WO2017059726A1 - 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 - Google Patents

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 Download PDF

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WO2017059726A1
WO2017059726A1 PCT/CN2016/092071 CN2016092071W WO2017059726A1 WO 2017059726 A1 WO2017059726 A1 WO 2017059726A1 CN 2016092071 W CN2016092071 W CN 2016092071W WO 2017059726 A1 WO2017059726 A1 WO 2017059726A1
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compound
formula
polycystic ovary
ovary syndrome
group
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PCT/CN2016/092071
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English (en)
French (fr)
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易伟
徐华强
段小群
吴啸川
胡增仁
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浙江旭晨医药科技有限公司
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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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)

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  • the invention relates to the field of medicine, in particular to the application of a phthalic acid triglyceride compound in the preparation of a medicament for treating polycystic ovary syndrome.
  • PCOS Polycystic ovary syndrome
  • Symptoms include menstrual thinning or amenorrhea, chronic anovulation, infertility, hairy and hemorrhoids. Due to continued anovulation, severe endometrial hyperplasia will increase the risk of endometrial cancer. Therefore, early prevention of polycystic ovary syndrome to prevent menstrual disorders and infertility.
  • 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 also used in the preparation of polycapsules for citrate triglyceride. The application of ovarian syndrome drugs has not been reported.
  • a first aspect of the invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of (i) a composition or formulation for treating polycystic ovary syndrome; and/or (ii) reducing a mammal Androgen level composition or formulation,
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of C 6 -C 12 alkyl, C 6 -C 12 alkenyl, and C 6 -C 12 alkynyl.
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of C 7 -C 11 alkyl, C 7 -C 11 alkenyl, and C 7 -C 11 alkynyl.
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of C 8 -C 10 alkyl, C 8 -C 10 alkenyl, and C 8 -C 10 alkynyl.
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of octyl and decyl.
  • 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 fluorenyl groups.
  • 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 (iii) reduce the ovarian coefficient of a mammal.
  • the androgen is selected from the group consisting of testosterone, androstenedione, dihydrotestosterone, or a combination thereof.
  • the "reducing androgen levels in mammals” refers to reducing testosterone levels in serum or blood of a mammal.
  • the composition is an oral preparation.
  • the composition e.g., a pharmaceutical composition
  • the mammal comprises a female mammal.
  • the mammal comprises a mammal having polycystic ovary syndrome.
  • the mammal comprises a human or a non-human mammal.
  • the non-human mammal comprises a rodent such as a mouse or a rat.
  • a second aspect of the invention provides a pharmaceutical composition comprising:
  • (a2) a second active ingredient for treating polycystic ovary syndrome, the second active ingredient being selected from the group consisting of: a metformin 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 polycystic ovary syndrome, the method comprising the steps of:
  • test compound if the test compound has a significantly lower degree of ovarian coefficient and/or androgen level in the non-human animal model than the negative control group, the test compound is suggested to be a drug candidate for treating polycystic ovary syndrome.
  • step (b) the test group is compared to the positive control group and V1 is compared Ratio to V2, where V1 is the decrease in the ovarian coefficient and/or androgen level of the test compound to a non-human animal model, and V2 is the ovarian coefficient and/or male of the positive control compound for the non-human animal model.
  • V1 is the decrease in the ovarian coefficient and/or androgen level of the test compound to a non-human animal model
  • V2 is the ovarian coefficient and/or male of the positive control compound for the non-human animal model.
  • the method further comprises the step (c) of further determining the therapeutic effect on the polycystic ovary syndrome for the test compound selected in the step (b).
  • said "significantly higher" means V1/V0 ⁇ 2, preferably ⁇ 3, more preferably ⁇ 4,
  • V1 is the decrease in the ovarian coefficient and/or androgen level of the test compound to the non-human animal model; and V0 is the ovarian coefficient and/or androgen of the human animal model in the negative control group (or model group). The level of reduction.
  • the method is non-diagnostic and non-therapeutic.
  • a fourth aspect of the invention provides a method of treating polycystic ovary syndrome 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 in the first aspect of the invention Said.
