WO2022099615A1 - 化合物在制备药物中的用途 - Google Patents

化合物在制备药物中的用途 Download PDF

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WO2022099615A1
WO2022099615A1 PCT/CN2020/128684 CN2020128684W WO2022099615A1 WO 2022099615 A1 WO2022099615 A1 WO 2022099615A1 CN 2020128684 W CN2020128684 W CN 2020128684W WO 2022099615 A1 WO2022099615 A1 WO 2022099615A1
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compound
stem cells
intestinal stem
use according
small intestinal
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PCT/CN2020/128684
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English (en)
French (fr)
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刘兴国
杨亮
林晓冰
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中国科学院广州生物医药与健康研究院
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Priority to PCT/CN2020/128684 priority Critical patent/WO2022099615A1/zh
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system

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  • the present invention relates to the field of biomedicine, in particular, the present invention relates to the use of the compound in the preparation of medicine, the use of the compound in the preparation of a kit, the use of the composition in the preparation of a pharmaceutical composition, and the use of the composition in the preparation of food or health products use in.
  • Stem cells exist in many mammalian tissues and have the ability to self-renew and differentiate.
  • the intestinal tissue is mainly composed of the small intestine and the colon.
  • the inner layer of the small intestine is called the mucosa in anatomy.
  • small intestinal stem cells exist at the bottom of the small intestinal fossa and have the ability to differentiate into transiently expanding cells that further differentiate into two major cell types, including the absorptive system and the secretory system.
  • Intestinal stem cells are a kind of potential stem cells.
  • organs such as the small intestine are first involved, and intestinal stem cells are the main reason for the aging of the small intestine. At present, there is an urgent need for drugs to prevent and treat the aging of small intestinal stem cells.
  • the present invention proposes the use of a compound in the preparation of medicine, the compound is a compound represented by formula I or a stereoisomer, nitrogen oxide, solvate of the compound represented by formula I , metabolites, pharmaceutically acceptable salts, prodrugs or derivatives thereof.
  • the medicine is used for treating or preventing senescence of small intestinal stem cells.
  • each R is independently H, D, F, Cl, Br, I, OH, NH 2 , NO 2 , CN, N 3 or C 1-6 alkyl;
  • n 0, 1, 2, 3 or 4.
  • intestinal stem cell senescence needs to be understood in a broad sense, not only refers to the treatment or prevention of small intestinal stem cell senescence patients, but also refers to the treatment or prevention of small intestinal stem cell dysfunction.
  • the above-mentioned use may further include at least one of the following additional technical features:
  • each R is independently H, D, F, Cl , Br, I, OH, NH2 , NO2 , CN, N3 or C1-4 alkyl.
  • each R is independently H, D, F, Cl, Br, I, OH, NH 2 , NO 2 , CN, N 3 , methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl or tert-butyl.
  • the compound has the following structure:
  • the derivative of the compound is NADH or NAD + .
  • the senescence of the small intestinal stem cells is caused by mtDNA mutation.
  • the mtDNA mutation includes point mutation and deletion mutation.
  • mtDNA mutations can cause senescence
  • nuclear gene mutations such as new point mutations in lamina nuclear A (LAMNA)
  • LAMNA lamina nuclear A
  • telomere shortening can also cause senescence. Therefore, it is completely unknown whether anti-aging drugs can treat or prevent the senescence of small intestinal stem cells caused by mtDNA mutations.
  • mtDNA mutations can be caused by aging or other environmental factors.
  • the inventors found for the first time that mitochondrial DNA mutation can lead to a significant decrease in the number of intestinal stem cells.
  • the inventors were consciously surprised to find that NMN can reverse the decrease in the number of intestinal stem cells caused by mitochondrial DNA mutation, and play a significant improvement role.
  • the compounds according to the embodiments of the present invention have a significant curative effect on the senescence of small intestinal stem cells caused by mtDNA mutation.
  • the mtDNA mutation-induced senescence of small intestinal stem cells is caused by egg cell mtDNA mutation (eg, point mutation).
  • egg cell mtDNA mutation eg, point mutation
  • the drug is used to restore mtDNA mutation or reduce mtDNA mutation rate.
