、R2和R3各自独立地选自下组：C7、C9烷基、C7、C9链烯基、和C7、C9链炔基。
在另一优选例中，R1、R2和R3各自独立地选自下组：C9烷基、C9链烯基、和C9链炔基。
在另一优选例中，R1、R2和R3各自独立地选自下组：C9烷基。
在另一优选例中，R1、R2和R3是不同的。
在另一优选例中，R1、R2和R3是相同的。
在另一优选例中，R1、R2和R3都是C9烷基。
在另一优选例中，所述式I化合物为偶数链甘油三酯。
在另一优选例中，所述式I化合物为癸酸甘油三酯。
在另一优选例中，所述的组合物包括：药物组合物、保健品组合物、或食品组合物、或膳食补充剂组合物。
在另一优选例中，所述的组合物为药物组合物。
在另一优选例中，所述的食品组合物包括饮料组合物。
在另一优选例中，所述的药物组合物含有(a)式I所示的化合物以及(b)药学上可接受的载体。
在另一优选例中，所述组分(a)占所述药物组合物总重量的0.1-99.9wt％,较佳地10-99.9wt％，更佳地70％-99.9wt％。
在另一优选例中，所述组分(a)占所述药物组合物总重量的60.0％-99.5wt％，较佳地70.0-99.5wt％，更佳地80.0％-99.5wt％。
在另一优选例中，所述药物组合物为液态、固体、或半固体。
在另一优选例中，所述药物组合物的剂型包括片剂、颗粒剂、胶囊、口服液、或注射剂。
在另一优选例中，所述的组合物或制剂还用于(i)提高哺乳动物组织中PPARγ蛋白的表达；(ii)降低哺乳动物组织中Aβ淀粉样蛋白的表达；和/或(iii)降低哺乳动物组织中NF-κB、iNOS和IL-1β的表达。
在另一优选例中，所述哺乳动物包括人或非人哺乳动物。
在另一优选例中，所述非人哺乳动物包括啮齿动物，如大鼠、小鼠。
在另一优选例中，所述哺乳动物包括患有神经退行性疾病的哺乳动物。
在另一优选例中，所述组织包括脑组织。
在另一优选例中，所述组合物为口服制剂。
在另一优选例中，所述的组合物(如药物组合物)通过以下方式施用于哺乳动物：口服、静脉注射、或局部注射。
在另一优选例中，所述神经退行性疾病选自下组：阿尔茨海默病(AD)、帕金森综合症(PD)、克雅二氏病、小脑萎缩症、肌肉萎缩性侧索硬化症、亨廷顿病(HD)、或其组合。
本发明第二方面提供了一种药物组合物，包括：
(a1)用于治疗神经退行性疾病的第一活性成分，所述第一活性成分为式I化合物或其可接受的盐；
(a2)用于治疗神经退行性疾病的第二活性成分，所述第二活性成分选自：左旋多巴化合物或其可接受的盐；和
(b)药学上可接受的载体，
其中式I化合物的定义如本发明第一方面所述。
在另一优选例中，所述第一活性成分和第二活性成分的重量比为1:100至100：1，较佳地为1:10至10：1。
本发明第三方面提供了一种筛选治疗神经退行性疾病的候选药物的方法，所述方法包括步骤：
(a)提供一待测化合物以及阳性对照化合物，所述的阳性对照化合物为式I化合物或其药学上可接受的盐，其中式I化合物的定义如本发明第一方面所述；
(b)在测试组中，检测所述待测化合物对非人动物模型的Aβ淀粉样蛋白和/或NF-κB、iNOS、IL-1β的影响，并与阳性对照组以及阴性对照组中相应的实验结果进行比较，其中，在阳性对照组中，检测阳性对照化合物对Aβ淀粉样蛋白和/或NF-κB、iNOS、IL-1β的影响；
其中，如果所述待测化合物对非人动物模型的Aβ淀粉样蛋白和/或NF-κB、 iNOS、IL-1β的降低程度显著高于阴性对照组，则提示所述待测化合物是治疗神经退行性疾病的候选药物。
在另一优选例中，在步骤(b)中，将测试组与阳性对照组相比，并比较V1与V2的比值，其中V1为所述待测化合物对非人动物模型的β淀粉样蛋白和/或NF-κB、iNOS、IL-1β的降低幅度V1，而V2为阳性对照化合物对非人动物模型的β淀粉样蛋白和/或NF-κB、iNOS、IL-1β的降低幅度，如果V1/V2≥80％，则提示所述待测化合物是治疗神经退行性疾病的候选药物。
在另一优选例中，所述的方法还包括步骤(c)：对步骤(b)中筛选出的待测化合物，进一步测定其对神经退行性疾病的治疗效果。
