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CN117959290A - Application of N-benzyl-5/6-formylamino indole-2-carboxylic acid derivative in preparation of medicine for preventing and treating polycystic ovary syndrome - Google Patents

Application of N-benzyl-5/6-formylamino indole-2-carboxylic acid derivative in preparation of medicine for preventing and treating polycystic ovary syndrome Download PDF

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CN117959290A
CN117959290A CN202410018259.2A CN202410018259A CN117959290A CN 117959290 A CN117959290 A CN 117959290A CN 202410018259 A CN202410018259 A CN 202410018259A CN 117959290 A CN117959290 A CN 117959290A
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halogen
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易伟
刘夏雯
郑秀芬
陈梓楷
马磊
张思琳
张淑允
梁妙
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Guangzhou Medical University
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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis

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Abstract

The invention belongs to the field of biological medicine, and in particular relates to an application of N-benzyl-5/6-formamidoindole-2-carboxylic acid derivatives or pharmaceutically acceptable salts thereof in preparing medicines for preventing and/or treating polycystic ovary syndrome or lead compounds thereof. The N-benzyl-5/6-formylamino indole-2-carboxylic acid derivative or the pharmaceutically acceptable salt thereof provided by the invention has the effects of improving PCOS polycystic lesions, normalizing the estrus cycle of disorder, effectively reducing the androgen level in serum and reducing the insulin resistance index, has good bioavailability, has no potential cardiotoxicity, and can be applied to development and preparation of novel PCOS prevention and/or treatment drugs or lead compounds or health care products thereof.

Description

Application of N-benzyl-5/6-formylamino indole-2-carboxylic acid derivative in preparation of medicine for preventing and treating polycystic ovary syndrome
Technical Field
The invention belongs to the field of biological medicine, and in particular relates to an application of N-benzyl-5/6-formamidoindole-2-carboxylic acid derivatives or pharmaceutically acceptable salts thereof in preparing medicines for preventing and/or treating polycystic ovary syndrome or lead compounds thereof.
Background
Polycystic ovary syndrome (Polycystic ovary syndrome, PCOS) is a syndrome of common endocrine and metabolic disorders in women, characterized clinically by hyperandrogenism, anovulation and polycystic ovary, and is often accompanied by insulin resistance, glucose tolerance and obesity. PCOS severely jeopardizes reproductive health in women of childbearing age and also has an impact on health in child-bearing, childhood, childbearing, and even the middle-aged and senior. However, due to the clinical heterogeneity of PCOS and the complexity of syndromes, the pathogenic cause and pathophysiological mechanism of PCOS have not been elucidated, and no therapeutic drug for PCOS exists at home and abroad at present. The current clinical drug treatment approaches and limitations mainly include: 1. aiming at the patients with the fertility-free requirement in puberty and the childhood, an oral contraceptive is used for adjusting the menstrual cycle, but the means can only cause artificial period 'menstrual cycle', so that single estrogen caused by long-term anovulation is protected to stimulate endometrium, acne and hair caused by high male is reduced, PCOS can not be treated, and irregular menstruation and amenorrhea still occur after stopping; 2. for anti-hyperandrogens with poor contraceptive treatment effects, spironolactone is often used, but the medicine has long treatment period, and long-term use of large dosage often causes side effects such as hypotension, hyperkalemia, headache or urination; 3. the medical guidelines recommend treatment with metformin or an insulin sensitizer for patients suffering from obesity and glycolipid metabolic disorders, and long-term use of common gastrointestinal side effects, vitamin B12 deficiency, and exacerbation of liver and kidney injury. In conclusion, each type of existing medicine aims at the single symptom treatment, the complications of hormone medicines are more, and the curative effects of other medicines are poor. Thus, there is currently a lack of comprehensive drugs that are effective in treating PCOS.
Disclosure of Invention
To overcome the above-mentioned drawbacks and disadvantages of the prior art, a primary object of the present invention is to provide an application of an N-benzyl-5/6-carboxamido indole-2-carboxylic acid derivative or a pharmaceutically acceptable salt thereof in preparing a medicament for preventing and/or treating polycystic ovary syndrome (PCOS) or a lead compound thereof.
