WO2024005587A1 - Nouvelle utilisation d'un dérivé d'isoxazole ou d'un sel de celui-ci - Google Patents

Nouvelle utilisation d'un dérivé d'isoxazole ou d'un sel de celui-ci Download PDF

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WO2024005587A1
WO2024005587A1 PCT/KR2023/009225 KR2023009225W WO2024005587A1 WO 2024005587 A1 WO2024005587 A1 WO 2024005587A1 KR 2023009225 W KR2023009225 W KR 2023009225W WO 2024005587 A1 WO2024005587 A1 WO 2024005587A1
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disease
pharmaceutical composition
formula
microorganisms
group
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Korean (ko)
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이윤석
김경선
김정아
문안나
송동근
정주영
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일동제약(주)
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel use of isoxazole derivatives or salts thereof, and more specifically, to the use of isoxazole derivatives or salts thereof to regulate the level of intestinal microorganisms in subjects suffering from liver disease, obesity, or metabolic disease. will be.
  • Nonalcoholic fatty liver disease is the most common liver disorder in developed countries, especially seen in obese patients, and refers to a condition in which excessive fat accumulates in the liver regardless of alcohol intake.
  • NAFLD ranges from the initial stage of nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) accompanied by inflammation, and if the condition gradually worsens, it can ultimately cause cirrhosis. Progression to NASH significantly increases the risk of cirrhosis, liver failure, and hepatocellular carcinoma (HCC).
  • Gastrointestinal diseases which refer to abnormalities in the digestive system, often show symptoms such as vomiting, abdominal pain, and indigestion.
  • IBD inflammatory bowel disease
  • symptoms such as vomiting, abdominal pain, and indigestion.
  • IBD inflammatory bowel disease
  • symptoms such as abdominal pain, diarrhea, bloody stool, and weight loss usually appear for several months
  • Crohn's disease and ulcerative colitis Ulcerative colitis
  • Patent Document 1 discloses an isoxazole derivative compound that can act as an agonist for FXR, but does not disclose at all the effect of the compound on regulating the level of intestinal microorganisms.
  • the present inventors discovered a novel use of isoxazole derivatives or salts thereof to regulate the level of intestinal microorganisms in subjects suffering from liver disease, gastrointestinal disease, obesity, or metabolic disease and completed the present invention.
  • One aspect relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula 1 below or a pharmaceutically acceptable salt thereof that modulates intestinal microbial levels in subjects suffering from liver disease, gastrointestinal disease, obesity, or metabolic disease:
  • Another aspect relates to a food composition
  • a food composition comprising the compound of Formula 1 or a food-chemically acceptable salt thereof that regulates the level of intestinal microorganisms in subjects suffering from liver disease, gastrointestinal disease, obesity, or metabolic disease.
  • Another aspect is providing a use for regulating intestinal microorganism levels in a subject suffering from liver disease, gastrointestinal disease, obesity, or metabolic disease.
  • Another aspect is to provide a method of modulating intestinal microbial levels in a subject suffering from liver disease, gastrointestinal disease, obesity, or metabolic disease.
  • One aspect provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof that modulates the level of intestinal microorganisms in a subject suffering from liver disease, gastrointestinal disease, obesity, or metabolic disease.
  • Another aspect provides a food composition
  • a food composition comprising the compound of Formula 1 or a food-chemically acceptable salt thereof that regulates the level of intestinal microorganisms in subjects suffering from liver disease, gastrointestinal disease, obesity, or metabolic disease.
  • Another aspect provides the use of the compound of Formula 1, or a pharmaceutically or foodologically acceptable salt thereof, for controlling the level of intestinal microorganisms in a subject suffering from liver disease, gastrointestinal disease, obesity, or metabolic disease.
  • Another aspect is a method of using the compound of Formula 1, or a pharmaceutically or foodologically acceptable salt thereof, to control the level of intestinal microorganisms in a subject suffering from liver disease, gastrointestinal disease, obesity, or metabolic disease. to provide.
  • the compound of Formula 1 or a pharmaceutically or foodologically acceptable salt thereof, or a pharmaceutical or food composition containing the same is administered in the intestine in a subject suffering from liver disease, gastrointestinal disease, obesity, or metabolic disease.
  • Microbial levels can be controlled. In one embodiment, it may promote the growth of specific microorganisms or inhibit the growth of other specific microorganisms, or may promote the growth of specific microorganisms and simultaneously inhibit the growth of other specific microorganisms.