在另一优选例中，所述的“显著高于”指V1/V0≥2，较佳地≥3，更佳地≥4，
其中，V1为所述待测化合物对非人动物模型的β淀粉样蛋白和/或NF-κB、iNOS、IL-1β的降低幅度；而V0为阴性对照组(或模型组)中人动物模型的β淀粉样蛋白和/或NF-κB、iNOS、IL-1β的降低幅度。
在另一优选例中，所述的方法是非诊断和非治疗性的。
本发明第四方面提供了一种治疗神经退行性疾病的方法，包括：给需要的哺乳动物施用式I化合物或其药学上可接受的盐，其中式I化合物如本发明第一方面所述。
在另一优选例中，所述的式I化合物为癸酸甘油三酯。
在另一优选例中，所述哺乳动物包括患有神经退行性疾病的哺乳动物。
在另一优选例中，所述神经退行性疾病选自下组：阿尔茨海默病(AD)、帕金森症综合症(PD)、克雅二氏病、小脑萎缩症、肌肉萎缩性侧索硬化症、或其组合。
在另一优选例中，所述的哺乳动物包括人。
在另一优选例中，所述哺乳动物包括非人哺乳动物。
在另一优选例中，所述哺乳动物包括啮齿动物，如大鼠、小鼠。
在另一优选例中，施用剂量为100-10000mg/kg/天，较佳地，500-10000mg/kg/天，更佳地，1000-10000mg/kg/天。
在另一优选例中，施用频率为1-5次/天，较佳地1-2次/天。
在另一优选例中，施用包括一个或多个周期，各周期为2-30天，较佳地3-7天。
本发明第五方面提供了一种体外非治疗性的提高哺乳动物组织中PPARγ蛋白 和/或降低Aβ淀粉样蛋白水平的方法，包括：给需要的哺乳动物施用式I化合物或其药学上可接受的盐，其中式I化合物如本发明第一方面所述。
在另一优选例中，所述的式I化合物为癸酸甘油三酯。
在另一优选例中，所述哺乳动物包括患有神经退行性疾病的哺乳动物。
在另一优选例中，所述组织包括脑组织。
在另一优选例中，所述的哺乳动物包括人。
在另一优选例中，所述哺乳动物包括非人哺乳动物。
在另一优选例中，所述哺乳动物包括啮齿动物，如大鼠、小鼠。
在另一优选例中，施用剂量为10-10000mg/kg/天，较佳地，500-10000mg/kg/天，更佳地，1000-10000mg/kg/天。
在另一优选例中，施用频率为1-5次/天，较佳地1-2次/天。
在另一优选例中，施用包括一个或多个周期，各周期为2-30天，较佳地3-7天。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了本发明实施例空白组小鼠、模型组小鼠、癸酸甘油三酯200mg/kg、600mg/kg和1000mg/kg剂量组小鼠的病理检查图(HE染色)，图中显示模型组细胞排列较紊乱，较多细胞空泡变性、固缩坏死，经药物治疗后，得到不断改善，其中高剂量组细胞完整程度接近于正常组。
图2显示了空白组小鼠、模型组小鼠及癸酸甘油三酯在剂量为200mg/kg、600mg/kg和1000mg/kg对D-半乳糖致老年痴呆模型小鼠脑组织中PPARγ基因表达的影响；其中，模型组PPARγ的表达明显降低，给药组随剂量的增加PPARγ的表达呈剂量依赖性的增多。
图3显示了PPARγ基因表达含量的柱状图。
图4显示了空白组小鼠、模型组小鼠及癸酸甘油三酯在剂量为200mg/kg、600mg/kg和1000mg/kg对D-半乳糖致老年痴呆模型小鼠脑组织中NF-κB基因表达的影响；其中，模型组NF-κB的表达明显增多，给药组随剂量的增加 NF-κB的表达呈剂量依赖性的降低。
图5显示了NF-κB基因表达含量的柱状图。
图6显示了空白组小鼠、模型组小鼠及癸酸甘油三酯在剂量为200mg/kg、600mg/kg和1000mg/kg对D-半乳糖致老年痴呆模型小鼠脑组织中iNOS基因表达的影响，其中，模型组iNOS的表达明显增多，给药组随剂量的增加iNOS的表达呈剂量依赖性的降低。
图7显示了iNOS基因表达量的柱状图。
图8显示了空白组小鼠、模型组小鼠及癸酸甘油三酯在剂量为200mg/kg、600mg/kg和1000mg/kg对D-半乳糖致老年痴呆模型小鼠脑组织中Aβ蛋白基因表达的影响，模型组Aβ的表达明显增多，给药组随剂量的增加Aβ的表达呈剂量依赖性的降低。