The N-benzyl-5/6-formylamino indole-2-carboxylic acid derivative or the pharmaceutically acceptable salt thereof provided by the invention has the effects of improving PCOS polycystic lesions, normalizing the estrus cycle of disorder, effectively reducing the androgen level in serum and reducing the insulin resistance index, and can be applied to development and preparation of novel medicaments for treating PCOS.
It is another object of the present invention to provide a pharmaceutical composition for treating PCOS.
The invention also aims to provide the application of the N-benzyl-5/6-formamido indole-2-carboxylic acid derivative or the pharmaceutically acceptable salt thereof in preparing health care products for preventing and/or treating polycystic ovary syndrome (PCOS).
The aim of the invention is achieved by the following scheme:
Use of an N-benzyl-5/6-carboxamido indole-2-carboxylic acid derivative or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention and/or treatment of polycystic ovary syndrome (PCOS) or a lead compound thereof.
The N-benzyl-5/6-formylamino indole-2-carboxylic acid derivative has a structure shown in the following formula I:
Wherein R 0 is each independently selected from: Halogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, -OH, -NO 2, -CN; wherein the substitution is with one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 haloalkyl and phenyl;
And at least one R 0 is
N is a positive integer from 1 to 4;
r 1 is selected from: a substituted or unsubstituted C1-C10 alkyl group; substituted or unsubstituted C3-C10 cycloalkyl; Z-Y-and R 5(R6) N-; wherein said substitution is with one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 haloalkyl;
R 5 and R 6 are each independently selected from hydrogen, substituted or unsubstituted C1-C10 alkyl-carbonyl, substituted or unsubstituted C1-C10 alkoxy-carbonyl, or substituted or unsubstituted C5-C20 aryl; wherein said substitution is with one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 haloalkyl, carboxyl, -OH, -NH 2 and phenyl;
z is selected from: a substituted or unsubstituted C5-C20 aryl group, a substituted or unsubstituted C3-C20 heteroaryl group, and a substituted or unsubstituted 5-20 membered heterocyclic group; wherein said substitution is with one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 haloalkyl and phenyl;
y is an unsubstituted, substituted or unsubstituted C1-C10 alkylene group, wherein the substitution is with one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, and C2-C4 alkenyl;
R 2 is selected from the group consisting of: H. halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C3-C8 cycloalkyl, -NO 2, -CN, -OH, substituted or unsubstituted C1-C6 alkyl-carbonyl, or substituted or unsubstituted C1-C6 alkoxycarbonyl; wherein substituted means having one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, C2-C4 alkenyl and phenyl;
R 3 is selected from the group consisting of: substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C5-C20 aryl, R 9 -C (O) -, cyano, carboxamide and tetrazole; wherein substituted means having one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 haloalkyl, carboxyl, -OH, -NH 2 and phenyl;
R 4 are each independently selected from: halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C5-C20 aryl, -NO 2、-CN、-OH、R9-C(O)-、R10(R11) N-or C5-C20 aryl-C (O) -N (R 10)R11 -; wherein substituted means having one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 haloalkyl, carboxyl, -OH, -NH 2 and phenyl;
R 9 is the following group: hydroxy, mercapto, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, and R 10(R11) N-; wherein substituted means having one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, C2-C4 alkenyl and phenyl;
R 10 and R 11 are each independently hydrogen, C1-C10 alkyl or C1-C10 haloalkyl;
m is an integer of 0 to 5.
Further, the medicaments, which are the same or different, each include a therapeutically effective amount of an N-benzyl-5/6-carboxamido indole-2-carboxylic acid derivative or a pharmaceutically acceptable salt thereof.
Further, the medicines, which are the same or different, can be prepared into various medicinal dosage forms by adopting a conventional method, and the dosage forms comprise: tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, buccal agents, granules, medicinal granules, pills, pellets, suspensions, wines, tinctures, drops and other oral administration forms, and injection and other oral administration forms, such as injection and the like.
Furthermore, the medicines which are the same or different can also contain one or more pharmaceutically acceptable carriers or auxiliary materials.
Further, the carrier or adjuvant may include diluents, binders, surfactants, wetting agents, adsorption carriers, lubricants, fillers, disintegrants, preservatives, etc.
The invention also provides a pharmaceutical composition for treating PCOS, which comprises the N-benzyl-5/6-formamidoindole-2-carboxylic acid derivative or pharmaceutically acceptable salt thereof or other pharmaceutically acceptable components thereof.
