CN111617093A - Use of compounds for the preparation of medicaments - Google Patents

Use of compounds for the preparation of medicaments Download PDF

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CN111617093A
CN111617093A CN201910509686.XA CN201910509686A CN111617093A CN 111617093 A CN111617093 A CN 111617093A CN 201910509686 A CN201910509686 A CN 201910509686A CN 111617093 A CN111617093 A CN 111617093A
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compound
independently
optionally
composition
formula
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刘兴国
杨亮
林晓冰
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Guangzhou Institute of Biomedicine and Health of CAS
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Priority to PCT/CN2020/077426 priority patent/WO2020248630A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives

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Abstract

The invention relates to application of a compound in preparing a medicament, 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 preparing a medicament for treating or preventing female infertility.

Description

Use of compounds for the preparation of medicaments
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 a health-care product.
Background
In recent years, infertility and poor fertility have increased, the most likely explanation being due to rapid changes in the environment. At present, more and more people believe that mitochondria play an important role in age and environment-induced infertility. Mitochondrial transplantation has been used to improve fertility in women with poor innate reproductive capacity by autologous mitochondrial injection therapy. However, this method is complicated and costly and does not provide a preventive effect.
Therefore, there is an urgent need in the market for drugs for preventing and treating female infertility or fertility difficulties.
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 fertility of a mouse which is sterile or difficult to breed, particularly the fertility of a mouse which is sterile or difficult to breed caused by mtDNA mutation, and shows great application value of the compound shown in the formula I in the reproductive field.
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 of a compound of formula I, a prodrug thereof or a derivative thereof, for the manufacture of a medicament for the treatment or prevention of female infertility,
Figure BDA0002093052820000011
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 is to be noted that the term "treatment or prevention of infertility" in a female is to be understood in a broad sense and refers not only to the treatment or prevention of women who are not pregnant or fertile, but also to the treatment or prevention of women who are pregnant or have difficulty in fertility. In addition, there is no direct relationship between senescence and fertility, senescence is only one cause but not a requirement for infertility, which may be caused by senescence, but also by other environmental factors. Therefore, it is completely unknown whether anti-aging drugs can treat or prevent infertility. The inventors have surprisingly found that compounds according to embodiments of the invention may be effective in the treatment or prevention of infertility in women.
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:
Figure BDA0002093052820000021
according to an embodiment of the invention, the derivative of said compound is NADH or NAD+。
According to an embodiment of the invention, the female infertility is caused by a mutation of mtDNA. Wherein the mtDNA mutation comprises a point mutation and a deletion mutation. It should be noted that the mtDNA mutation may be caused by aging or other environmental factors. The inventor discovers for the first time that the fertility is remarkably reduced due to mitochondrial DNA mutation, and at the same time, the inventor surprisingly discovers that NMN can reverse the fertility reduction caused by mitochondrial DNA mutation, so that the method has a remarkable improvement effect. Thus, the compounds according to the embodiments of the present invention have a significant therapeutic effect on female infertility caused by mutation of mtDNA.
According to an embodiment of the invention, the female infertility is caused by a point mutation of the egg cell mtDNA. The inventor finds that the compound according to the embodiment of the invention can effectively treat or prevent female infertility caused by the point mutation of the oocyte mtDNA.
According to an embodiment of the invention, the female infertility is caused by an increase of the point mutation of the mtDNA of the egg cell. The inventor finds that the compound according to the embodiment of the invention can effectively treat or prevent female infertility caused by the increase of the mtDNA point mutation of the egg cell.
In a second aspect, the invention provides the use of a compound of formula I or a stereoisomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of formula I, a prodrug thereof or a derivative thereof, in the manufacture of a kit for reverting mtDNA mutations or reducing mtDNA point mutation rates,
Figure BDA0002093052820000031
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 point 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 point mutation rate for scientific research.
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:
Figure BDA0002093052820000032
according to an embodiment of the invention, the derivative of said compound is NADH or NAD+。
In a third aspect of the invention, the invention proposes the use of a composition for the preparation of a pharmaceutical composition for the treatment or prevention of infertility in women, said composition comprising a compound as described above.
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 medicines for treating or preventing female infertility.
In a fourth aspect of the invention, the invention proposes the use of a composition comprising a compound as described above for the preparation of a nutraceutical for the prevention of infertility in women.
Drawings
FIG. 1 is a graph showing the results of a fertility test of a POLG-mutated mouse according to an embodiment of the present invention;
fig. 2 is a graph showing the results of NMN detection of increased fertility in POLG mutated mice, 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" and "… independently" and "… independently" are interchangeable and should be understood broadly to mean that the specific options expressed between the same symbols do not affect each other in different groups. 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.
Figure BDA0002093052820000041
Figure BDA0002093052820000051
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 present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug 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.Sympossium Series, Edward B.Roche, ed., Bioredeliers in Drug designs, American Pharmaceutical Association and PergammonPress, 1987, J.Rautio et al, Prodrugs in Design and Clinical Applications, NatureReview Drug Discovery,2008,7,255 Option 270, and S.J.Hener et al, Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
"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, descriptive 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, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, malates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pamoic acidsSalts, pectates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanates, p-toluenesulfonates, undecanoates, pentanoates, 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 infertility or fertility difficulty caused by random mutation of mtDNA. 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 female infertility or improving female fertility.
Figure BDA0002093052820000071
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 random mutation of mtDNA induces infertility or fertility difficulties that are at least one selected from the group consisting of: old women with accumulated random mutation of mtDNA and female sterility caused by mitochondrial dysfunction due to random mutation of mtDNA. The mtDNA random mutation in the female infertility caused by mitochondrial dysfunction caused by mtDNA random mutation is caused by non-age factors, such as environmental factors and the like.
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 mouse fertility assay
Mitochondrial DNA Polymerase (POLG) plays an important role in replication and repair of mitochondrial DNA, and due to the fact that the deletion of POLG function causes mitochondrial dysfunction, the equilibrium and steady state of generation and removal of ROS is broken, so that the function of adult stem cells is possibly influenced, tissues and organs cannot be updated and repaired, and the aging appearance of an organism appears. POLG mutant mice with a D257A mutation at the position of POLG exonuclease that results in loss of exonuclease activity, correction defects in mtDNA replication leading to mtDNA mutations, accumulate a large number of random mutations during development: including point mutation and deletion mutation, and develops various characteristics of presenility, and is a good model for researching mitochondrial DNA mutation. The inventor selects 6 pairs of 2-month POLG mutant homozygote female and male mice (Mut), respectively performs cage combination, and detects the fertility of each pair of mice; meanwhile, 6 pairs of 2-month wild-type female and male mice (WT) were selected and housed together, and the fertility of each pair of mice was tested as a control. The inventors found that POLG mutant mice had very low fertility, with an average litter size of only 1 ± 0.4 in the first litter and 0 in the second and third litters per pair of mice. While the average litter size of each pair of wild-type mice was 9.3. + -. 0.2 in the first litter, 9.6. + -. 0.3 in the second litter and 8.5. + -. 0.2 in the third litter, as shown in FIG. 1. These results indicate that mtDNA mutations significantly reduce the fertility of mice, resulting in a substantial loss of fertility in mice.
Example 2 NMN increasing fertility of POLG mutant mice
Next, the inventors modeled this POLG mutant mouse and conducted drug screening capable of improving the fertility of the mouse. Finally, the inventors used 6-week POLG mutant female mice with NMN added to 900 mg/kg/day of drinking water, and water without NMN as a control. And the fertility of POLG mutant female mice was tested after 2 weeks of feeding the mice with NMN or control water, i.e. after crossing with wild male mice at 8 weeks of mice. As a result, as shown in fig. 2, the first litter size of the NMN-treated POLG mutant female (n ═ 6) was greater than that of the water-treated POLG mutant female mouse (n ═ 6). The result shows that NMN has obvious improvement effect on the fertility of the POLG mutant female mouse.
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 (9)