  • liver disease gastrointestinal disease, obesity, or metabolic disease suffered by the subject, and preferably, intestinal microorganisms in a subject suffering from or capable of suffering from non-alcoholic steatohepatitis (NASH).
  • NASH non-alcoholic steatohepatitis
  • IBD inflammatory bowel disease
  • Crohn's disease Crohn's disease
  • ulcerative colitis and other gastrointestinal and colon-related diseases. You can.
  • the microorganisms whose growth is promoted are selected from the group consisting of Lactobacillaceae ( Lactobacillus spp., Weissella spp. ), Odoribacteraceae ( Odoribacter spp. ), and Bifidobacteriaceae ( Bifidobacterium ) There may be one or more types.
  • the microorganism whose growth is inhibited may be one or more species selected from the group consisting of Prevotellaceae ( Prevotella spp.) and Bacteroidaceae ( Bacteroides spp. ).
  • the present invention promotes the growth of Lactobacillaceae , Odoribacteraceae , and Bifidobacteriaceae , thereby protecting the intestinal lining through the formation of mucus in the intestine, inhibiting the growth of harmful bacteria, and inhibiting the growth of harmful bacteria in the intestine. It is expected to relieve inflammation and improve chronic inflammatory bowel disease.
  • the present invention inhibits the proliferation of Prevotellaceae and Bacteroidaceae , and is therefore expected to have an improvement effect on metabolic diseases and inflammatory bowel diseases, including ulcerative colitis.
  • Figures 1a and 1b show the taxonomic levels of intestinal microorganisms in the negative control group (Control Chow), vehicle group, 10 mg/kg drug administration group, 30 mg/kg drug administration group, and 100 mg/kg drug administration group, respectively, in the diet-induced NASH hamster obesity model. It is analyzed and shown at the Phylum ( Figure 1a) and Family ( Figure 1b) levels, respectively.
  • FIG 2 shows the results of LDA Effect Size (LEfSe) analysis in the drug administration group (dose 1: 10 mg/kg) and vehicle group.
  • Figure 3 shows the results of LEfSe analysis in the drug administration group (dose 2: 30 mg/kg) and vehicle group.
  • Figure 4 shows the LEfSe analysis results in the drug administration group (dose 3: 100 mg/kg) and vehicle group.
  • Figure 5 shows the results of LEfSe analysis in the negative control and vehicle groups.
  • Figure 6 shows the relative abundance (%) of each intestinal microorganism in the negative control group, vehicle group, and drug administration group (dose 2: 30 mg/k).
  • Figure 6 shows the average value and standard error, respectively (A: Lactobacillus , B: Bifidobacterium , C: Odoribacter , D: Prevotellaceae , E: Bacteroideae ( Bacteroidaceae )).
  • Figures 7a and 7b show the results of calculating the diversity of intestinal microorganisms, and are the results visualized by analyzing alpha diversity (Figure 7a) and beta diversity (Figure 7b) for each sample.
  • Figure 7a shows a graph (top) and table (bottom) analyzing and visualizing alpha diversity for Observed, Chao1, Shannon, Simpson, InvSimpson, and PD.
  • Figure 7b is a graph visualized by analyzing the beta diversity (Figure 7b) of the negative control group (Control Chow), vehicle group, 10 mg/kg drug administration group, 30 mg/kg drug administration group, and 100 mg/kg drug administration group.
  • One aspect provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula 1 below or a pharmaceutically acceptable salt thereof for controlling the level of intestinal microorganisms in a subject suffering from liver disease, gastrointestinal disease, obesity, or metabolic disease.
  • the compound of Formula 1 is '5-((2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) It is also referred to as ‘ethynyl)-2-cyclopropylbenzo[d]oxazole-7-carboxylic acid’.
  • the compound of Formula 1 can be prepared according to the method described in International Publication No. 2018-190643 or Korean Publication No. 10-2168543, and these documents are incorporated by reference in their entirety.
  • the salt of the compound of Formula 1 may be provided in a pharmaceutically acceptable salt form.
  • the pharmaceutically acceptable salts are intended to encompass any and all pharmaceutically suitable salt forms and include both acid and base addition salts.
  • the pharmaceutically acceptable salt may be a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable base addition salt.
  • the pharmaceutically acceptable salt may be meglumine salt.