The invention also provides application of the N-benzyl-5/6-formamidoindole-2-carboxylic acid derivative or pharmaceutically acceptable salt thereof in preparing health-care products for preventing and/or treating polycystic ovary syndrome (PCOS).
The invention also provides application of the N-benzyl-5/6-formylamino indole-2-carboxylic acid derivative or pharmaceutically acceptable salt thereof in preparing health care products for preventing and/or treating polycystic ovary syndrome.
The invention also provides application of the N-benzyl-5/6-formamidoindole-2-carboxylic acid derivative or pharmaceutically acceptable salt thereof in preparing medicines or health care products for reducing androgen level.
The N-benzyl-5/6-formylamino indole-2-carboxylic acid derivative or the pharmaceutically acceptable salt thereof provided by the invention has the effects of improving PCOS polycystic lesions, normalizing the estrus cycle of disorder, effectively reducing the androgen level in serum and reducing the insulin resistance index, has good bioavailability, has no potential cardiotoxicity, and can be applied to development and preparation of novel PCOS prevention and/or treatment drugs or lead compounds or health care products thereof.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the embodiments will be briefly described below, it being understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and other related drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is an H & E stained ovarian morphology observation;
FIG. 2 is an ultrasound ovarian morphology observation;
FIG. 3 is an ultrasonic ovarian diameter;
FIG. 4 is an ultrasound ovarian area;
FIG. 5 is a microscopic view of vaginal secretion from a mouse;
FIG. 6 is a graph showing the estrus cycle statistics of mice;
FIG. 7 is serum testosterone levels in mice;
FIG. 8 is a graph of mouse insulin resistance levels;
FIG. 9 is a graph of the intravenous injection of VSP-51-2 plasma drug into rats;
FIG. 10 is a graph of the time profile of a rat lavage VSP-51-2 plasma drug.
Detailed Description
The present invention will be described in further detail with reference to examples, but embodiments of the present invention are not limited thereto. The materials referred to in the examples below are available commercially unless otherwise specified. The method is conventional unless otherwise specified.
In one embodiment, the use of an N-benzyl-5/6-carboxamido indole-2-carboxylic acid derivative or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention and/or treatment of polycystic ovary syndrome (PCOS) or a lead compound thereof.
In one embodiment, the N-benzyl-5/6-carboxamido indole-2-carboxylic acid derivative has the structure shown in formula I:
Wherein R 0 is each independently selected from: Halogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, -OH, -NO 2, -CN; wherein the substitution is with one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 haloalkyl and phenyl;
And at least one R 0 is
N is a positive integer from 1 to 4;
r 1 is selected from: a substituted or unsubstituted C1-C10 alkyl group; substituted or unsubstituted C3-C10 cycloalkyl; Z-Y-and R 5(R6) N-; wherein said substitution is with one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 haloalkyl;
R 5 and R 6 are each independently selected from hydrogen, substituted or unsubstituted C1-C10 alkyl-carbonyl, substituted or unsubstituted C1-C10 alkoxy-carbonyl, or substituted or unsubstituted C5-C20 aryl; wherein said substitution is with one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 haloalkyl, carboxyl, -OH, -NH 2 and phenyl;
z is selected from: a substituted or unsubstituted C5-C20 aryl group, a substituted or unsubstituted C3-C20 heteroaryl group, and a substituted or unsubstituted 5-20 membered heterocyclic group; wherein said substitution is with one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 haloalkyl and phenyl;
y is an unsubstituted, substituted or unsubstituted C1-C10 alkylene group, wherein the substitution is with one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, and C2-C4 alkenyl;
R 2 is selected from the group consisting of: H. halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C3-C8 cycloalkyl, -NO 2, -CN, -OH, substituted or unsubstituted C1-C6 alkyl-carbonyl, or substituted or unsubstituted C1-C6 alkoxycarbonyl; wherein substituted means having one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, C2-C4 alkenyl and phenyl;
R 3 is selected from the group consisting of: substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C5-C20 aryl, R 9 -C (O) -, cyano, carboxamide and tetrazole; wherein substituted means having one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 haloalkyl, carboxyl, -OH, -NH 2 and phenyl;
R 4 are each independently selected from: halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C5-C20 aryl, -NO 2、-CN、-OH、R9-C(O)-、R10(R11) N-or C5-C20 aryl-C (O) -N (R 10)R11 -; wherein substituted means having one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 haloalkyl, carboxyl, -OH, -NH 2 and phenyl;
R 9 is the following group: hydroxy, mercapto, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, and R 10(R11) N-; wherein substituted means having one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, C2-C4 alkenyl and phenyl;
R 10 and R 11 are each independently hydrogen, C1-C10 alkyl or C1-C10 haloalkyl;
m is an integer of 0 to 5.