  • the compound of formula I is capric triglyceride.
  • the mammal comprises a female mammal.
  • the mammal comprises a mammal having polycystic ovary syndrome.
  • 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.
  • a fifth aspect of the invention provides a method for non-therapeutic in vitro reduction of serum androgen levels in a mammal 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 Said in the first aspect of the invention.
  • the compound of formula I is capric triglyceride.
  • the mammal comprises a female mammal.
  • the mammal comprises a mammal having polycystic ovary syndrome.
  • 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.
  • the androgen is selected from the group consisting of testosterone, androstenedione, dihydrotestosterone, or a combination thereof.
  • Fig. 1 is a view showing the pathological examination (HE staining) of a blank control group rat, a model group rat, and a glyceric acid triglyceride 2 g/kg dose group in the present invention.
  • a triglyceride compound (a compound of formula I) or a pharmaceutically acceptable salt thereof can be effectively used for (i) treatment of polycystic ovary syndrome; Ii) reducing mammalian androgen levels; and/or (iii) reducing the mammalian ovarian coefficient.
  • the inventors completed the present invention.
  • C 6 -C 12 alkyl refers to a straight or branched alkyl group of 6 to 12 carbon atoms, such as hexane, heptyl, octyl, nonyl, or the like.
  • C 6 -C 12 alkenyl refers to a straight or branched alkenyl group of 6 to 12 carbon atoms, such as hexenyl, heptenyl, octenyl, decenyl, or the like.
  • C 6 -C 12 alkynyl refers to a straight or branched alkynyl group of 6 to 12 carbon atoms, such as hexynyl, heptynyl, octynyl, decynyl, or the like.
  • C 7 -C 11 alkyl refers to a straight or branched alkyl group of 7 to 11 carbon atoms, such as hexane, heptyl, octyl, nonyl, or the like.
  • C 7 -C 11 alkenyl refers to a straight or branched alkenyl group of 7 to 11 carbon atoms, such as hexenyl, heptenyl, octenyl, decenyl, or the like.
  • C 7 -C 11 alkynyl refers to a straight or branched alkynyl group of 7 to 11 carbon atoms, such as hexynyl, heptynyl, octynyl, decynyl, or the like.
  • a triglyceride compound is used as an active ingredient for (i) treatment of polycystic ovarian syndrome; (ii) reduction of mammalian androgen levels; and/or (iii) reduction of mammalian ovaries coefficient.
  • 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 6 -C 12 alkyl, C 6 -C 12 alkenyl, and C 6 -C 12 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,
  • the active ingredients and medicaments of the present invention are particularly suitable for the treatment of polycystic ovary syndrome, and in particular, can significantly reduce the representative index "ovarian coefficient" of polycystic ovary syndrome and the level of androgen.
  • the effectiveness of a compound of formula I (such as citric acid triglyceride) in the treatment of polycystic ovary syndrome is judged by measuring the ovarian coefficient.
  • a compound of formula I (such as citrate triglyceride) has a therapeutic effect on polycystic ovary syndrome.
  • 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 polycystic ovary syndrome.
  • 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 glycerol citrate compound (a compound of formula I) or a pharmaceutically 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 from 1 to 1000 mg of glycerol citrate compound/agent, more preferably from 100 to 8000 mg of glyceryl citrate compound/agent, optimally containing from 200 to 6000 mg of glyceryl citrate compound/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 Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
  • 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 excipients include water, ethanol, polyols and A suitable mixture 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 compound of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., a metformin compound or a pharmaceutically acceptable salt thereof, etc.).
  • other pharmaceutically acceptable compounds e.g., a metformin compound 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 formula I) has activity for treating polycystic ovary syndrome.
  • triglyceride compounds (compounds of formula I) have (i) reduced androgen levels in mammalian serum; and (ii) reduced mammalian ovarian coefficients.
  • 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 control group 2 model group 3 citrate triglyceride (GT) 2g / kg dose group.
  • GT citrate triglyceride
  • Model establishment 38 SD rats were taken, of which 12 rats were blank control group, 13 rats were model group, and 13 rats were blank group.