图9显示了Aβ蛋白基因表达量的柱状图。
图10显示了空白组小鼠、模型组小鼠及癸酸甘油三酯在剂量为200mg/kg、600mg/kg和1000mg/kg对D-半乳糖致老年痴呆模型小鼠血清中IL-1β含量的影响，其中，模型组IL-1β含量明显增加，给药组随剂量的增加组IL-1β含量呈剂量依赖性的减少。
具体实施方式
本发明人经过广泛而深入的研究，首次意外地发现，甘油三酯类化合物(式I化合物)或其药学上可接受的盐可以有效地用于(i)治疗神经退行性疾病；(ii)提高哺乳动物脑组织PPARγ蛋白水平；(iii)降低哺乳动物脑组织中Aβ淀粉样蛋白的表达；和/或(iv)降低哺乳动物脑组织中NF-κB、iNOS和IL-1β的表达。在此基础上，本发明人完成了本发明。
术语
术语“C5、C7、C9、C11烷基”指5、7、9、11个碳原子的直链或支链烷基，例如戊烷基、庚烷基、壬烷基、十一烷基、或类似基团。
术语“C5、C7、C9、C11链烯基”指5、7、9、11个碳原子的直链或支链的烯基，例如戊烯基、庚烯基、壬烯基、十一烯基、或类似基团。
术语“C5、C7、C9、C11链炔基”指5、7、9、11个碳原子的直链或支链的炔基，例如炔基、庚炔基、壬炔基、十一炔基、或类似基团。
术语“偶数链甘油三酯”指含有偶数碳原子(如6、8、10、12)的甘油三酯，例如，己酸甘油三酯、辛酸甘油三酯、癸酸甘油三酯、十二烷酸甘油三酯、或类似的甘油三酯。
活性成分
在本发明中，将甘油三酯类化合物用作活性成分，用于i)治疗神经退行性疾病；(ii)提高哺乳动物脑组织PPARγ蛋白水平；(iii)降低哺乳动物脑组织中Aβ淀粉样蛋白的表达；和/或(iv)降低哺乳动物脑组织中NF-κB、iNOS和IL-1β的表达。
如本文所用，所述“本发明的活性成分”、“式I化合物”、“本发明的甘油三酯类化合物”、“甘油三酯类化合物”可以互为使用，均指从天然产物(如椰子油)中提取出来的式I化合物或其药学上可接受的盐，
Figure PCTCN2016092068-appb-000002
式中，各基团的定义如上所述。
式中，R1、R2和R3各自独立地选自下组：C5、C7、C9、C11烷基、C5、C7、C9、C11链烯基和C5、C7、C9、C11链炔基。
一类特别优选的式I化合物为实施例所述的化合物，即癸酸甘油三酯。
在本发明中，还包括式I化合物的药学上可接受的盐。术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸，苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。
Aβ淀粉样蛋白
Aβ淀粉样蛋白分子量约4kDa，由β淀粉样前体蛋白水解而来，由细胞分泌， 在细胞基质沉淀聚积后具有很强的神经毒性作用。
Aβ的沉积不仅与神经元的退行性病变有关，而且可以激活一系列病理事件，包括星型胶质细胞和小胶质细胞的激活、血脑屏障的破环和微循环的变化等，是AD病人脑内老年斑周边神经元变性和死亡的主要原因。
在本发明中，通过检测Aβ淀粉样蛋白表达水平，从而判断式I化合物(如癸酸甘油三酯)在治疗神经退行性疾病的有效性。
在一个优选的实施方式中，当Aβ淀粉样蛋白表达水平降低时，表明式I化合物(如癸酸甘油三酯)对神经退行性疾病有治疗作用。
NF-κB、iNOS和IL-1β
核转录因子-kappa B(nuclear factor-kappa B,NF-κB)是一种具有多向转录调节作用的蛋白质,广泛存在于真核细胞内,参与多种基因的转录调控,与炎症反应、免疫应答以及细胞的增生、转化和凋亡等重要的生理病理过程密切相关。