In one embodiment, the medicaments are identical or different and each comprise a therapeutically effective amount of an N-benzyl-5/6-carboxamido indole-2-carboxylic acid derivative or a pharmaceutically acceptable salt thereof.
The amount of the drug or the pharmaceutical composition of the present invention to be administered can be varied according to the formulation method, the administration mode, the age, weight, sex, disease state, diet, administration time, administration route, excretion rate and response sensitivity of the patient, and the skilled doctor can easily determine the prescription and the dose to be administered for the desired treatment or prevention.
By a therapeutically effective amount is meant an amount that produces a therapeutic effect in and is acceptable to humans and/or animals. For example, a pharmaceutically or pharmaceutically effective amount refers to the amount of drug required to produce a desired therapeutic effect, which can be reflected by the results of a clinical trial, a model animal study, and/or an in vitro study. The pharmaceutically effective amount depends on several factors, including but not limited to: the characteristic factors of the subject (such as the subject's height, weight, sex, age, and history of administration), the severity of the disease.
In particular embodiments of the invention, the therapeutically effective amount is that amount which is capable of producing a therapeutic effect in a patient with polycystic ovary syndrome and which is acceptable to the patient.
In particular embodiments of the invention, the mode of administration of the drug or pharmaceutical composition includes, but is not limited to: oral administration, parenteral administration, administration by inhalation spray, topical administration, rectal administration, nasal administration, buccal administration, vaginal administration or administration by an implanted reservoir. Oral administration or injection administration is preferred.
In particular embodiments of the present invention, any orally acceptable dosage form may be used, including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
In particular embodiments of the invention, liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
In particular embodiments of the present invention, solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
In a specific embodiment of the invention, the medicament or pharmaceutical composition further comprises a pharmaceutically acceptable carrier or adjuvant. The pharmaceutically acceptable carrier or adjuvant may comprise inert ingredients which do not unduly inhibit the biological activity of the compound. The pharmaceutically acceptable carrier or adjuvant should be biocompatible, e.g., non-toxic, non-inflammatory, non-immunogenic, or free of other undesirable reactions or side effects upon administration to a subject. Standard pharmaceutical formulation techniques may be used.
Pharmaceutically acceptable carriers or excipients include, but are not limited to, diluents, binders, surfactants, wetting agents, adsorption carriers, lubricants, fillers, disintegrants, preservatives, and the like. These substances are used as needed to aid stability of the formulation or to aid in enhancing the activity or its bioavailability or to give acceptable mouthfeel or odor in the case of oral administration, and the formulation which may be used in such a pharmaceutical composition may be in the form of its original compound itself or optionally in the form of its pharmaceutically acceptable salt, and the pharmaceutical composition so formulated may be administered by any suitable means known to those skilled in the art as needed.
Wherein the diluents include, but are not limited to lactose, sodium chloride, dextrose, urea, starch, water.
Binders include, but are not limited to, starch, pregelatinized starch, dextrin, maltodextrin, sucrose, acacia, gelatin, methylcellulose, carboxymethylcellulose, ethylcellulose, polyvinyl alcohol, polyethylene glycol, polyvinyl pyrrolidone, alginic acid and its salts, xanthan gum, hydroxypropyl cellulose and hydroxypropyl methylcellulose.
Surfactants include, but are not limited to, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride of stearic acid, cetyl alcohol.
The wetting agent includes, but is not limited to, glycerin, starch.
Adsorption carriers include, but are not limited to, starch, lactose, bentonite, silica gel, kaolin, and soap clay.
Lubricants include, but are not limited to, zinc stearate, glycerol monostearate, polyethylene glycol, talc, calcium and magnesium stearate, polyethylene glycol, boric acid powder, hydrogenated vegetable oil, sodium stearyl fumarate, polyoxyethylene monostearate, monolauryl saccharate, sodium lauryl sulfate, magnesium lauryl sulfate, and magnesium lauryl sulfate.
