CN114469977A - Use of compounds for the preparation of medicaments - Google Patents
Use of compounds for the preparation of medicaments Download PDFInfo
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- CN114469977A CN114469977A CN202011271565.5A CN202011271565A CN114469977A CN 114469977 A CN114469977 A CN 114469977A CN 202011271565 A CN202011271565 A CN 202011271565A CN 114469977 A CN114469977 A CN 114469977A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 61
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- 150000003839 salts Chemical class 0.000 claims abstract description 18
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000000651 prodrug Substances 0.000 claims abstract description 13
- 229940002612 prodrug Drugs 0.000 claims abstract description 13
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- 108020005196 Mitochondrial DNA Proteins 0.000 claims description 39
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 claims description 5
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
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- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
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- 239000011734 sodium Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 108091035539 telomere Proteins 0.000 description 1
- 210000003411 telomere Anatomy 0.000 description 1
- 102000055501 telomere Human genes 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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- 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
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- 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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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
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Abstract
The invention relates to application of a compound in preparation of a medicine, and particularly provides application of a compound shown in a formula I or a stereoisomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, a prodrug or a derivative of the compound shown in the formula I in preparation of the medicine, wherein the medicine is used for treating or preventing the aging of small intestinal stem cells.
Description
Technical Field
The invention relates to the field of biomedicine, in particular to application of a compound in preparing a medicament, application of the compound in preparing a kit, application of a composition in preparing a medicinal composition, and application of the composition in preparing food or health care products.
Background
Stem cells are present in many mammalian tissues and have the ability to self-renew and differentiate. The intestinal tissue is mainly composed of the small intestine and colon, the inner layer of the small intestine is anatomically called mucosa, the mucosa protrudes towards the inner cavity of the intestine and is in a strip shape, also called villus, the fossa is positioned near the villus, the small intestine stem cells exist at the bottom of the fossa of the small intestine, and have the capacity of differentiating into transient expanded cells, and the cells can further differentiate into two main cell types, including an absorption system and a secretion system. The small intestine stem cell is a potential stem cell. In the aging process of the body, organs such as small intestine and the like are affected first, and small intestine stem cells are the main cause of small intestine aging. At present, drugs for preventing and treating the aging of the small intestine stem cells are urgently needed in the market.
Disclosure of Invention
The present application is based on the discovery and recognition by the inventors of the following facts and problems:
the inventor finds that the compound shown in the formula I can obviously improve the number of the small intestinal stem cells of a small intestinal stem cell disorder mouse, particularly the number of the small intestinal stem cells of a premature senility mouse caused by mtDNA mutation, and shows great application value of the compound shown in the formula I.
To this end, in a first aspect of the invention, the invention proposes the use of a compound of formula I or a stereoisomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, a prodrug or a derivative thereof of a compound of formula I for the manufacture of a medicament. According to an embodiment of the invention, the medicament is for treating or preventing aging of small intestinal stem cells.
Wherein:
each R is independently H, D, F, Cl, Br, I, OH, NH2、NO2、CN、N3Or C1-6An alkyl group;
n is 0, 1,2, 3 or 4.
It should be noted that the term "treating or preventing aging of small intestine stem cells" is to be understood in a broad sense and refers not only to patients who are treated or prevented from aging of small intestine stem cells, but also to patients who are treated or prevented from dysfunction of small intestine stem cells.
According to an embodiment of the present invention, the above-mentioned use may further include at least one of the following additional technical features:
according to an embodiment of the invention, each R is independently H, D, F, Cl, Br, I, OH, NH2、NO2、CN、N3Or C1-4An alkyl group.