  • the present invention proposes the use of a compound in the preparation kit, the compound is a compound represented by formula I or a stereoisomer, nitrogen oxide, solvate, metabolite of the compound represented by formula I Product, pharmaceutically acceptable salt, prodrug or derivative thereof.
  • the kit is used to restore mtDNA mutation or reduce mtDNA mutation rate,
  • each R is independently H, D, F, Cl, Br, I, OH, NH 2 , NO 2 , CN, N 3 or C 1-6 alkyl;
  • n 0, 1, 2, 3 or 4.
  • the inventors found that the compounds according to the embodiments of the present invention can effectively restore the mtDNA mutation or reduce the mtDNA mutation rate, and further, the kit prepared according to the compounds according to the embodiments of the present invention can effectively restore the mtDNA mutation or reduce the mtDNA mutation rate, so as to be used in science research or clinical application.
  • the above-mentioned use may further include at least one of the following additional technical features:
  • each R is independently H, D, F, Cl , Br, I, OH, NH2 , NO2 , CN, N3 or C1-4 alkyl.
  • each R is independently H, D, F, Cl, Br, I, OH, NH 2 , NO 2 , CN, N 3 , methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl or tert-butyl.
  • the compound has the following structure:
  • the derivative of the compound is NADH or NAD + .
  • the present invention proposes the use of a composition for the manufacture of a pharmaceutical composition, said composition comprising a compound as described above.
  • the pharmaceutical composition is used for treating or preventing senescence of small intestinal stem cells.
  • the compounds of the present invention can effectively prevent or treat the senescence of small intestinal stem cells, especially the senescence of small intestinal stem cells caused by mtDNA mutation. Thereby, the composition is imparted with corresponding effects.
  • the above-mentioned use may further include at least one of the following additional technical features:
  • the composition further comprises: a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or a combination thereof.
  • the composition further comprises: other drugs for treating or preventing the senescence of small intestinal stem cells.
  • the present invention proposes the use of a composition comprising the aforementioned compound in the preparation of a food or health product.
  • the food or health product is used to prevent the senescence of small intestinal stem cells.
  • the compounds of the present invention can effectively prevent or treat the senescence of small intestinal stem cells, especially the senescence of small intestinal stem cells caused by mtDNA mutation. Thereby, the composition is imparted with corresponding effects.
  • the present invention provides a method for preventing or treating senescence of small intestinal stem cells.
  • the method comprises: administering to small intestinal stem cells a compound as defined in the aforementioned uses.
  • 1 is a schematic diagram of the detection results of the number of small intestinal stem cells in POLG mutant mice according to an embodiment of the present invention
  • FIG. 2 is a schematic diagram of the detection result of NMN increasing the number of small intestinal stem cells in POLG mutant mice according to an embodiment of the present invention.
  • C1-6 alkyl specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl groups .
  • the substituent group is attached to the central ring by a bond to form a ring system (such as the compound of formula I), which means that the substituent group can be substituted at any substitutable position on the ring.
  • a ring system such as the compound of formula I
  • the compound represented by formula I represents that the substituent R can be mono- or poly-substituted at any possible substituted position on the ring directly connected to the substituent, as shown in formulas 1 to 7.
  • prodrug refers to the conversion of a compound into a compound of formula (I) in vivo. Such conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion to the parent structure in blood or tissue.
  • the prodrug compounds of the present invention can be esters.
  • esters can be used as prodrugs such as phenyl esters, aliphatic (C 1 -C 24 ) esters, acyloxymethyl esters, carbonic acid Esters, carbamates and amino acid esters.
  • a compound of the present invention contains a hydroxyl group, which can be acylated to give the compound in prodrug form.
  • prodrug forms include phosphates, such as these phosphates are phosphorylated by the hydroxyl group on the parent.
  • phosphates such as these phosphates are phosphorylated by the hydroxyl group on the parent.
  • a complete discussion of prodrugs can be found in the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry , 2008, 51, 2328-2345.
  • Metal refers to a product obtained by metabolism of a specific compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and their activity can be characterized using assays as described herein. Such products may be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
  • pharmaceutically acceptable salts refer to organic and inorganic salts of the compounds of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
  • Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups including hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or obtained by other methods such as ion exchange method described in books and literature these salts.
  • salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, Gluconate, Hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lacturonate, Lactate, Laurate, Lauryl Sulfate, Malate, Mesylate, 2-Naphthalenesulfonate, Nicotinate, Nitrate, Oleate, Palmitate, Pamoate, Pectate, Persulfate, 3-Phenylpropionic Acid Salt, picrate, pivalate, propionate, stearate,
  • Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also contemplates the quaternary ammonium salts formed by any compound containing an N group. Water- or oil-soluble or dispersible products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that resist the formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1 -8 Sulfonates and aromatic sulfonates.
  • counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1 -8 Sulfonates and aromatic sulfonates.
  • a “solvate” of the present invention refers to an association of one or more solvent molecules with a compound of the present invention.
  • Solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate refers to an association in which the solvent molecule is water.
  • the term "hydrate" may be used.
  • one molecule of the compound of the present invention may be associated with one molecule of water, such as a monohydrate; in other embodiments, a molecule of the compound of the present invention may be associated with more than one molecule of water, such as a dihydrate In yet other embodiments, one molecule of the compound of the present invention may be associated with less than one molecule of water, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the bioavailability of the non-hydrated form of the compounds.
  • treating any disease or condition, as used herein, refers to all that can slow, interrupt, arrest, control or stop the progression of the disease or condition, but does not necessarily mean that all symptoms of the disease or condition disappear, which also includes Prophylactic treatment of such symptoms, especially in patients prone to such diseases or disorders. In some of these embodiments refers to ameliorating a disease or disorder (ie slowing or arresting or alleviating the development of a disease or at least one clinical symptom thereof). In other embodiments, “treating” refers to alleviating or improving at least one physical parameter, including a physical parameter that may not be perceived by a patient.
  • treating refers to modulating a disease or disorder physically (eg, stabilizing an observable symptom) or physiologically (eg, stabilizing a physical parameter), or both. In other embodiments, “treating” refers to preventing or delaying the onset, occurrence or worsening of a disease or disorder.
  • composition refers to a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • the meaning of this term in relation to a pharmaceutical composition includes a product comprising the active ingredient (single or multiple) and inert ingredient (single or multiple) that make up the carrier, as well as a mixture, complex or aggregate of any two or more ingredients , or any product that results directly or indirectly from the decomposition of one or more components, or from other types of reactions or interactions of one or more components.
  • the pharmaceutical compositions of the present invention include any composition prepared by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • the invention provides the use of a pharmaceutical composition in preventing and treating the senescence of small intestinal stem cells.
  • the pharmaceutical composition comprises: the compound represented by formula I and its precursors and derivatives such as NADH or NAD + or its pharmaceutically acceptable salts as active ingredients; and pharmaceutically acceptable excipients.
  • the medicine is used for preventing and treating the senescence of small intestinal stem cells, especially the senescence of small intestinal stem cells caused by mtDNA mutation.
  • the pharmaceutical composition is in the form of at least one of tablets, capsules, granules or injections.
  • the pharmaceutical composition further comprises auxiliary substances, optionally, the auxiliary substances are wetting agents, emulsifying agents, preservatives or buffers.
  • the senescence of small intestinal stem cells induced by mtDNA mutation is at least one selected from the group consisting of: elderly people who have accumulated random mtDNA mutations, and small intestinal dysfunction caused by mitochondrial dysfunction caused by random mtDNA mutations.
  • the "mtDNA mutation” in the “mtDNA mutation causes mitochondrial dysfunction and then small intestine disorder" is caused by non-age factors, such as environmental factors.
  • reagents and materials used in the following examples are commercially available, and if not specified, the methods and conditions used are also processed according to well-known methods and conditions.
  • Example 1 The number of small intestinal stem cells in mice with POLG mutation is reduced
  • POLG D257A Progeria mice have a D257A mutation at the POLG exonuclease site that inactivates the exonuclease, resulting in a proofreading defect during mtDNA replication, causing mtDNA mutations that accumulate a large amount of random chance during development. Mutations, which trigger aging traits, are a very good model for studying aging. Small intestinal stem cells can be traced and imaged in LGR5-GFP mice. Therefore, we will obtain LGR5-GFP-labeled POLG mutant mice by crossing LGR5-GFP mice and POLG mice, and select LGR5-GFP-labeled wild-type ( WT) mice and POLG mutant mice to detect the number of intestinal stem cells in the aging process.