Fillers include, but are not limited to, mannitol (granular or powdered), xylitol, sorbitol, maltose, erythrose, microcrystalline cellulose, polymeric sugars, coupling sugars, glucose, lactose, sucrose, dextrin, starch, sodium alginate, laminarin powder, agar powder, calcium carbonate, and sodium bicarbonate.
Disintegrants include, but are not limited to, crospovidone, sodium carboxymethyl starch, low substituted hydroxypropyl methyl, croscarmellose sodium, and soy polysaccharide.
In particular embodiments of the invention, the medicament or pharmaceutical composition further comprises other medicaments for treating polycystic ovary syndrome, i.e., the N-benzyl-5/6-carboxamido-indole-2-carboxylic acid derivatives may be administered in combination with other compounds useful in treating polycystic ovary syndrome, including, but not limited to, clomiphene, letrozole, gonadotrophin, and the like.
Example 1: preparation of N-benzyl-5/6-carboxamido indole-2-carboxylic acid derivatives
Preparation of 5- (benzylcarbamoyl) -1- (4-chloro-3-fluorobenzyl) -1H-indole-2-carboxylic acid (designated VSP-51-2) can be referred to CN 105175309A; the specific structural formula is as follows:
example 2: anti-polycystic ovary syndrome (PCOS) Activity of N-benzyl-5/6-formylaminobndole-2-carboxylic acid derivatives
(1) Establishment of PCOS model
Clean laboratory animal house C57 mice raised in Guangzhou medical university are adopted;
Letrozole is an aromatase inhibitor that inhibits the conversion of ovarian androgens to estrogens, thereby causing hyperandrogenism. While high fat feeding can cause insulin resistance. The C57 mice of four weeks of age were given a high fat feed, while the letrozole (6 mg/kg/day) was given by gavage, and the PCOS model was developed for 21 days of administration to cause hyperandrogenism and insulin resistance.
(2) Experimental grouping and dosing: the experiment is divided into a normal Control group (Control), a model group (PCOS), a positive Control metformin group (Metformine) and a VSP-51-2 group; each group was set with 3 replicates of 5 mice each. After successful molding, the Control and PCOS groups were given an equivalent amount of PEG300 per day by gavage, the metformin group was given 50mg/kg per day by gavage (in 0.2mL PEG 300), and the VSP-51-2 was given 50mg/kg per day (in 0.2mL PEG 300) for 28 days.
(3) Experimental result detection and data collection
Starting on the 10 th day of administration, vaginal smear staining was taken daily to observe estrus cycle, blood glucose was measured every 7 days after fasting, and ovarian morphology was observed ultrasonically prior to the 28 th day after administration treatment. Ovarian tissue was stained by paraffin embedded section HE to observe changes in ovary morphology; serum samples were assayed for testosterone and insulin levels by ELISA.
(4) Analysis of results
① VSP-51-2 significantly improves PCOS mouse ovarian polycystic lesions
The key feature of reproductive dysfunction in PCOS patients is follicular development dysfunction. The ovarian follicle is changed in a polycystic manner, the follicles and the closed follicles are in different degrees under the leucoderma, so that the follicular change is formed, and the follicular development is anovulatory.
FIG. 1 shows the morphology of the ovaries of each group observed under H & E staining. As shown in fig. 1, the ovaries of the normal control mice can be seen as a plurality of follicles and corpus luteum in different development stages, and the granulosa cells are complete in morphology and orderly arranged; the PCOS model group mice have the advantages that the ovarian lock is increased to be in saccular expansion, no egg cells are found in follicles in the mature period, the granule cells are loosely arranged, the number of layers is thin, the parts of the egg cells fall off, the follicular membrane cells are proliferated, the oocytes are in hours, and the corpus luteum is little; the VSP-51-2 group of the invention can be used for observing follicles at different stages of development, the arrangement of granulosa cells is compact, the number of layers is increased, the follicular membrane cells are thinner, the follicular membrane cells are similar to that of a metformin positive control group, and the morphology is similar to that of a normal control group.
