Use of triazole compounds as ghrelin receptor agonists

Abstract

The present invention relates to the use of triazole compounds as ghrelin receptor agonists, and more particularly to compositions containing triazole compounds that bind strongly to the ghrelin receptor with very high specificity for the prevention or treatment of diseases mediated by the ghrelin receptor. The compounds provided by the present invention exhibit strong binding affinity with very high specificity to the ghrelin receptor and can be very useful in the development of preventive or therapeutic agents for diseases mediated by the ghrelin receptor.

Description

[Technical Field]

[0001] This application claims priority to Korean Patent Application No. 10-2020-0122540, filed on September 22, 2020, the entire specification of which is incorporated herein by reference. The present invention relates to the use of triazole compounds as ghrelin receptor agonists, and more particularly to compositions containing triazole compounds that bind strongly to the ghrelin receptor with very high specificity for the prevention or treatment of diseases mediated by the ghrelin receptor. [Background technology]

[0002] Ghrelin is an endogenous ligand for the growth hormone (GH) secretagogue receptor. Ghrelin is a 28-amino acid peptide hormone originally purified from the stomach and n-octanolized at position 3 of the serine. Because ghrelin has potential GH-releasing properties, it is believed to play an important role in GH release and energy homeostasis (Non-Patent Document 1). In particular, it is believed to have potential appetite-stimulating properties. Ghrelin agonists have also been used to treat and / or prevent cancer anorexia / cachexia (Non-Patent Documents 2, 3, 4); anticancer drug-induced cachexia and anorexia (Non-Patent Documents 4, 5); anticancer drug-induced hyperalgesia (Non-Patent Document 5); COPD / COPD cachexia (Non-Patent Documents 6, 7); sarcopenia (Non-Patent Document 8); eating disorders and eating disorder nervosa (Non-Patent Document 9); suppression of weight loss (Non-Patent Document 10); postoperative generalized wasting in cancer patients (Non-Patent Document 11); chronic airway infections (Non-Patent Document 7); inflammation (Non-Patent Document 12); IBD (Non-Patent Document 12); FD (Non-Patent Document 13); It is known to be useful for the treatment of: constipation (Non-Patent Document 9); diabetic gastroparesis and gastroparesis (Non-Patent Documents 4, 13); heart failure (Non-Patent Documents 14, 15, 16); myocardial infarction (Non-Patent Documents 14, 15, 16); diabetic neuropathy (Non-Patent Document 17); diagnosis and treatment of growth hormone deficiency (Non-Patent Document 18); improving quality of life in the elderly (Non-Patent Document 18); defecation disorders in patients with spinal cord injuries (Non-Patent Document 19); postoperative colonic obstruction (Non-Patent Documents 4, 20); achlorhydria (Patent Document 1); and morphine-induced colonic obstruction (Non-Patent Document 20). [Advanced Technology Documents] [Chartered documents]

[0003]

Patent Document 1

Non-licensed literature

[0004] [Non-licensed document 1] Scientifica2013, Article ID518909(http: / / dx.doi.org / 10.1155 / 2013 / 518909), 25pages, 2013 [Non-licensed document 2] The Oncologist 12, 594-600, 2007. [Non-licensed document 3] Support Care Cancer21, 2409-2415, 2013

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

[0005] Therefore, it is desirable to search for new compounds that modulate ghrelin receptor action.

[0006] The present inventors have conducted extensive research to develop a ghrelin receptor agonist that binds to the ghrelin receptor with extremely high specificity, and have discovered that triazole compounds exhibit this effect, leading to the completion of the present invention. Therefore, an object of the present invention is to provide a pharmaceutical composition for preventing or treating a disease mediated by the ghrelin receptor, comprising a compound of the following formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

[0007] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating a disease mediated by the ghrelin receptor, comprising a compound of the following Formula 1 or a pharmaceutically acceptable salt thereof:

[0008] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating a disease mediated by the ghrelin receptor, which essentially comprises a compound of the following formula 1 or a pharmaceutically acceptable salt thereof: [ka] In the above formula, R1 is hydrogen; straight or branched chain alkyl having 1 to 15 carbon atoms; or substituted or unsubstituted alkylcarbonyl having 1 to 5 carbon atoms; R2 is hydrogen; or straight or branched chain alkyl having 1 to 15 carbon atoms; alkenyl having 2 to 10 carbon atoms; or alkynyl having 2 to 10 carbon atoms.