  • the meglumine salt of the compound of Formula 1 may also be represented by the compound of Formula 1a below.
  • meglumine is also referred to as '(2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentol'.
  • the meglumine salt of the compound of Formula 1 is '5-((2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl )methoxy)phenyl)ethynyl)-2-cyclopropylbenzo[d]oxazole-7-carboxylic acid; Also referred to as '(2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentol'.
  • the compound of Formula 1 or a pharmaceutically acceptable salt thereof may be provided as a polymorph, solvate, hydrate, cocrystal, or other molecular complex.
  • microbiome refers to the entire genetic information of microorganisms living in the human body or the microorganisms themselves.
  • the pharmaceutical composition may promote or inhibit the growth of specific microorganisms, or may promote the growth of specific microorganisms and simultaneously inhibit the growth of other specific microorganisms.
  • the pharmaceutical composition may promote the growth of one or more types of microorganisms selected from the group consisting of Lactobacillaceae , Odoribacteraceae , and Bifidobacteriaceae .
  • the pharmaceutical composition can inhibit the growth of one or more types of microorganisms selected from the group consisting of Prevotellaceae and Bacteroidaceae .
  • the pharmaceutical composition promotes the growth of one or more types of microorganisms selected from the group consisting of Lactobacillaceae , Odoribacteraceae , and Bifidobacteriaceae , and It can inhibit the growth of one or more types of microorganisms selected from the group consisting of Prevotellaceae and Bacteroidaceae .
  • the Lactobacillus family includes the Lactobacillus genus
  • the Odoribacteriaceae includes the Odoribacter genus
  • the Bifidobacterium family includes the Bifidobacterium genus
  • the Prevotella family includes the Prevotella genus
  • the Bacteroides family may include the genus Bacteroides .
  • the structure of human intestinal microorganisms is that in infancy, L actobacillaceae and Bifidobacteriaceae are acquired from the mother and are retained as the main intestinal microorganisms, but as adults enter the diet, Prevotellaceae ) and intestinal microorganisms such as Bacteroidaceae account for most.
  • Prevotella spp. of Prevotellaceae is found frequently in people who mainly consume vegetable fiber, and Bacteroides spp. of the Bacteroidaceae family is commonly found in people who mainly consume meat.
  • the lactobacillus family (L actobacillaceae ) includes Lactobacillus spp. and Weissella spp., which are beneficial bacteria. Lactobacillus spp. has effects such as protecting the intestinal lining through the formation of mucus in the intestine, inhibiting the proliferation of harmful bacteria, and alleviating intestinal inflammation. It is reported that it has [2] Among these, Lactobacillus rhamnosus GG strain was shown to be effective in reducing recurrence of chronic enteritis in enteritis-inducing animal tests.
  • Weissella spp belonging to the lactic acid bacteria family (L actobacillaceae ). It is mainly found in fermented foods such as kimchi, and no specific pathogenic properties have been reported.
  • the compound of Formula 1 or a pharmaceutically acceptable salt thereof may be sufficiently distributed to the liver or gastrointestinal tract, for example, the small intestine, after drug administration.
  • the pharmaceutical composition may regulate the level of intestinal microorganisms in a subject suffering from liver disease, gastrointestinal disease, obesity, or metabolic disease.
  • the pharmaceutical composition may be used to prevent, improve, or treat liver disease, gastrointestinal disease, obesity, or metabolic disease by controlling the level of intestinal microorganisms.
  • the liver disease includes hepatic steatosis, nonalcoholic fatty liver (NAFL), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and liver It may be any one selected from fibrosis (hepatic fibrosis).
  • the gastrointestinal disease may be any one selected from inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis.
  • IBD inflammatory bowel disease
  • Crohn's disease Crohn's disease
  • ulcerative colitis ulcerative colitis
  • the metabolic disease includes hypercholesterol, cyclopoproteinemia, hypertriglyceridemia, dyslipidemia, lipodystrophy, cholestasis/fibrosis, cholesterol gallstone disease, hyperglycemia, diabetes, insulin resistance, metabolic rigidity, and nephropathy. , arteriosclerosis, cancer, inflammatory disorders, and osteoporosis.
  • the subject suffering from liver disease, gastrointestinal disease, obesity, or metabolic disease may be a subject showing abnormalities in the level or composition of intestinal microorganisms (intestinal dysbiosis).