  • the model group and the drug-administered group were modeled by the Poresky method, that is, each SD female rat was injected subcutaneously with hCG 1.5U twice daily for 22 days; insulin (INS) started at 0.5 U/d on the first day. Then gradually increase to 6.0 U / d at 0.5 IU / d, and maintained to the 22nd day according to this dose; drug therapy is given at the same time of modeling, drug GT is dissolved in peanut oil at a dose of 2g / kg, once a day, Once a day; the model group and the blank group were given a blank solvent at the same time.
  • INS insulin
  • ovarian coefficient bilateral ovary weight / rat body weight; testosterone content according to the strict requirements of the kit operation, using the Elisa method; pathological observation, taking the same part of the rat ovary tissue, in 10% Sexual formalin is fixed, dehydrated, embedded, sliced, dewaxed, routinely HE stained, and mounted. The pathological condition of ovarian tissue was analyzed under microscope.

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Abstract

本发明提供了一种甘油三酯类化合物在制备治疗多囊卵巢综合征药物中的应用。本发明还提供了一种甘油三酯类化合物在制备降低哺乳动物雄激素水平的组合物或制剂中的应用。

Description

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 技术领域
本发明涉及药物领域，具体地，涉及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。
背景技术
多囊卵巢综合征(PCOS)是以稀发排卵或无排卵、高雄激素或胰岛素抵抗、多囊卵巢为特征的内分泌紊乱的症候群。病征包括月经稀发或闭经、慢性无排卵、不孕、多毛及痤疮等。因持续无排卵，严重情况下会使子宫内膜过度增生，增加子宫内膜癌的风险。因此，通过早期预防多囊卵巢综合征以阻止月经紊乱与不孕现象的发生。
目前，针对防治多囊性卵巢综合征的药物品种很多，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，开发防治多囊卵巢综合征的新产品意义重大。
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多囊卵巢综合征药物中的应用，尚未见报道。
因此，本领域迫切需要开发一种副作用小、成本低的治疗多囊性卵巢综合征的药物。
发明内容
本发明的目的是提供一种副作用小、可有效治疗多囊性卵巢综合征的药物。
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(i)治疗多囊卵巢综合征的组合物或制剂；和/或(ii)降低哺乳动物雄激素水平的组合物或制剂，
Figure PCTCN2016092071-appb-000001
式中，
R1、R2和R3各自独立地选自下组：C6-C12烷基、C6-C12链烯基、和C6-C12链炔基。
在另一优选例中，R1、R2和R3各自独立地选自下组：C7-C11烷基、C7-C11链烯基、和C7-C11链炔基。
在另一优选例中，R1、R2和R3各自独立地选自下组：C8-C10烷基、C8-C10链烯基、和C8-C10链炔基。
在另一优选例中，R1、R2和R3各自独立地选自下组：辛基和癸基。
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都是癸基。
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(iii)降低哺乳动物的卵巢系数。
在另一优选例中，所述的雄激素选自下组：睾酮、雄烯二酮、双氢睾酮、或其组合。
在另一优选例中，所述的“降低哺乳动物雄激素水平”指降低哺乳动物血清或血液中的睾酮水平。
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，所述哺乳动物包括雌性哺乳动物。
在另一优选例中，所述哺乳动物包括患有多囊卵巢综合征的哺乳动物。
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，如小鼠、大鼠。
本发明第二方面提供了一种药物组合物，包括：
(a1)用于治疗多囊卵巢综合征的第一活性成分，所述第一活性成分为式I化合物或其可接受的盐；
(a2)用于治疗多囊卵巢综合征的第二活性成分，所述第二活性成分选自：二甲双胍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中所述。