NF-κB是一种能调节多种炎症反应和免疫基因表达的重要转录因子，很多细胞外刺激物如炎性细胞因子等都可激活NF-κB信号通路，NF-κB激活后在炎症相关因子等的基因表达中起着关键作用。这些炎症因子又可进一步活化NF-κB，激活的NF-κB可诱导神经细胞产生促凋亡因子如iNOS、IL-1β等，最后导致神经元凋亡。NF-κB的异常激活是机体炎症反应放大与持续的分子生物学机制，故NF-κB不仅是炎性标志物，也是炎性反应的关键递质，参与了包括AD在内的诸多疾病的病理过程。同时大量研究表明抑制NF-κB信号通路的激活可对抗细胞凋亡、炎症免疫反应和Aβ沉积而发挥脑保护作用。病理状态下NF-κB转录因子调控诱导型一氧化氮合酶(inducible nitric oxide synthase，i NOS)基因启动，iNOS表达，持续产生大量NO，NO是神经系统重要的信号分子，在AD中有介导神经毒性作用，与AD发病的tau过磷酸化、Aβ沉积等病理过程密切相关，还调节AD的氧化应激和微血管损伤，影响AD的发生和发展。
在本发明中，通过检测NF-κB、iNOS和IL-1β的表达水平，从而间接判断式I化合物(如癸酸甘油三酯)在治疗神经退行性疾病的有效性。
在一个优选的实施方式中，当NF-κB、iNOS和IL-1β的表达水平降低时，表明式I化合物(如癸酸甘油三酯)对神经退行性疾病有治疗作用。
组合物及其应用
本发明的甘油三酯类化合物(式I化合物或其药学上可接受的盐)以及含有本发明化合物为主要活性成分的组合物可用于治疗、预防以及缓解神经退行性疾病。
本发明所述的组合物包括(但并不限于)：药物组合物、食品组合物、保健组合物、膳食补充剂、饮料组合物等。
本发明的药物组合物包含安全有效量范围内的甘油三酯类化合物(式I化合物)或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-10000mg甘油三酯类化合物/剂，更佳地，含有100-8000mg甘油三酯类化合物/剂，最佳地含有200-6000mg甘油三酯类化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2016092068-appb-000003
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药，优选的给药方式为口服给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润 滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、娇味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药(如左旋多巴或其药学上可接受的盐等)。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～10000mg，优选100～8000mg，更优选为200-6000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点包括：
(1)本发明首次发现甘油三酯类化合物(式I化合物)具有治疗神经退行性疾病的活性。
(2)本发明首次发现甘油三酯类化合物(式I化合物)具有以下特点：(i)治疗神经退行性疾病；(ii)提高哺乳动物脑组织PPARγ蛋白水平；(iii)降低哺乳动物脑组织中Aβ淀粉样蛋白的表达；和/或(iv)降低哺乳动物脑组织中NF-κB、iNOS和IL-1β的表达。
(3)甘油三酯类化合物(式I化合物)来源于天然产物(如椰子油)，具有副作用小、成本低、安全性好的特点。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。以下实施例在统计学上均以*P<0.05、**p<0.01vs空白组、#p<0.05、##p<0.01vs模型组视为显著差异。
实施例
1.材料
1.1动物
动物SPF级KM雌性小鼠50只，体重20±2g，由湖南斯莱克公司提供。
1.2药品与试剂
癸酸甘油三酯购于sigma-aldrich公司。
1.3仪器
TLL-C台式冷冻离心机，购自北京四环科学仪器厂；
AU600全自动生化检测仪，由奥林巴斯生产；
752型分光光度计，购自上海第三分析仪器厂；
O1ymPus BX51显微镜，由奥林巴斯生产；
BS1105电子天平，购自德国sartorius公司。
2.方法
2.1分组和模型建立
实验分组：①空白组(正常组)②模型组③癸酸甘油三酯(GT)200mg/kg④癸酸甘油三酯(GT)600mg/kg⑤癸酸甘油三酯(GT)100mg/kg剂量组。