  • the subject is inhibited in the growth of one or more microorganisms selected from the group consisting of Lactobacillaceae , Odoribacteraceae , and Bifidobacteriaceae .
  • the growth of one or more types of microorganisms selected from the group consisting of Prevotellaceae and Bacteroidaceae may be promoted.
  • the subject may be a subject suffering from liver disease, gastrointestinal disease, obesity, or metabolic disease derived from or worsened by intestinal dysbiosis.
  • a compound of formula 1 below, or a pharmaceutically thereof is used to prevent, treat, or improve gastrointestinal diseases by controlling the level of intestinal microorganisms in subjects suffering from or capable of suffering from nonalcoholic steatohepatitis (NASH).
  • a pharmaceutical composition containing an acceptable salt can be provided.
  • the gastrointestinal disease may be any one selected from inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis.
  • IBD inflammatory bowel disease
  • Crohn's disease Crohn's disease
  • ulcerative colitis ulcerative colitis
  • Modulation of the level of intestinal microorganisms such as normalization of the intestinal microbial flora according to the increase or decrease of specific microorganisms, or promotion or inhibition of growth of specific microorganisms;
  • An increase in the body's microbiome which is beneficial for preventing, improving, or treating liver disease, gastrointestinal disease, obesity, or metabolic disease;
  • liver disease Prevention, improvement or treatment of liver disease, gastrointestinal disease, obesity, or metabolic disease
  • hepatic steatosis non-alcoholic simple fatty liver (NAFL), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and liver fibrosis;
  • NAFL non-alcoholic simple fatty liver
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • liver fibrosis liver fibrosis
  • Hypercholesterol hyperlipidemia, hypertriglyceridemia, dyslipidemia, lipodystrophy, cholestasis/fibrosis, cholesterol gallstone disease, hyperglycemia, diabetes, insulin resistance, metabolic rigidity, nephropathy, arteriosclerosis, cancer, inflammatory disorders, and preventing, improving, or treating any one selected from the group consisting of osteoporosis;
  • NAFL non-alcoholic simple fatty liver
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • HCC hepatocellular carcinoma
  • NASH non-alcoholic steatohepatitis
  • IBD inflammatory bowel disease
  • Crohn's disease Crohn's disease
  • ulcerative colitis Or treatment.
  • the compound of Formula 1, or a pharmaceutically acceptable salt thereof, or the meglumine salt of Formula 1, or a pharmaceutical composition containing the same may be administered orally or parenterally.
  • Oral administration includes, for example, solid dosage forms such as tablets, powders, capsules containing liquids or powders, chews, microparticles, gels, liposomes, films, sprays, and liquid dosage forms such as suspensions, solutions, syrups and elixirs. Including, but not limited to, administration by.
  • Parenteral administration can be administered directly into the bloodstream, muscles, or internal organs and includes, but is not limited to, intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intramuscular, and subcutaneous injection.
  • Suitable devices for parenteral administration include, but are not limited to, needle (including microneedle) syringes, needleless syringes, and injection techniques.
  • the administration may be topical administration to the skin or mucosa, that is, dermal administration or transdermal administration, but is not limited thereto.
  • the compound of Formula 1, or a pharmaceutically acceptable salt thereof, or the meglumine salt of Formula 1, or a pharmaceutical composition containing the same is administered once a day (qd), twice a day (bid). , may be administered three times a day (tid), four times a day (qid), or once a day (every other day) (qod).
  • the compound of Formula 1, or a pharmaceutically acceptable salt thereof, or the meglumine salt of Formula 1, or a pharmaceutical composition containing the same is administered in an amount of 0.01 to 10 g/kg, 0.1 to 1 g/kg, or 1 to 1 g/kg. It can be administered at a dose of 500 mg/kg. In one embodiment, the compound of Formula 1 or a pharmaceutically acceptable salt thereof, or the meglumine salt of Formula 1, or a pharmaceutical composition containing the same is administered in an amount of 10 to 500 mg/kg, 10 to 100 mg/kg, such as 10 mg/kg.
  • the total daily dose of the compound of Formula 1, a pharmaceutically acceptable salt thereof, or meglumine salt of Formula 1 in the pharmaceutical composition is 0.001 to 1000 mg per kg, 0.01 mg per kg, based on the body weight of the subject. to 900 mg, 0.05 to 1000 mg, 0.1 to 800 mg, 1 to 700 mg, 1.5 to 600 mg, 2 to 500 mg, 5 to 400 mg, 8 to 200 mg, 10 to 200 mg, 10 to 100 mg, 20 to 100 mg, It may be included in an administered amount of 30 to 100 mg, 30 to 150 mg, or 30 to 200 mg.