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多囊卵巢综合征的候选药物的方法，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卵巢系数和/或雄激素水平的影响，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卵巢系数和/或雄激素水平的影响；
其中，如果所述待测化合物对非人动物模型的卵巢系数和/或雄激素水平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多囊卵巢综合征的候选药物。
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卵巢系数和/或雄激素水平的降低幅度V1，而V2为阳性对照化合物对非人动物模型的卵巢系数和/或雄激素水平的降低幅度，如果V1/V2≥80％，则提示所述待测化合物是治疗多囊卵巢综合征的候选药物。
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，进一步测定其对多囊卵巢综合征的治疗效果。
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卵巢系数和/或雄激素水平的降低幅度；而V0为阴性对照组(或模型组)中人动物模型的卵巢系数和/或雄激素水平的降低幅度。
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多囊卵巢综合征的方法，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中所述。
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，所述哺乳动物包括雌性哺乳动物。
在另一优选例中，所述哺乳动物包括患有多囊卵巢综合征的哺乳动物。
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降低哺乳动物血清雄激素水平的方法，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中所述。
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，所述哺乳动物包括雌性哺乳动物。
在另一优选例中，所述哺乳动物包括患有多囊卵巢综合征的哺乳动物。
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。
在另一优选例中，所述雄激素选自下组：睾酮、雄烯二酮、双氢睾酮、或其组合。
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对照组大鼠、模型组大鼠、癸酸甘油三酯2g/kg剂量组大鼠的病理检查图(HE染色)。
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)治疗多囊性卵巢综合征；(ii)降低哺乳动物雄激素水平；和/或(iii)降低哺乳动物的卵巢系数。在此基础上，本发明人完成了本发明。
术语
术语“C6-C12烷基”指6-12个碳原子的直链或支链烷基，例如己烷基、庚烷基、辛烷基、癸烷基、或类似基团。
术语“C6-C12链烯基”指6-12个碳原子的直链或支链的烯基，例如己烯基、庚烯基、辛烯基、癸烯基、或类似基团。
术语“C6-C12链炔基”指6-12个碳原子的直链或支链的炔基，例如己炔基、 庚炔基、辛炔基、癸炔基、或类似基团。
术语“C7-C11烷基”指7-11个碳原子的直链或支链烷基，例如己烷基、庚烷基、辛烷基、癸烷基、或类似基团。
术语“C7-C11链烯基”指7-11个碳原子的直链或支链的烯基，例如己烯基、庚烯基、辛烯基、癸烯基、或类似基团。
术语“C7-C11链炔基”指7-11个碳原子的直链或支链的炔基，例如己炔基、庚炔基、辛炔基、癸炔基、或类似基团。
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)治疗多囊性卵巢综合征；(ii)降低哺乳动物雄激素水平；和/或(iii)降低哺乳动物的卵巢系数。
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 PCTCN2016092071-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：C6-C12烷基、C6-C12链烯基、和C6-C12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。
多囊卵巢综合征及其指标
本发明的活性成分和药物特别适合治疗多囊卵巢综合征，尤其可以显著降低多囊卵巢综合征的代表指标“卵巢系数”以及雄性激素的水平。
如本文所用，所述“卵巢系数”指雌性大鼠双侧卵巢的重量与雌性大鼠体重的比值，即卵巢系数＝双侧卵巢重量/大鼠体重。
在本发明中，通过测量卵巢系数，从而判断式I化合物(如癸酸甘油三酯)在治疗多囊性卵巢综合征方面的有效性。
在一个优选的实施方式中，当卵巢系数显著降低时，表明式I化合物(如癸酸甘油三酯)对多囊性卵巢综合征有治疗作用。
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、预防以及缓解多囊性卵巢综合征。
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癸酸甘油酯类化合物(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癸酸甘油酯类化合物/剂，更佳地，含有100-8000mg癸酸甘油酯类化合物/剂，最佳地含有200-6000mg癸酸甘油酯类化合物/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 PCTCN2016092071-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(如二甲双胍化合物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)具有治疗多囊性卵巢综合征的活性。