模型建立：取SD小鼠50只，其中10只小鼠为空白组，10只小鼠为模型组，30只小鼠为给药组。其中模型组和给药组采用皮下D-gal 50mg/kg/d法进行造模，每日1次，共40d
在建模的同时给予药物治疗，药物GT按200mg/kg、600mg/kg和1000mg/kg剂量溶于花生油中，每天灌胃一次，每天一次；模型组和空白组同时给予空白溶剂。
2.2检测指标
蛋白质免疫印迹法测定各组小鼠脑组织Aβ、IL-1β、iNOS、NF-κB、PPARγ蛋白的表达；同时以水迷宫实验法测定其学习记忆能力；病理学观察，取各小鼠脑部同一部位组织，以10％中性福尔马林固定，脱水，包埋，切片，脱蜡，做常规HE染色，封片。镜下观察分析脑组织病理情况。
2.3数据处理
用SPSS13.0软件进行统计学分析。试验数据用平均值±标准误(mean±SE)表示，各组间均数的比较采用单因素方差分析(one-way ANOVEA)，再采用Dunnett-t检验，以P＜0.05作为显著性差异标准。
3.结果
3.1癸酸甘油三酯对老年痴呆学习记忆的影响。
用Morris水迷宫检测小鼠的空间学习记忆能力，各组小鼠在造模及药物干预结束后进行检测。
结果如表1所示。结果表明，与空白组(正常组)相比，模型组在平台象限的停留时间显著减少，表明其记忆明显减弱；而GT给药组随剂量增多记忆得到进一步的改善。与模型组相比，GT给药组的平台象限停留时间明显升高，接近空白组水平。
表1 癸酸甘油三酯对D-半乳糖致老年痴呆模型小鼠空间学习记忆能力的影响(Mean±S.E.M)
Figure PCTCN2016092068-appb-000004
Figure PCTCN2016092068-appb-000005
3.2癸酸甘油三酯对D-半乳糖致老年痴呆模型小鼠的病理学检查
结果如图1所示。结果显示，正常小鼠海马CA3区锥体细胞排列尚整齐，鲜见细胞空泡变性及坏死模型组小鼠海马CA1区锥体细胞排列紊乱，大量细胞空泡变性、固缩坏死。GT低剂量组海马CA1区椎体细胞排列较紊乱，较多细胞空泡变性、固缩坏死；GT中剂量组海马CA1区锥体细胞排列较整齐，少量细胞空泡变性但未见坏死；GT高剂量组海马CA1区锥体细胞完整程度接近于正常组。
结果表明，癸酸甘油三酯能够显著改善模型小鼠的老年痴呆症状。
3.3癸酸甘油三酯对D-半乳糖致老年痴呆模型小鼠脑组织中PPARγ的影响
结果如表2和图2－3所示。结果表明，与空白组(正常组)相比，模型组的PPARγ的表达降低了37％，与模型组相比，GT1000mg/kg小鼠的PPARγ的表达显著提高了253％。
表2.
Figure PCTCN2016092068-appb-000006
3.4癸酸甘油三酯对D-半乳糖致老年痴呆模型小鼠脑组织中NF-κB的影响
结果如表3和图4－5所示。结果表明，与空白组(正常组)相比，模型组NF-κB的水平升高了20％，与模型组相比，GT1000mg/kg小鼠的NF-κB的水平降低了36.7％。
表3.
Figure PCTCN2016092068-appb-000007
3.5癸酸甘油三酯对D-半乳糖致老年痴呆模型小鼠脑组织中iNOS的影响
结果如表4和图6-7所示。结果表明，与空白组(正常组)相比，模型组iNOS 的水平升高13％，与模型组相比，GT1000mg/kg小鼠的iNOS的水平降低了49.5％。
表4.
Figure PCTCN2016092068-appb-000008
3.6癸酸甘油三酯对D-半乳糖致老年痴呆模型小鼠脑组织中Aβ蛋白表达的影响
结果如表5和图8-9所示。结果表明，与空白组(正常组)相比，模型组Aβ蛋白表达的水平升高68％，与模型组相比，GT1000mg/kg小鼠的Aβ蛋白表达水平降低了48.8％。
表5.
Figure PCTCN2016092068-appb-000009
3.7癸酸甘油三酯对D-半乳糖致老年痴呆模型小鼠血清中IL-1β含量的影响