  • the dosage may be an amount administered orally once a day.
  • the total daily dosage according to one embodiment may vary depending on the type of compound, administration route, administration time, type of other compounds used in combination, age, gender, weight, condition, previous medical history, etc. of the subject. Accordingly, the dosage of the compound may be a therapeutically effective amount and may be set within a range in which the desired therapeutic effect is achieved without causing harmful or deleterious serious side effects.
  • the dosage may be administered in single or divided doses. These dosages can be based on an average human subject weighing about 65 kg to about 70 kg. The physician will readily determine dosages for subjects whose weight falls outside the above range, such as infants and the elderly.
  • the pharmaceutical composition may further include one or more pharmaceutically acceptable carriers or excipients.
  • Examples of the carrier may be ingredients commonly used in the pharmaceutical field, and may include, for example, lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, etc., but are not limited thereto.
  • excipients examples include sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; Starch derivatives such as corn starch, potato starch, ⁇ -starch, dextrin, and carboxymethyl starch; Cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose, and internally-crosslinked sodium carboxymethylcellulose; acacia; dextran; pullulan; Silicate derivatives such as light silicate anhydride, synthetic aluminum silicate, and aluminum magnesium metasilicate; Phosphoric acid derivatives such as calcium phosphate; Carbonate derivatives such as calcium carbonate; Sulfate derivatives such as calcium sulfate; It may include, but is not limited to, etc.
  • sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol
  • Starch derivatives such as corn starch, potato starch
  • Another aspect provides a food composition
  • a food composition comprising the compound of Formula 1 or a food-chemically acceptable salt thereof that regulates the level of intestinal microorganisms in subjects suffering from liver disease, gastrointestinal disease, obesity, or metabolic disease.
  • the salt of the compound of Formula 1 may be provided in a foodologically acceptable salt form.
  • the above food-acceptable salts are intended to encompass any and all food-acceptable salt forms, and include both acid and base addition salts.
  • the foodologically acceptable salt may be a foodologically acceptable acid addition salt or a pharmaceutically acceptable base addition salt.
  • the foodologically acceptable salt may be meglumine salt.
  • Another aspect provides the use of the compound of Formula 1, or a pharmaceutically or foodologically acceptable salt thereof, for controlling the level of intestinal microorganisms in a subject suffering from liver disease, gastrointestinal disease, obesity, or metabolic disease.
  • the use may be to effect a desirable change in the composition of intestinal microorganisms or to resolve intestinal dysbiosis in a subject suffering from NASH disease.
  • Another aspect provides a method of using the compound of Formula 1 or a pharmaceutically or foodologically acceptable salt thereof to control the level of intestinal microorganisms in a subject suffering from liver disease, gastrointestinal disease, obesity, or metabolic disease. do.
  • the method includes preventing, ameliorating, or treating liver disease, gastrointestinal disease, obesity, or metabolic disease in a subject.
  • the compound of formula 1 or a food-acceptable salt thereof, the target disease, the method for controlling the level of intestinal microorganisms, the carrier or excipient may be described in the pharmaceutical composition unless otherwise defined. there is.
  • prophylaxis refers to preventing a disease, e.g., preventing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder but has not yet experienced or exhibited symptoms or pathology of the disease. It says what to do.
  • treatment includes alleviation of symptoms, reduction of the degree of disease or damage, maintenance of the disease without worsening, delay of disease progression, improvement or alleviation of the disease state, and (partial or complete) relief. Additionally, treatment may mean an improved state compared to the expected disease state if no treatment is received.
  • the terms “subject,” “patient,” or “individual” refer to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or transgenic species thereof. This includes adults, adolescents, infants, and fetuses.
  • an “effective amount”, “therapeutically effective amount” or “pharmaceutically effective amount” is a compound that, when administered to a subject or patient for the purpose of treating, ameliorating, or preventing a disease, is an amount sufficient to bring about such treatment, amelioration, or prevention. means the amount of
  • the numerical values described in this specification are considered to include the meaning of “about” even if not specified.