  • WT wild-type
  • POLG mutant mice (PolgA Mut/Mut ) had a sharp decrease in the number of intestinal stem cells at 8 and 12 months of age, while the number of intestinal stem cells in wild-type mice remained unchanged. As shown in Figure 1. These results indicate that mtDNA mutation significantly reduces the number of intestinal stem cells in mice, suggesting that mtDNA mutation triggers intestinal stem cell senescence.
  • Example 2 increases the number of intestinal stem cells in POLG mutant mice

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Abstract

化合物在制备药物中的用途，具体地，提出了式(I)所示化合物或式(I)所示化合物的立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、其前药或其衍生物在制备药物中的用途，所述药物用于治疗或预防小肠干细胞衰老。

Description

化合物在制备药物中的用途 技术领域
本发明涉及生物医药领域，具体地，本发明涉及化合物在制备药物中的用途，化合物在制备试剂盒中的用途，组合物在制备药物组合物中的用途，以及组合物在制备食品或保健品中的用途。
背景技术
干细胞存在于许多哺乳类组织当中，具有自我更新及分化的能力。其中，肠组织主要由小肠及结肠所组成，小肠的内层在解剖学上称作粘膜，该粘膜会朝着肠内腔的方向凸出呈长条状，又称为绒毛，而腺窝则位于绒毛附近，小肠干细胞存在于小肠腺窝底端，其具有分化成短暂扩增细胞的能力，该细胞会更进一步分化为二种主要细胞类型，包括吸收系统及分泌系统。小肠干细胞是一种有潜力的干细胞。在机体衰老过程中，小肠等器官率先受累，小肠干细胞是小肠衰老的主要原因。目前，市场上急需预防和治疗小肠干细胞衰老的药物。
发明内容
本申请是基于发明人对以下事实和问题的发现和认识作出的：
发明人通过小鼠实验发现，式I所示化合物能显著提高小肠干细胞障碍小鼠的小肠干细胞数目，尤其是mtDNA突变引发的早衰小鼠的小肠干细胞数目，显示了式I所示化合物的巨大应用价值。
为此，在本发明的第一方面，本发明提出了化合物在制备药物中的用途，所述化合物为式I所示化合物或式I所示化合物的立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、其前药或其衍生物。根据本发明的实施例，所述药物用于治疗或预防小肠干细胞衰老。
Figure PCTCN2020128684-appb-000001
其中：
各R独立地为H、D、F、Cl、Br、I、OH、NH 2、NO 2、CN、N 3或C 1-6烷基；
n为0、1、2、3或4。
需要说明的是，治疗或预防“小肠干细胞衰老”需要进行广义理解，不仅仅指治疗或预防小肠干细胞衰老的病人，也指治疗或预防小肠干细胞功能障碍的病人。
根据本发明的实施例，上述用途还可进一步包括如下附加技术特征至少之一：
根据本发明的实施例，各R独立地为H、D、F、Cl、Br、I、OH、NH 2、NO 2、CN、N 3或C 1-4烷基。
根据本发明的实施例，各R独立地为H、D、F、Cl、Br、I、OH、NH 2、NO 2、CN、N 3、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。
根据本发明的实施例，所述化合物具有以下结构：
Figure PCTCN2020128684-appb-000002
根据本发明的实施例，所述化合物的衍生物为NADH或NAD +。
根据本发明的实施例，所述小肠干细胞衰老是由mtDNA突变引起的。其中，所述mtDNA突变包括点突变和缺失突变。需要说明的是，mtDNA突变可以引发衰老，核基因突变(如核纤层A(LAMNA)中的新点突变)也可能引发衰老，端粒缩短等也可以引发衰老。因此，能够抗衰老的药物是否能够治疗或预防mtDNA突变引发的小肠干细胞衰老，完全是一个未知数。发明人惊喜地发现，根据本发明实施例的化合物可以有效治疗或预防mtDNA突变引发的小肠干细胞衰老。另外，mtDNA突变可以是由衰老引起的，也可以是由其他环境因素引起的。发明人首次发现，线粒体DNA突变会导致小肠干细胞数目显著下降，同时，发明人惊喜地发现，NMN能够逆转线粒体DNA突变导致的小肠干细胞数目下降，起到明显的改善作用。由此，根据本发明实施例的化合物对由mtDNA突变引起的小肠干细胞衰老具有显著疗效。