结果如表6和图10所示。结果表明，与空白组(正常组)相比，模型组IL-1β的含量升高99.8％，与模型组相比，GT1000mg/kg小鼠的IL-1β的含量降低了48.7％，接近空白组水平。
表6.
Figure PCTCN2016092068-appb-000010
综上，结果表明，癸酸甘油三酯对神经退行性疾病具有良好的治疗作用；癸酸甘油三酯能够上调脑组织中PPARγ蛋白的表达，降低Aβ淀粉样蛋白表达水平，同时降低脑组织中NF-κB、iNOS、IL-1β的表达水平，改善老年痴呆的记忆。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种式I化合物或其药学上可接受的盐的用途，其特征在于，用于制备治疗神经退行性疾病的组合物或制剂，
    Figure PCTCN2016092068-appb-100001
    式中，
    R1、R2和R3各自独立地选自下组：C5、C7、C9、C11烷基、C5、C7、C9、C11链烯基、和C5、C7、C9、C11链炔基。
  2. 如权利要求1所述的用途，其特征在于，R1、R2和R3各自独立地选自下组：C7、C9烷基、C7、C9链烯基、和C7、C9链炔基。
  3. 如权利要求1所述的用途，其特征在于，所述的组合物包括：药物组合物、保健品组合物、或食品组合物、或膳食补充剂组合物。
  4. 如权利要求1所述的用途，其特征在于，所述的组合物或制剂还用于(i)提高哺乳动物组织中PPARγ蛋白的表达；(ii)降低哺乳动物组织中Aβ淀粉样蛋白的表达；和/或(iii)降低哺乳动物组织中NF-κB、iNOS和IL-1β的表达。
  5. 一种药物组合物，其特征在于，包括：
    (a1)用于治疗神经退行性疾病的第一活性成分，所述第一活性成分为式I化合物或其可接受的盐；
    (a2)用于治疗神经退行性疾病的第二活性成分，所述第二活性成分选自：左旋多巴化合物或其可接受的盐；和
    (b)药学上可接受的载体，
    其中式I化合物的定义如权利要求1所述。
  6. 如权利要求5所述的药物组合物，其特征在于，所述第一活性成分和第二活性成分的重量比为1:100至100：1，较佳地为1:10至10：1。
  7. 一种筛选治疗神经退行性疾病的候选药物的方法，其特征在于，所述方法包括步骤：
    (a)提供一待测化合物以及阳性对照化合物，所述的阳性对照化合物为式I化合物或其药学上可接受的盐，其中式I化合物的定义如权利要求1所述；
    (b)在测试组中，检测所述待测化合物对非人动物模型的Aβ淀粉样蛋白和/或NF-κB、iNOS、IL-1β的影响，并与阳性对照组以及阴性对照组中相应的实验结果进行比较，其中，在阳性对照组中，检测阳性对照化合物对Aβ淀粉样蛋白和/或NF-κB、iNOS、IL-1β的影响；
    其中，如果所述待测化合物对非人动物模型的Aβ淀粉样蛋白和/或NF-κB、iNOS、IL-1β的降低程度显著高于阴性对照组，则提示所述待测化合物是治疗神经退行性疾病的候选药物。
  8. 如权利要求7所述的方法，其特征在于，所述的方法还包括步骤(c)：对步骤(b)中筛选出的待测化合物，进一步测定其对神经退行性疾病的治疗效果。
  9. 一种治疗神经退行性疾病的方法，其特征在于，包括：给需要的哺乳动物施用式I化合物或其药学上可接受的盐，其中式I化合物如权利要求1所述。
  10. 一种体外非治疗性的提高哺乳动物组织中PPARγ蛋白和/或降低Aβ淀粉样蛋白水平的方法，其特征在于，包括：给需要的哺乳动物施用式I化合物或其药学上可接受的盐，其中式I化合物如权利要求1所述。
PCT/CN2016/092068 2015-12-29 2016-07-28 甘油三酯类化合物在制备治疗神经退行性疾病药物中的应用 WO2017113775A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201511016441.1A CN105663109A (zh) 2015-12-29 2015-12-29 甘油三酯类化合物在制备治疗神经退行性疾病药物中的应用
CN201511016441.1 2015-12-29