  • the term “about” means within 5% of a predetermined value or range, preferably within 1% to 2%.
  • “about 10%” means 9.5% to 10.5%, preferably 9.8% to 10.2%.
  • “about 100°C” means 95°C to 105°C, preferably 98°C to 102°C.
  • terms such as “have,” “may have,” “includes,” or “may include” indicate the presence of the corresponding feature (e.g., numerical value, or component such as an ingredient). indicates, does not rule out the presence of additional features.
  • the present inventors evaluated the in vitro activity and selectivity and in vivo pharmacological action of the compound of Formula 1. Additionally, the effects of the compound of Formula 1 on the intestinal microflora and bile acid profile of the NASH hamster obesity model were investigated. The results suggest that compounds of formula 1 may serve as a promising therapeutic option for the treatment of NASH, with potential benefits for gut microbiota and bile acid profiles.
  • meglumine salt of the compound of Formula 1 was prepared as follows, and it was used to measure changes in intestinal microorganisms in a diet-induced NASH hamster obesity model (mutagenomics study).
  • the compound of Formula 1 was prepared by the method described in International Publication No. 2018-190643 or Korean Registration Publication No. 10-2168543.
  • the compound of Formula 1 (950g, 1.53mol, 1.0wt) and N-methyl-D-glucamine (304g, 1.58mol, 0.32wt) were added to the reaction vessel and methanol (12L, 13.5 vol) and water (1.4 L, 1.5 vol) were charged and stirred at 50°C to 60°C under nitrogen conditions. Then, it was stirred at the same temperature for 15 to 30 minutes until completely dissolved and slowly cooled to -10°C to -15°C for 5 to 7 hours.
  • Example 1 Measurement of changes in intestinal microorganisms in diet-induced NASH hamster model (Mutagenomics study)
  • the control group that was not treated with drugs for hamsters with NASH disease was designated as the vehicle group.
  • the meglumine salt of the compound of Formula 1 was suspended and administered in a vehicle, and the drug administration group was treated with 10 mg/kg, 30 mg/kg, and 100 mg/kg (doses 1 to 3) of the drug, respectively.
  • the relative proportions of 16S rDNA bacterial taxa were determined from the samples.
  • the bacterial population contained in the sample was measured using next-generation high-throughput sequencing of the variable region (V3-V4) of the 16S rRNA bacterial gene.
  • the main output is a classification of reads at several taxonomic levels (phylum, class, order, family, and genus).
  • the relative proportions of the 16S rDNA bacterial taxa and the information and methodology used to measure them are as follows.
  • PCR amplification was performed using 16S universal primers targeting the V3-V4 region of the bacterial 16S ribosomal gene. Detection of sequencing fragments was performed by the 2 ⁇ 300 joined pair-end MiSeq kit V3 using MiSeq Illumina® technology.
  • Figure 1 shows the taxonomic level of intestinal microorganisms in the negative control (Control Chow), vehicle, 10 mg/kg drug administration group, 30 mg/kg drug administration group, and 100 mg/kg drug administration group, respectively, in the diet-induced NASH hamster model (Phylum) This is analyzed at the level of Figure 1a) and Family (Figure 1b), respectively, and shows the bacteria within the top 15.
  • LDA Effect Size (LEfSe) (Segata et. al 2011) is an algorithm for high-dimensional biomarker discovery that can identify taxonomic groups that characterize differences between two or more biological conditions. It emphasizes statistical significance and biological relevance to distinguish and identify quantitative features (abundant features) that also correspond to biologically meaningful categories (subclasses). LEfSe first strongly identifies features that are statistically different between biological classes.
  • Figure 2 shows the results of LEfSe analysis in the drug administration group (dose 1: 10 mg/kg) and vehicle group.
  • Figure 3 shows the results of LEfSe analysis in the drug administration group (dose 2: 30 mg/kg) and vehicle group.
  • Figure 4 shows the LEfSe analysis results in the drug administration group (dose 3: 100 mg/kg) and vehicle group.
  • Figure 5 shows the results of LEfSe analysis in the negative control (Control Chow) and vehicle groups.
  • Figure 6 shows the relative abundance (%) of each intestinal microorganism in the negative control group, vehicle group, or drug administration group (dose 2) (A: Lactobacillus , B: Bifidobacterium , C : Odoribacter , D: Prevotellaceae , E: Bacteroidaceae .