根据本发明的实施例，所述mtDNA突变引发的小肠干细胞衰老是由卵细胞mtDNA突变(例如点突变)引起的。发明人发现，根据本发明实施例的化合物可以有效治疗或预防由卵细胞mtDNA点突变而引起的小肠干细胞衰老。
根据本发明的实施例，所述药物用于回复mtDNA突变或降低mtDNA突变率。
在本发明的第二方面，本发明提出了化合物在制备试剂盒中的用途，所述化合物为式 I所示化合物或式I所示化合物的立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、其前药或其衍生物。根据本发明的实施例，所述试剂盒用于回复mtDNA突变或降低mtDNA突变率，
Figure PCTCN2020128684-appb-000003
其中：
各R独立地为H、D、F、Cl、Br、I、OH、NH 2、NO 2、CN、N 3或C 1-6烷基；
n为0、1、2、3或4。
发明人发现，根据本发明实施例的化合物可以有效回复mtDNA突变或降低mtDNA突变率，进而，根据本发明实施例的化合物制备的试剂盒可以有效回复mtDNA突变或降低mtDNA突变率，以便用于科学研究或临床应用。
根据本发明的实施例，上述用途还可进一步包括如下附加技术特征至少之一：
根据本发明的实施例，各R独立地为H、D、F、Cl、Br、I、OH、NH 2、NO 2、CN、N 3或C 1-4烷基。
根据本发明的实施例，各R独立地为H、D、F、Cl、Br、I、OH、NH 2、NO 2、CN、N 3、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。
根据本发明的实施例，所述化合物具有以下结构：
Figure PCTCN2020128684-appb-000004
根据本发明的实施例，所述化合物的衍生物为NADH或NAD +。
在本发明的第三方面，本发明提出了组合物在制备药物组合物的用途，所述组合物包括前面所描述的化合物。根据本发明的实施例，所述药物组合物用于治疗或预防小肠干细胞衰老。如前所述，本发明的化合物可以有效地预防或治疗小肠干细胞衰老，尤其是mtDNA突变引起的小肠干细胞衰老。由此，赋予了组合物相应地效果。
根据本发明的实施例，上述用途还可进一步包括如下附加技术特征至少之一：
根据本发明的实施例，所述组合物进一步包括：药学上可接受的赋形剂、载体、佐剂、溶媒或它们的组合。
根据本发明的实施例，所述组合物进一步包括：其他治疗或预防小肠干细胞衰老的药物。
在本发明的第四方面，本发明提出了组合物在制备食品或保健品中的用途，所述组合物包括前面所描述的化合物。根据本发明的实施例，所述食品或保健品用于预防小肠干细胞衰老。如前所述，本发明的化合物可以有效地预防或治疗小肠干细胞衰老，尤其是mtDNA突变引起的小肠干细胞衰老。由此，赋予了组合物相应地效果。
在本发明的第五方面，本发明提出了一种预防或治疗小肠干细胞衰老的方法。根据本发明的实施例，所述方法包括：给予小肠干细胞前面所述用途中限定的化合物。通过对小肠干细胞施加前面所述化合物，可以有效地预防或者治疗小肠干细胞衰老。
附图说明
图1是根据本发明实施例的POLG突变的小鼠小肠干细胞数目检测结果示意图；
图2是根据本发明实施例的NMN提高POLG突变的小鼠小肠干细胞数目的检测结果示意图。
具体实施方式
下面详细描述本发明的实施例，所述实施例的示例在附图中示出。下面通过参考附图描述的实施例是示例性的，旨在用于解释本发明，而不能理解为对本发明的限制。
需要说明的是，在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1-6烷基”特别指独立公开的甲基、乙基、C 3烷基、C 4烷基、C 5烷基和C 6烷基。
除非以其他方式明确指出，在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换，均应做广义理解，其是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响。以式I所示化合物为例，当n为2时，两个R的具体选项互相之间不受影响。
像本发明所描述的，取代基画一个键连接到中心的环上形成的环体系(如式I所示化合物)代表取代基在该环上任何可取代的位置都可以取代。例如，式I所示化合物代表取代基R可在与该取代基直接相连的环上任何可能被取代的位置上单取代或多取代，如式1～式7所示。