According to an embodiment of the invention, each R is independently H, D, F, Cl, Br, I, OH, NH2、NO2、CN、N3Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
According to an embodiment of the invention, the compound has the following structure:
according to an embodiment of the invention, the derivative of said compound is NADH or NAD+。
According to an embodiment of the present invention, the aging of the small intestine stem cell is caused by mutation of mtDNA. Wherein the mtDNA mutation comprises a point mutation and a deletion mutation. It should be noted that mutations in mtDNA may cause senescence, mutations in nuclear genes (e.g., mutations at new points in the nuclear fiber layer a (lamna)) may also cause senescence, telomere shortening, etc., may also cause senescence. Therefore, it is completely unknown whether an anti-aging drug can treat or prevent the aging of the small intestine stem cells caused by mtDNA mutation. The inventors have surprisingly found that compounds according to embodiments of the invention may be effective in treating or preventing aging of small intestinal stem cells induced by mtDNA mutations. In addition, mtDNA mutations may be caused by senescence or by other environmental factors. The inventor discovers for the first time that the mutation of mitochondrial DNA can cause the number of small intestine stem cells to be remarkably reduced, and at the same time, the inventor surprisingly discovers that NMN can reverse the reduction of the number of small intestine stem cells caused by the mutation of mitochondrial DNA, and the NMN plays a role in obviously improving. Thus, the compounds according to embodiments of the present invention have a significant therapeutic effect on the aging of small intestinal stem cells caused by mtDNA mutation.
According to an embodiment of the present invention, the mtDNA mutation-induced aging of the small intestine stem cell is caused by an oocyte mtDNA mutation (e.g., a point mutation). The inventors found that the compounds according to the embodiments of the present invention can effectively treat or prevent the aging of small intestine stem cells caused by the point mutation of oocyte mtDNA.
According to an embodiment of the invention, the medicament is for reverting mtDNA mutations or reducing mtDNA mutation rates.
In a second aspect of the invention, the invention proposes the use of a compound of formula I or a stereoisomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, a prodrug or a derivative of a compound of formula I for the preparation of a kit. According to an embodiment of the present invention, the kit is used for reverting mtDNA mutation or reducing mtDNA mutation rate,
wherein:
each R is independently H, D, F, Cl, Br, I, OH, NH2、NO2、CN、N3Or C1-6An alkyl group;
n is 0, 1,2, 3 or 4.
The inventor finds that the compound according to the embodiment of the invention can effectively recover mtDNA mutation or reduce mtDNA mutation rate, and furthermore, the kit prepared by the compound according to the embodiment of the invention can effectively recover mtDNA mutation or reduce mtDNA mutation rate so as to be used for scientific research or clinical application.
According to an embodiment of the present invention, the above-mentioned use may further include at least one of the following additional technical features:
according to an embodiment of the invention, each R is independently H, D, F, Cl, Br, I, OH, NH2、NO2、CN、N3Or C1-4An alkyl group.
According to an embodiment of the invention, each R is independently H, D, F, Cl, Br, I, OH, NH2、NO2、CN、N3Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
According to an embodiment of the invention, the compound has the following structure:
according to embodiments of the present inventionThe derivative of the compound is NADH or NAD+。
In a third aspect of the invention, the invention proposes the use of a composition comprising a compound as described hereinbefore for the preparation of a pharmaceutical composition. According to an embodiment of the invention, the pharmaceutical composition is for use in the treatment or prevention of aging of small intestinal stem cells. As described above, the compound of the present invention can effectively prevent or treat aging of small intestine stem cells, particularly aging of small intestine stem cells caused by mutation of mtDNA. Thereby, the composition is given a corresponding effect.
According to an embodiment of the present invention, the above-mentioned use may further include at least one of the following additional technical features:
according to an embodiment of the invention, the composition further comprises: a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof.
According to an embodiment of the invention, the composition further comprises: other drugs for treating or preventing aging of small intestinal stem cells.
In a fourth aspect of the invention, the invention proposes the use of a composition comprising a compound as described above in the preparation of a food or health care product. According to an embodiment of the present invention, the food or health product is used for preventing aging of small intestine stem cells. As described above, the compound of the present invention can effectively prevent or treat aging of small intestine stem cells, particularly aging of small intestine stem cells caused by mutation of mtDNA. Thereby, the composition is given a corresponding effect.
Drawings
FIG. 1 is a graph showing the results of a number test of POLG mutated mouse small intestine stem cells according to an embodiment of the present invention;
fig. 2 is a graph showing the results of NMN detection of increased number of POLG mutated mouse small intestinal stem cells, according to an embodiment of the present invention.
Detailed Description
Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings. The embodiments described below with reference to the drawings are illustrative and intended to be illustrative of the invention and are not to be construed as limiting the invention.