(2)本发明首次发现甘油三酯类化合物(式I化合物)具有(i)降低哺乳动物血清中雄激素水平；和(ii)降低哺乳动物卵巢系数的特点。
(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例均以*P<0.05视为显著差异。
实施例
1.材料
1.1动物
动物SPF级SD雌性大鼠38只，体重190±10g，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空白对照组②模型组③癸酸甘油三酯(GT)2g/kg剂量组。
模型建立：取SD大鼠38只，其中12只大鼠为空白对照组，13只大鼠为模型组，13只大鼠为空白组。其中模型组和给药组采用Poresky法进行造模,即每只SD雌性大鼠皮下注射hCG 1.5U,每日2次,共22d；胰岛素(INS)于第1天以0.5U/d开始,随后以0.5IU/d逐渐递增至6.0U/d,并按此剂量维持至第22天；在建模的同时给予药物治疗，药物GT按2g/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
按照公式：卵巢系数＝双侧卵巢重量/大鼠体重；睾酮含量按照严格按照试剂盒的要求规范操作，采用通过Elisa法测定；病理学观察，取各大鼠卵巢同一部位组织，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。镜下观察分析卵巢组织病理情况。
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癸酸甘油三酯对多囊卵巢综合征大鼠体重的影响。
结果如表1所示。结果表明，与空白组相比，模型组大鼠和GT 2g/kg组 均无明显变化。
表1癸酸甘油三酯对多囊卵巢综合征大鼠体重的影响(x±s)
Figure PCTCN2016092071-appb-000004
3.2癸酸甘油三酯对多囊卵巢综合征大鼠卵巢系数的影响。
结果如表2所示。结果表明，与空白组相比，模型组和GT 2g/kg组大鼠卵巢系数的分别增加了62.9％和8.5％；与模型组相比，GT 2g/kg组大鼠的卵巢系数有了显著下降，接近空白组水平。
表2癸酸甘油三酯对多囊卵巢综合征大鼠卵巢系数的影响(x±s)
Figure PCTCN2016092071-appb-000005
3.3癸酸甘油三酯对多囊卵巢综合征大鼠血清中睾酮值的影响。
结果如表3所示。结果表明，与空白组相比，模型组大鼠血清中的雄性激素的水平(如睾酮值)增加了57.4％，GT 2g/kg组的雄激素水平(如睾酮值)不仅没有增加，反而降低了12.5％。此外，与模型组相比，GT 2g/kg组可以显著降低模型动物中的雄性激素水平。
表3癸酸甘油三酯对多囊卵巢综合征大鼠血清中睾酮值的影响(x±s)
Figure PCTCN2016092071-appb-000006
3.4病理形态学观察(HE染色)
结果如图1所示。显微镜下观察的结果显示，模型组卵巢多囊卵泡代偿性病理性增生增多，镜下见卵泡颗粒层结构变薄；而癸酸甘油三酯组(GT 2g/kg组)也有多囊卵泡的现象，但卵泡内部颗粒层结构明显变薄后，卵泡变小，卵泡功能有所恢复。
综上，结果表明，以癸酸甘油三酯为代表的式I化合物对多囊卵巢综合征有显著治疗作用。
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(i)治疗多囊卵巢综合征的组合物或制剂；和/或(ii)降低哺乳动物雄激素水平的组合物或制剂，
    Figure PCTCN2016092071-appb-100001
    式中，
    R1、R2和R3各自独立地选自下组：C6-C12烷基、C6-C12链烯基、和C6-C12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：辛基和癸基。
  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(iii)降低哺乳动物的卵巢系数。
  5. 一种药物组合物，其特征在于，包括：
    (a1)用于治疗多囊卵巢综合征的第一活性成分，所述第一活性成分为式I化合物或其可接受的盐；
    (a2)用于治疗多囊卵巢综合征的第二活性成分，所述第二活性成分选自：二甲双胍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中所述。
  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. 一种筛选治疗多囊卵巢综合征的候选药物的方法，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卵巢系数和/或雄激素水平的影响，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卵巢系数和/或雄激素水平的影响；
    其中，如果所述待测化合物对非人动物模型的卵巢系数和/或雄激素水平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多囊卵巢综合征的候选药物。
  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，进一步测定其对多囊卵巢综合征的治疗效果。
  9. 一种治疗多囊卵巢综合征的方法，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中所述。
  10. 一种体外非治疗性的降低哺乳动物血清雄激素水平的方法，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中所述。
PCT/CN2016/092071 2015-10-10 2016-07-28 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 WO2017059726A1 (zh)

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