  • dose 2 A: Lactobacillus
  • B Bifidobacterium
  • C Odoribacter
  • D Prevotellaceae
  • E Bacteroidaceae .
  • the relative abundance ratio between the negative control group and the vehicle group or the vehicle group and the drug administration group showed a statistically significant difference through the Mann-Whitney test (*p-value ⁇ 0.05, **p-value ⁇ 0.001, ***p-value ⁇ 0.0001).
  • Figure 6A is Lactobacillus
  • Figure 6B is Bifidobacterium
  • Figure 6C is Odoribacter
  • Figure 6D is Prevotellaceae
  • Figure 6E is Bacteroidaceae relative abundance (%). ).
  • Figures 7a and 7b show the results of calculating the diversity of intestinal microorganisms, and are the results visualized by analyzing alpha diversity (Figure 7a) and beta diversity (Figure 7b) for each sample. From this, it can be seen that meglumine salt of Chemical Formula 1 changes the diversity of intestinal microorganisms.
  • Figure 7a shows a graph (top) and table (bottom) analyzing and visualizing alpha diversity for Observed, Chao1, Shannon, Simpson, Inverse Simpson (InvSimpson), and PD (Phylogenetic Diversity).
  • alpha diversity represents the taxonomic diversity within each sample and is analyzed at the OUT (Operational taxonomic units) level using six methods (Observed, Chao1, Shannon, Simpson, Inverse Simpson, PD (Phylogenetic Diversity)) in Median + interquartile format. was visualized as
  • Alpha diversity was calculated in terms of abundance for the Observed, Chao1, and PD indices.
  • Figure 7b is a graph visualized by analyzing the beta diversity (Figure 7b) of the negative control group (Control Chow), vehicle group, 10 mg/kg drug administration group, 30 mg/kg drug administration group, and 100 mg/kg drug administration group.
  • Figure 7b shows the beta diversity in each sample, and the beta diversity in Figure 7b was obtained by comparing the characteristic differences between each sample and generating a distance matrix between all samples.
  • PCoA Principal Coordinates Analysis

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Abstract

La présente invention concerne une utilisation d'un dérivé d'isoxazole ou d'un sel pharmaceutiquement ou cytologiquement acceptable de celui-ci, qui régule le niveau de micro-organismes intestinaux chez un sujet souffrant d'une maladie hépatique, d'une maladie gastro-intestinale, d'obésité ou d'une maladie métabolique.
PCT/KR2023/009225 2022-06-30 2023-06-30 Nouvelle utilisation d'un dérivé d'isoxazole ou d'un sel de celui-ci WO2024005587A1 (fr)

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KR10-2022-0080934 2022-06-30
KR20220080934 2022-06-30

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WO2024005587A1 true WO2024005587A1 (fr) 2024-01-04

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20180115126A (ko) * 2017-04-12 2018-10-22 일동제약(주) 담즙산 수용체의 효능제인 치환된 이중고리 화합물 및 이의 용도
KR20190117687A (ko) * 2017-02-23 2019-10-16 인터셉트 파마슈티컬즈, 인크. 담즙산 유도체와 마이크로바이옴의 약학 조성물 및 이의 용도
KR102168543B1 (ko) * 2017-04-12 2020-10-21 일동제약(주) 핵 수용체의 효능제인 아이속사졸 유도체 및 이의 용도

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20190117687A (ko) * 2017-02-23 2019-10-16 인터셉트 파마슈티컬즈, 인크. 담즙산 유도체와 마이크로바이옴의 약학 조성물 및 이의 용도
KR20180115126A (ko) * 2017-04-12 2018-10-22 일동제약(주) 담즙산 수용체의 효능제인 치환된 이중고리 화합물 및 이의 용도
KR102168543B1 (ko) * 2017-04-12 2020-10-21 일동제약(주) 핵 수용체의 효능제인 아이속사졸 유도체 및 이의 용도

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
YAN, M. et al. Effects of intestinal FXR-related molecules on intestinal mucosal barriers in biliary tract obstruction. Frontiers in pharmacology. 13 June 2022, vol. 13, article no. 906452, pp. 1-15. *
ZHANG, D. -Y. et al. The protective effect and mechanism of the FXR agonist obeticholic acid via targeting gut microbiota in non-alcoholic fatty liver disease. Drug design, development and therapy. 2019, vol. 13, pp. 2249-2270. *

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