FIG. 2 is an ultrasound ovarian morphology observation; FIG. 3 is an ultrasonic ovarian diameter; figure 4 is an ultrasound ovarian area. As shown in fig. 2, the PCOS model group is surrounded by a large number of sinus follicles around the central interstitium of the ovary relative to the control group, and the area and the diameter of the two-dimensional gray scale image of the ovary are remarkably increased; the VSP-51-2 group of the invention has obviously reduced area and diameter of the two-dimensional gray scale image of the ovary compared with the PCOS group, and is superior to the metformin positive control group. As can be seen from figures 3-4, the PCOS group ovary diameter (1.3-1.9 mm) and area (1.5-2.0 mm 2) were significantly higher than the normal control group; the VSP-51-2 group of the invention has significantly reduced diameter and area, and is superior to the metformin positive control group and is close to the normal control group.
② VSP-51-2 significantly improved the estrus cycle of PCOS mouse disorders
FIG. 5 is a microscopic observation of vaginal secretion from mice. FIG. 6 is a graph showing the estrus cycle statistics of mice.
As can be seen from fig. 5, the normal control group (preestrus) can see that spindle-shaped epithelial cells are distributed in leukocytes, i.e., are about to enter estrus. The PCOS group (estrus period) only sees a large number of leukocytes, no other cells; white blood cells, anucleated epithelial cells and fusiform epithelial cells were seen in the metformin positive control group (late estrus); whereas the VSP-51-2 group of the invention (estrus) is seen as a large number of squamous epithelial cells, coreless and leucocyte free.
As can be seen from fig. 6, observations from day 10 of administration after successful PCOS modeling show that the normal control group shows regular estrus cycles of 4-5 days (Pro-estrus: pro-estrus, estrus: estrus, metestrus: post-estrus, diestrus: estrus); the PCOS model group is disordered in estrus cycle and stays in estrus intervals; the period of the metformin positive control group is recovered compared with that of the PCOS group; the VSP-51-2 group estrus cycle of the invention is recovered to the normal level, which is obviously superior to that of the metformin positive control group.
③ VSP-51-2 significantly reduces PCOS mouse hyperandrogenism
Hyperandrogenism is a major clinical manifestation and detection indicator of PCOS. The application uses ELISA method to detect serum testosterone level of each group, which is operated according to the instruction of the kit (Finetest, wuhan). Figure 7 is serum testosterone levels in mice.
As shown in the figure, the testosterone content in the serum of the normal control group is 2.1-5.0ng/mL; the content of the serum testosterone in the PCOS group is 10.1-19.0ng/mL, and is obviously increased compared with the normal control group; the concentration of the serum testosterone of the metformin positive control group is 3.7-7.7ng/mL, and the concentration level is obviously reduced compared with that of the PCOS group; the VSP-51-2 group of the invention has the testosterone content of 3.0-5.0ng/mL, and the level of the VSP-51-2 group is lower than that of the metformin positive control group and is closer to that of the normal control group. Therefore, the VSP-51-2 provided by the invention can obviously reduce the hyperandrogenism of PCOS mice, and the effect is obviously better than that of the positive control drug metformin.
④ VSP-51-2 significantly reduces PCOS mouse insulin resistance
Insulin resistance is another major clinical manifestation and measure of PCOS. The degree of insulin resistance is clinically determined primarily by calculating the steady state model insulin resistance index (Homeostatic Model Assessment for Insulin Resistance, HOMA-IR). The specific calculation formula is as follows: HOMA-ir=fasting blood glucose (mmol/L) ×fasting insulin (mIU/L)/22.5. Different groups of mice began fasting and water-deprivation at the 27 th day of treatment, and blood was taken from the tail tip 12 hours later, and fasting blood glucose was measured using blood glucose. Serum insulin levels were detected by ELISA, specifically according to ELISA kit instructions (Shanghai ELISA, shanghai). FIG. 8 is a graph of mouse insulin resistance levels.
As can be seen from the graph, the HOMA-IR of the normal control group is 0.20-0.26; PCOS group increased significantly to 0.28-0.36; the HOMA-IR of the VSP-51-2 group and the positive control metformin group are respectively obviously reduced, and are close to that of the normal control group. This demonstrates that VSP-51-2 of the present invention significantly reduces the insulin resistance index of PCOS mice, and its effect is comparable to that of the positive control drug metformin.