1. Use of a compound of formula I or a stereoisomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of formula I, a prodrug thereof or a derivative thereof in the manufacture of a medicament for the treatment or prevention of female infertility,
Figure FDA0002093052810000011
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:
Figure FDA0002093052810000012
optionally, the derivative of the compound is NADH or NAD+。
3. The use according to claim 1, wherein the female infertility is caused by egg cell mtDNA mutation;
optionally, the female infertility is caused by egg cell mtDNA point mutation.
4. Use of a compound of formula I or a stereoisomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of formula I, a prodrug thereof or a derivative thereof in the manufacture of a kit for reverting mtDNA mutations,
Figure FDA0002093052810000021
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.
5. The use according to claim 4, 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:
Figure FDA0002093052810000022
optionally, the derivative of the compound is NADH or NAD+。
6. Use of a composition for the preparation of a pharmaceutical composition for the treatment or prevention of infertility in a female, the composition comprising a compound as defined in any of claims 1-2.
7. Use according to claim 6, characterized in that the composition further comprises: a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof.
8. Use according to claim 6, characterized in that the composition further comprises: other medicines for treating or preventing female infertility.
9. Use of a composition for the preparation of a health product for the prevention of female infertility, the composition comprising a compound as defined in any of claims 1-2.
CN201910509686.XA 2019-06-13 2019-06-13 Use of compounds for the preparation of medicaments Pending CN111617093A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114848664A (en) * 2022-06-09 2022-08-05 中国药科大学 Pharmaceutical composition and application thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130059384A1 (en) * 2011-06-29 2013-03-07 President And Fellows Of Harvard College Compositions and methods for enhancing bioenergetic status in female germ cells

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130059384A1 (en) * 2011-06-29 2013-03-07 President And Fellows Of Harvard College Compositions and methods for enhancing bioenergetic status in female germ cells

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114848664A (en) * 2022-06-09 2022-08-05 中国药科大学 Pharmaceutical composition and application thereof

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