Figure PCTCN2020128684-appb-000005
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C 1-C 24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整 的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N +(C 1-4烷基) 4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C 1-8磺酸化物和芳香磺酸化物。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯， 乙酸和氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
当所述溶剂为水时，可以使用术语“水合物”。在一些实施例中，一个本发明化合物分子可以与一个水分子相结合，比如一水合物；在另外一些实施例中，一个本发明化合物分子可以与多于一个的水分子相结合，比如二水合物，还有一些实施例中，一个本发明化合物分子可以与少于一个的水分子相结合，比如半水合物。应注意，本发明所述的水合物保留有非水合形式的所述化合物的生物有效性。
如本发明所使用的术语“治疗”任何疾病或病症，是指所有可以减缓、中断、阻止、控制或停止疾病或病症的进展，但不一定表示所有疾病或病症的症状全部消失，其也包括对所述症状的预防性治疗，尤其是在容易患有这样疾病或障碍的患者中。在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中，“治疗”指缓和或改善至少一种身体参数，包括可能不为患者所察觉的身体参数。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
如本发明所使用的术语“组合物”是指包含规定量的规定成分的产物，以及规定量的规定成分的组合所直接或间接地产生的任何产物。与药物组合物相关的这种术语的含义包括包含活性成分(单个或者多个)和组成载体的惰性成分(单个或者多个)的产物，以及由任何两种或多种成分混合、复合或聚集，或者由一种或多种成分分解，或者由一种或多种成分的其他类型的反应或相互作用而直接或间接产生的任何产物。因此，本发明药物组合物包括通过将本发明化合物与可药用载体混合而制备的任何组合物。
本发明提供了一种药物组合物在预防和治疗小肠干细胞衰老的用途。该药物组合物包含：式I所示化合物及其前体及衍生物如NADH或NAD +或其药学上可接受的盐作为活性成份；以及药学上可以接受的赋形剂。所述药物用于预防和治疗小肠干细胞衰老，尤其是mtDNA突变引发的小肠干细胞衰老。
Figure PCTCN2020128684-appb-000006
在一些实施例中，所述药物组合物呈片剂、胶囊剂、颗粒剂或注射剂的至少一种的剂型。
在一些实施例中，所述药物组合物进一步包含辅助物质，任选地，所述辅助物质为湿润剂、乳化剂、防腐剂或缓冲液。
在一些实施例中，mtDNA突变引发的小肠干细胞衰老为选自下列的至少之一：积累了mtDNA随机突变的年老人、mtDNA随机突变导致线粒体功能障碍进而导致的小肠功能障碍。其中，所述“mtDNA突变导致线粒体功能障碍进而导致的小肠障碍”中的“mtDNA突变”是由非年龄因素引发的，如环境因素等。
下面将结合具体实施例对本发明进行进一步的解释说明。
在下面实施例中所采用的试剂和材料均是市售可得的，如果未明确说明，则所采用的方法和条件，也均按照公知的方法和条件进行相关处理。
实施例1 POLG突变的小鼠小肠干细胞数目减少
POLG D257A早衰小鼠在POLG核酸外切酶的位置有一个D257A突变使其核酸外切酶活性丧失，导致mtDNA复制过程中的校正缺陷，引起mtDNA突变，该小鼠在发育过程中会积累大量随机突变，引发衰老特征，是研究衰老的一个非常好的模型。LGR5-GFP小鼠可以对小肠干细胞进行示踪成像。因此，我们将通过LGR5-GFP小鼠和POLG小鼠杂交，来获得LGR5-GFP标记的POLG突变小鼠，选取不同年龄(3月、8月和12月)的LGR5-GFP标记的野生型(WT)小鼠和POLG突变小鼠，检测衰老进程小肠干细胞的数目。发明人发现POLG突变小鼠(PolgA Mut/Mut)8和12月龄时，小肠干细胞数目急剧下降，而野生型小鼠小肠干细胞数目不变。如图1所示。这些结果表明，mtDNA突变会显著降低小鼠的小肠干细胞数目，表明mtDNA突变引发小肠干细胞衰老。