Example 3: pharmacokinetic properties of N-benzyl-5/6-carboxamido indole-2-carboxylic acid derivatives
The pharmacokinetic properties of the drugs are important indexes for evaluating the potential and safety of the patent drugs in the research and development of new drugs. The invention respectively researches the intravenous injection and the gastrolavage pharmacokinetic parameters of VSP-51-2 in the rat body. SD rats (200 g or so) were fasted for 12 hours and then randomized into 2 groups (4 groups, 3 groups) of which 4 were given 20mg/kg of VSP-51-2 by gavage and the remaining 3 were given 5mg/kg of VSP-51-2 by intravenous injection. After administration, 0.5mL of fundus vein blood is taken out at 0.1 h, 0.5 h, 1 h, 2h, 4h, 6 h and 8h, a blood sample is centrifuged at 8000r/min for 5min, and a plasma sample is separated and stored at-20 ℃ to be tested. 0.2mL of plasma was taken, 0.6mL of acetonitrile was added thereto, the mixture was vortexed and mixed with 1min, and the mixture was centrifuged at 12000r/min for 10min, and 20. Mu.L of the supernatant was taken for HPLC analysis. The results are shown in tables 1-2 and FIGS. 9-10.
Table 1 is a statistical table of pharmacokinetic parameters of rat intravenous injection VSP-51-2; table 2 is a statistical table of pharmacokinetic blood parameters of the rat lavage VSP-51-2; FIG. 9 is a graph of the intravenous injection of VSP-51-2 plasma drug into rats; FIG. 10 is a graph of the time profile of a rat lavage VSP-51-2 plasma drug.
TABLE 1
TABLE 2
The results show that after the gastric lavage of VSP-51-2, the blood concentration reaches the peak value (7937+/-2110 ng/mL) for 0.25h, the half life of the drug is 1.37+/-0.228 h, the average residence time is not 1.8+/-0.357 h, and the absolute bioavailability is about 21%. The above data demonstrate that VSP-51-2 of the present invention can be rapidly absorbed and enter the circulation after administration by gavage, with absolute bioavailability greater than 20% for gavage administration, achieving acceptable bioavailability.
Example 4: hERG inhibition by N-benzyl-5/6-carboxamido indole-2-carboxylic acid derivatives
Since some non-cardiovascular drugs are successively found to have cardiotoxicity, the cardiotoxicity of the drug is one of the key indicators of current drug safety evaluation. In cardiomyocytes, hERG (human Ether-a-go-go RELATED GENE) -encoded potassium channel inhibition is an important mechanism leading to cardiotoxicity. Thus, the present invention detects the inhibition of hERG potassium channels by compounds.
Different concentrations (0.0128, 0.064, 0.32, 1.6, 8, 40. Mu.M) of VSP-51-2 compound were added to stably transformed hERG-HEK293 cells, with Cisapride (CISAPRIDE) as positive control. hERGK + channel current was recorded using Nanion Patchliner channel full-automatic patch clamp technology (patch clamp setup: hERG current inhibition was calculated at different concentrations by collecting and storing hERG potassium channel current (Ikr) data on a computer using PATCHMASTER software via an EPC-10 amplifier.
The calculated hERG inhibition rate (IC 50) of VSP-51-2 was greater than 40. Mu.M, and the 40. Mu.M inhibition rate of VSP-51-2 was less than 20%, indicating that VSP-51-2 had no potential cardiotoxicity.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims (10)

  1. Use of an n-benzyl-5/6-carboxamido indole-2-carboxylic acid derivative or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention and/or treatment of polycystic ovary syndrome or a lead compound thereof.
  2. Use of an n-benzyl-5/6-carboxamido indole-2-carboxylic acid derivative or a pharmaceutically acceptable salt thereof in the preparation of a health product for the prevention and/or treatment of polycystic ovary syndrome.
  3. Use of an n-benzyl-5/6-carboxamido indole-2-carboxylic acid derivative or a pharmaceutically acceptable salt thereof in the preparation of a medicament or health care product for reducing androgen levels.
  4. Use of an n-benzyl-5/6-carboxamido indole-2-carboxylic acid derivative or a pharmaceutically acceptable salt thereof in the preparation of a medicament or health care product for ameliorating PCOS polycystic lesions.