In the respective portions of the present specification, substituents of the compounds disclosed in the present invention are disclosed according to the kind or range of the group. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C1-6Alkyl "means in particular independently disclosed methyl, ethyl, C3Alkyl radical, C4Alkyl radical, C5Alkyl and C6An alkyl group.
Unless otherwise expressly indicated, the recitations employed in the present disclosure of "each … independently being" and "… independently being" and "… independently being" are interchangeable, and should be understood broadly, meaning that in different groups, the particular choice expressed between the same symbol does not affect each other. Taking the compound shown in the formula I as an example, when n is 2, the specific options of two R are not influenced with each other.
As described herein, a substituent may be substituted at any substitutable position on the ring by a ring system formed on the ring with a bond to the center (e.g., a compound of formula I). For example, the compound represented by formula I represents that the substituent R can be mono-substituted or multi-substituted at any possible substituted position on the ring directly connected with the substituent, as shown in formulas 1 to 7.
The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)1-C24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the invention comprising a hydroxy group may be acylated to give a prodrugA compound in its form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S.Symphosis Series, Edward B.Roche, ed., Bioreversible Carriers in Drug designs, American Pharmaceutical Association and Pergamon Press,1987, J.Rautio et al, Prodrugs in Design and Clinical Applications, Nature Review Drug Discovery,2008,7, 255-.
"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, 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.
As used herein, "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 are: berge et al, description of the scientific acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, and anticonvulsantsExamples of suitable organic solvents include, but are not limited to, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, sulfate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N+(C1-4Alkyl radical)4A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8Sulfonates and aromatic sulfonates.
"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.
When the solvent is water, the term "hydrate" may be used. In some embodiments, a molecule of a compound of the present invention may be associated with a molecule of water, such as a monohydrate; in other embodiments, one molecule of the compound of the present invention may be associated with more than one molecule of water, such as a dihydrate, and in still 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 biological effectiveness of the compound in its non-hydrated form.
The term "treating" any disease or condition, as used herein, means all that can slow, halt, arrest, control or halt the progression of the disease or condition, but does not necessarily mean that all the symptoms of the disease or condition have disappeared, and also includes prophylactic treatment of the symptoms, particularly in patients susceptible to such disease or disorder. In some of these embodiments, refers to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.
The term "composition" as used herein refers to a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The meaning of such terms in relation to pharmaceutical compositions includes products comprising the active ingredient(s) and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from mixing, complexation or aggregation of any two or more of the ingredients, or from decomposition of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, 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 an application of a pharmaceutical composition in preventing and treating small intestine stem cell aging. The pharmaceutical composition comprises: a compound of formula I and its precursor and derivatives such as NADH or NAD+Or a pharmaceutically acceptable salt thereof as an active ingredient; and pharmaceutically acceptable excipients. The medicine is used for preventing and treating the aging of the small intestine stem cells, in particular to the aging of the small intestine stem cells caused by mtDNA mutation.
In some embodiments, the pharmaceutical composition is in the dosage form of at least one of a tablet, a capsule, a granule, or an injection.
In some embodiments, the pharmaceutical composition further comprises an auxiliary substance, optionally the auxiliary substance is a wetting agent, an emulsifier, a preservative or a buffer.
In some embodiments, the mtDNA mutation-induced senescence of small intestinal stem cells is selected from at least one of: elderly with accumulated random mutation of mtDNA, and small intestine dysfunction caused by mitochondrial dysfunction due to random mutation of mtDNA. Wherein, the "mtDNA mutation" in the "mtDNA mutation causes mitochondrial dysfunction and thus small intestine dysfunction" is caused by non-age factors, such as environmental factors.
The invention will be further explained with reference to specific examples.
The reagents and materials used in the following examples are commercially available, and if not explicitly indicated, the methods and conditions used are also well known and used in the relevant art.