实施例2 NMN提高POLG突变小鼠的小肠干细胞数目
接下来，发明人以此POLG突变小鼠为模型，发明人进行了能提高小鼠小肠干细胞药物筛选。最终，发明人将8月龄的POLG突变雄性小鼠在900mg/kg/天的饮用水中加入NMN，不加NMN的水处作为对照。并在加入NMN或者对照水饲养小鼠2周后，检测POLG突变雄性小鼠的小肠干细胞数目。结果如图2所示，经NMN处理的POLG突变小鼠小肠干细胞数目显著性增加。结果表明，NMN对POLG突变雌性小鼠的小肠干细胞衰老有明显的改善作用。
Figure PCTCN2020128684-appb-000007
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (18)

  1. 化合物在制备药物中的用途，所述化合物为式I所示化合物或式I所示化合物的立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、其前药或其衍生物，其特征在于，所述药物用于治疗或预防小肠干细胞衰老，
    Figure PCTCN2020128684-appb-100001
    其中：
    各R独立地为H、D、F、Cl、Br、I、OH、NH 2、NO 2、CN、N 3或C 1-6烷基；
    n为0、1、2、3或4。
  2. 根据权利要求1所述的用途，其特征在于，各R独立地为H、D、F、Cl、Br、I、OH、NH 2、NO 2、CN、N 3或C 1-4烷基。
  3. 根据权利要求1所述的用途，其特征在于，各R独立地为H、D、F、Cl、Br、I、OH、NH 2、NO 2、CN、N 3、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。
  4. 根据权利要求1所述的用途，其特征在于，所述化合物具有以下结构：
    Figure PCTCN2020128684-appb-100002
  5. 根据权利要求1所述的用途，其特征在于，所述化合物的衍生物为NADH或NAD +。
  6. 根据权利要求1所述的用途，其特征在于，所述小肠干细胞衰老是由mtDNA突变引起的。
  7. 根据权利要求1所述的用途，其特征在于，所述小肠干细胞衰老是由卵细胞mtDNA突变引起的。
  8. 根据权利要求1所述的用途，其特征在于，所述药物用于回复mtDNA突变或降低mtDNA突变率。
  9. 化合物在制备试剂盒中的用途，所述化合物为式I所示化合物或式I所示化合物的立体异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐、其前药或其衍生物，其特征在于，所试剂盒用于回复mtDNA突变或降低mtDNA突变率，
    Figure PCTCN2020128684-appb-100003
    其中：
    各R独立地为H、D、F、Cl、Br、I、OH、NH 2、NO 2、CN、N 3或C 1-6烷基；
    n为0、1、2、3或4。
  10. 根据权利要求9所述的用途，其特征在于，各R独立地为H、D、F、Cl、Br、I、OH、NH 2、NO 2、CN、N 3或C 1-4烷基。
  11. 根据权利要求9所述的用途，其特征在于，各R独立地为H、D、F、Cl、Br、I、OH、NH 2、NO 2、CN、N 3、甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。
  12. 根据权利要求9所述的用途，其特征在于，所述化合物具有以下结构：
    Figure PCTCN2020128684-appb-100004
  13. 根据权利要求9所述的用途，其特征在于，所述化合物的衍生物为NADH或NAD +。
  14. 组合物在制备药物组合物的用途，所述组合物包括权利要求1～8任一项所述用途中所限定的化合物，其特征在于，所述药物组合物用于治疗或预防小肠干细胞衰老。
  15. 根据权利要求14所述的用途，其特征在于，所述组合物进一步包括：药学上可接受的赋形剂、载体、佐剂、溶媒或它们的组合。
  16. 根据权利要求14所述的用途，其特征在于，所述组合物进一步包括：其他治疗或预防小肠干细胞衰老的药物。
  17. 组合物在制备食品或保健品中的用途，所述组合物包括权利要求1～8任一项所述用途中所限定的化合物，其特征在于，所述食品或保健品用于预防小肠干细胞衰老。
  18. 一种预防或治疗小肠干细胞衰老的方法，其特征在于，包括：给予小肠干细胞权利要求1～8任一项所述用途中限定的化合物。
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