  5. 5. The use according to any one of claims 1 to 4, characterized in that the N-benzyl-5/6-carboxamido indole-2-carboxylic acid derivative has the structure of formula i:
    Wherein R 0 is each independently selected from: Halogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, -OH, -NO 2, -CN; wherein the substitution is with one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 haloalkyl and phenyl;
    And at least one R 0 is
    N is a positive integer from 1 to 4;
    r 1 is selected from: a substituted or unsubstituted C1-C10 alkyl group; substituted or unsubstituted C3-C10 cycloalkyl; Z-Y-and R 5(R6) N-; wherein said substitution is with one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 haloalkyl;
    R 5 and R 6 are each independently selected from hydrogen, substituted or unsubstituted C1-C10 alkyl-carbonyl, substituted or unsubstituted C1-C10 alkoxy-carbonyl, or substituted or unsubstituted C5-C20 aryl; wherein said substitution is with one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 haloalkyl, carboxyl, -OH, -NH 2 and phenyl;
    z is selected from: a substituted or unsubstituted C5-C20 aryl group, a substituted or unsubstituted C3-C20 heteroaryl group, and a substituted or unsubstituted 5-20 membered heterocyclic group; wherein said substitution is with one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 haloalkyl and phenyl;
    y is an unsubstituted, substituted or unsubstituted C1-C10 alkylene group, wherein the substitution is with one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, and C2-C4 alkenyl;
    R 2 is selected from the group consisting of: H. halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C3-C8 cycloalkyl, -NO 2, -CN, -OH, substituted or unsubstituted C1-C6 alkyl-carbonyl, or substituted or unsubstituted C1-C6 alkoxycarbonyl; wherein substituted means having one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, C2-C4 alkenyl and phenyl;
    R 3 is selected from the group consisting of: substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C5-C20 aryl, R 9 -C (O) -, cyano, carboxamide and tetrazole; wherein substituted means having one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 haloalkyl, carboxyl, -OH, -NH 2 and phenyl;
    R 4 are each independently selected from: halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C5-C20 aryl, -NO 2、-CN、-OH、R9-C(O)-、R10(R11) N-or C5-C20 aryl-C (O) -N (R 10)R11 -; wherein substituted means having one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 haloalkyl, carboxyl, -OH, -NH 2 and phenyl;
    R 9 is the following group: hydroxy, mercapto, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, and R 10(R11) N-; wherein substituted means having one or more substituents selected from the group consisting of: halogen, C1-C3 alkyl, C2-C4 alkenyl and phenyl;
    R 10 and R 11 are each independently hydrogen, C1-C10 alkyl or C1-C10 haloalkyl;
    m is an integer of 0 to 5.
  6. 6. The use according to claim 1, 3 or 4, characterized in that: the medicament comprises a therapeutically effective amount of an N-benzyl-5/6-carboxamido indole-2-carboxylic acid derivative or a pharmaceutically acceptable salt thereof.
  7. 7. The use according to claim 1, 3 or 4, characterized in that: the medicine is prepared into various medicinal dosage forms by adopting a conventional method, and the dosage forms comprise: tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, buccal agents, granules, medicinal granules, pills, pellets, suspensions, wines, tinctures and drops.
  8. 8. The use according to claim 1, 3 or 4, characterized in that: the medicine also contains one or more pharmaceutically acceptable carriers or auxiliary materials.
  9. 9. The use according to claim 8, characterized in that: the carrier or auxiliary material comprises at least one of diluent, adhesive, surfactant, wetting agent, adsorption carrier, lubricant, filler, disintegrating agent and preservative.
  10. 10. A pharmaceutical composition for the treatment of polycystic ovary syndrome, characterized by comprising an N-benzyl-5/6-carboxamido indole-2-carboxylic acid derivative or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable other component thereof.
CN202410018259.2A 2024-01-05 2024-01-05 Application of N-benzyl-5/6-formylamino indole-2-carboxylic acid derivative in preparation of medicine for preventing and treating polycystic ovary syndrome Pending CN117959290A (en)

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CN202410018259.2A CN117959290A (en) 2024-01-05 2024-01-05 Application of N-benzyl-5/6-formylamino indole-2-carboxylic acid derivative in preparation of medicine for preventing and treating polycystic ovary syndrome

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CN202410018259.2A CN117959290A (en) 2024-01-05 2024-01-05 Application of N-benzyl-5/6-formylamino indole-2-carboxylic acid derivative in preparation of medicine for preventing and treating polycystic ovary syndrome

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