Publications (1)

Publication Number Publication Date
WO2017113775A1 true WO2017113775A1 (zh) 2017-07-06

Family

ID=56297932

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/092068 WO2017113775A1 (zh) 2015-12-29 2016-07-28 甘油三酯类化合物在制备治疗神经退行性疾病药物中的应用

Country Status (2)

Country Link
CN (1) CN105663109A (zh)
WO (1) WO2017113775A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105663109A (zh) * 2015-12-29 2016-06-15 浙江旭晨医药科技有限公司 甘油三酯类化合物在制备治疗神经退行性疾病药物中的应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103844271A (zh) * 2012-12-06 2014-06-11 孙天民 一种防治痴呆症的营养组合剂
CN105663109A (zh) * 2015-12-29 2016-06-15 浙江旭晨医药科技有限公司 甘油三酯类化合物在制备治疗神经退行性疾病药物中的应用

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070179197A1 (en) * 2000-05-01 2007-08-02 Accera, Inc. Compositions and methods for improving or preserving brain function
AU2008307494B2 (en) * 2007-10-04 2013-09-05 Société des Produits Nestlé S.A. Compositions and methods for enhancing cognitive function
KR20120129898A (ko) * 2009-12-30 2012-11-28 베일러 리서치 인스티튜트 알츠하이머 질환 및 노화 뇌를 위한 보충대사 치료요법
CN102551910A (zh) * 2010-12-28 2012-07-11 四川大学华西医院 一种恒河猴老年痴呆模型的建立方法及药物筛选方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103844271A (zh) * 2012-12-06 2014-06-11 孙天民 一种防治痴呆症的营养组合剂
CN105663109A (zh) * 2015-12-29 2016-06-15 浙江旭晨医药科技有限公司 甘油三酯类化合物在制备治疗神经退行性疾病药物中的应用

Also Published As

Publication number Publication date
CN105663109A (zh) 2016-06-15

Similar Documents

Publication Publication Date Title
JP2023153783A (ja) 遺伝性てんかん性障害の処置に使用するガナキソロン
US10342797B2 (en) Solubility of therapeutic agents
WO2016029868A1 (zh) 用于减少体重及减少体脂肪的组合物及其医药品与应用
US11523998B2 (en) Anti-inflammatory formulations and uses thereof including a combination of palmitoylethanolamide and plant-based polyphenols
CA3130761A1 (en) Compositions including cinnamic acid and methods of use thereof
EP2882495A1 (en) Laquinimod for treatment of cannabinoid receptor type 1 (cb1) mediated disorders
AU2021257523A1 (en) Ginsenoside composition having alcoholic fatty liver-preventing and -treating function
US20210030678A1 (en) Cannabinoid and cbd liposome formulations and uses thereof
AU2022200277A1 (en) The use of a benzoate containing composition to treat glycine encephalopathy
JP2018513204A (ja) 神経保護および神経変性の治療のための組成物および方法
US20130084334A1 (en) Pharmaceutical compositions highly dosed with biotin
WO2017113775A1 (zh) 甘油三酯类化合物在制备治疗神经退行性疾病药物中的应用
CA2897833C (en) A pharmaceutical composition comprising palmitoylethanolamide and cytidine-disphosphocholine
CN114007607A (zh) 用于治疗神经变性疾病的材料和方法
US20170368018A1 (en) Use of ellagic acid dihydrate in pharmaceutical formulations to regulate blood glucose levels
WO2020019938A1 (zh) 一种用于治疗肌萎缩性脊髓侧索硬化症的联合用药组合物及其制备方法和用途
US20240082184A1 (en) Improved treatment for globoid cell leukodsytrophy or krabbe disease
WO2016099947A1 (en) Use of ellagic acid dihydrate in food products and nutraceuticals
CN109562089A (zh) 苯甲酸锂用于治疗中枢神经系统疾病的用途
JP2018188377A (ja) 医薬組成物
WO2017059726A1 (zh) 癸酸甘油三酯类化合物在制备治疗多囊卵巢综合症药物中的应用
US20120201876A1 (en) Method of managing hypercortisolemia, headache disorders, neuropathic pain and related disorders
CN115212194B (zh) 纳多洛尔在制备治疗缺血/再灌注损伤药物及细胞保护药物中的应用
KR101719015B1 (ko) 프루네틴을 유효성분으로 함유하는 비만 또는 대사성 질환의 예방 또는 치료용 약학적 조성물
US20160296574A1 (en) Ephedra alata extracts and methods of use thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16880570

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16880570

Country of ref document: EP

Kind code of ref document: A1