Example 1 POLG mutant mice have a reduced number of intestinal stem cells
The POLG D257A senilism mouse has a D257A mutation at the position of POLG exonuclease so that the exonuclease activity of the POLG exonuclease is lost, correction defects in the mtDNA replication process are caused, mtDNA mutation is caused, and the mouse can accumulate a large number of random mutations in the development process to cause senescence characteristics, so that the model is a very good model for researching senescence. The LGR5-GFP mouse can be used for tracing and imaging the small intestine stem cells. Therefore, we will obtain LGR5-GFP mice by crossing LGR5-GFP mice with POLG miceGFP-labeled POLG mutant mice, LGR 5-GFP-labeled Wild Type (WT) mice and POLG mutant mice of different ages (3 months, 8 months and 12 months) were selected, and the number of aging-progressing small intestinal stem cells was examined. The inventors found POLG mutant mice (PolgA)Mut/Mut) At 8 and 12 months of age, the number of small intestinal stem cells decreased dramatically, while the number of small intestinal stem cells in wild-type mice did not change. As shown in fig. 1. These results indicate that mtDNA mutations significantly reduce the number of small intestinal stem cells in mice, indicating that mtDNA mutations trigger small intestinal stem cell senescence.
Example 2 NMN increase the number of intestinal Stem cells in POLG mutant mice
Next, the inventors modeled this POLG mutant mouse and conducted drug screening capable of improving mouse small intestinal stem cells. Finally, the inventors used 8-month-old POLG mutant male mice as controls in 900 mg/kg/day of drinking water with NMN added thereto and in water without NMN added thereto. And the number of small intestinal stem cells of POLG mutant male mice was measured 2 weeks after the mice were fed with NMN or control water. The results are shown in fig. 2, where the number of intestinal stem cells was significantly increased in POLG mutant mice treated with NMN. The result shows that NMN has obvious improvement effect on the small intestinal stem cell senescence of the POLG mutant female mice.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. Use of a compound of formula I or a stereoisomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, a prodrug or a derivative thereof of a compound of formula I for the preparation of a medicament for the treatment or prevention of aging of small intestinal stem cells,
wherein:
each R is independently H, D, F, Cl, Br, I, OH, NH2、NO2、CN、N3Or C1-6An alkyl group;
n is 0, 1,2, 3 or 4.
2. The use according to claim 1, wherein each R is independently H, D, F, Cl, Br, I, OH, NH2、NO2、CN、N3Or C1-4An alkyl group;
optionally, each R is independently H, D, F, Cl, Br, I, OH, NH2、NO2、CN、N3Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl;
optionally, the compound has the structure:
optionally, aThe derivative of the compound is NADH or NAD+。
3. The use according to claim 1, wherein the small intestine stem cell senescence is caused by mtDNA mutation;
optionally, the small intestine stem cell senescence is caused by mutation of the oocyte mtDNA.
4. The use according to claim 1, wherein the medicament is for reverting mtDNA mutations or reducing mtDNA mutation rates.
5. Use of a compound in the preparation of a kit, said compound being a compound of formula I or a stereoisomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, a prodrug or a derivative thereof of a compound of formula I, wherein the kit is for reverting mtDNA mutations or reducing mtDNA mutation rates,
wherein:
each R is independently H, D, F, Cl, Br, I, OH, NH2、NO2、CN、N3Or C1-6An alkyl group;
n is 0, 1,2, 3 or 4.
6. The use according to claim 5, wherein each R is independently H, D, F, Cl, Br, I, OH, NH2、NO2、CN、N3Or C1-4An alkyl group;
optionally, each R is independently H, D, F, Cl, Br, I, OH, NH2、NO2、CN、N3Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl;
optionally, the compound has the structure:
optionally, the derivative of the compound is NADH or NAD+。
7. Use of a composition comprising a compound as defined in any one of claims 1 to 6 for the preparation of a pharmaceutical composition for the treatment or prevention of aging of small intestine stem cells.
8. Use according to claim 7, characterized in that the composition further comprises: a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof.
9. Use according to claim 7, characterized in that the composition further comprises: other drugs for treating or preventing aging of small intestinal stem cells.
10. Use of a composition comprising a compound as defined in any one of claims 1 to 6 for the preparation of a food or nutraceutical for the prevention of aging of small intestinal stem cells.
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| Title |
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| ALESSIA GROZIO 等: "Slc12a8 is a nicotinamide mononucleotide transporter", 《NATURE METABOLISM》, vol. 1, pages 47 - 57 * |
| RYOEI UCHIDA 等: "Epigenetic silencing of Lgr5 induces senescence of intestinal epithelial organoids during the process of aging", 《NPJ AGING MECH DIS》, vol. 4, no. 12, pages 1 - 9 * |
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