[0009] Another object of the present invention is to provide a food composition for preventing or ameliorating a disease mediated by the ghrelin receptor, comprising a compound of the following formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

[0010] Another object of the present invention is to provide a food composition for preventing or ameliorating ghrelin receptor-mediated diseases, which comprises a compound of the following formula 1 or a pharmaceutically acceptable salt thereof:

[0011] Another object of the present invention is to provide a compound of the following formula 1 or a pharmaceutically acceptable salt thereof: The present invention provides a food composition for preventing or improving diseases mediated by the ghrelin receptor, which comprises: [ka] In the above formula, R1 is hydrogen; straight or branched chain alkyl having 1 to 15 carbon atoms; or substituted or unsubstituted alkylcarbonyl having 1 to 5 carbon atoms; R2 is hydrogen; or straight or branched chain alkyl having 1 to 15 carbon atoms; alkenyl having 2 to 10 carbon atoms; or alkynyl having 2 to 10 carbon atoms.

[0012] Another object of the present invention is to provide a compound of formula 2 or a salt thereof: [ka] In the above formula, R1 is hydrogen; straight or branched chain alkyl having 1 to 15 carbon atoms; or substituted or unsubstituted alkylcarbonyl having 1 to 5 carbon atoms.

[0013] Another object of the present invention is to provide a use of the compound of formula 1 or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical for the treatment of a disease mediated by the ghrelin receptor:

[0014] Another object of the present invention is to provide a method for treating a disease mediated by the ghrelin receptor, comprising administering an effective amount of a composition comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof to an individual in need thereof. [Means for solving the problem]

[0015] In order to achieve the above-mentioned object of the present invention, the present invention provides a pharmaceutical composition for preventing or treating a disease mediated by the ghrelin receptor, comprising a compound of the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

[0016] The present invention also provides a pharmaceutical composition for preventing or treating a disease mediated by the ghrelin receptor, comprising a compound of the following Formula 1 or a pharmaceutically acceptable salt thereof:

[0017] The present invention also provides a pharmaceutical composition for preventing or treating a disease mediated by the ghrelin receptor, which essentially comprises a compound of the following formula 1 or a pharmaceutically acceptable salt thereof: [ka] In the above formula, R1 is hydrogen; straight or branched chain alkyl having 1 to 15 carbon atoms; or substituted or unsubstituted alkylcarbonyl having 1 to 5 carbon atoms; R2 is hydrogen; or straight or branched chain alkyl having 1 to 15 carbon atoms; alkenyl having 2 to 10 carbon atoms; or alkynyl having 2 to 10 carbon atoms.

[0018] In order to achieve another object of the present invention, the present invention provides a food composition for preventing or ameliorating a disease mediated by the ghrelin receptor, comprising a compound of the following formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

[0019] The present invention also provides a pharmaceutical composition for preventing or treating a disease mediated by the ghrelin receptor, comprising a compound of the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

[0020] The present invention also provides a pharmaceutical composition for preventing or treating a disease mediated by the ghrelin receptor, comprising, as an active ingredient, a compound of the following formula 1 or a pharmaceutically acceptable salt thereof: [ka] In the above formula, R1 is hydrogen; straight or branched chain alkyl having 1 to 15 carbon atoms; or substituted or unsubstituted alkylcarbonyl having 1 to 5 carbon atoms; R2 is hydrogen; or straight or branched chain alkyl having 1 to 15 carbon atoms; alkenyl having 2 to 10 carbon atoms; or alkynyl having 2 to 10 carbon atoms.

[0021] In order to achieve another object of the present invention, the present invention provides a compound of the following formula 2 or a salt thereof: [ka] In the above formula, R1 is hydrogen; straight or branched chain alkyl having 1 to 15 carbon atoms; or substituted or unsubstituted alkylcarbonyl having 1 to 5 carbon atoms.

[0022] To achieve another object of the present invention, the present invention provides a use of the compound of Formula 1 or a pharmaceutically acceptable salt thereof for preparing a preparation for treating a disease mediated by the ghrelin receptor.

[0023] To achieve another object of the present invention, the present invention provides a method for treating a disease mediated by the ghrelin receptor, comprising administering an effective amount of a composition comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof to an individual in need thereof.

[0024] The present invention will be described in detail below.

[0025] The present invention provides a pharmaceutical composition for preventing or treating a disease mediated by the ghrelin receptor, comprising, as an active ingredient, a compound of the following formula 1 or a pharmaceutically acceptable salt thereof: [ka] In the above formula, R1 is hydrogen; straight or branched chain alkyl having 1 to 15 carbon atoms; or substituted or unsubstituted alkylcarbonyl having 1 to 5 carbon atoms; R2 is hydrogen; or straight or branched chain alkyl having 1 to 15 carbon atoms; alkenyl having 2 to 10 carbon atoms; or alkynyl having 2 to 10 carbon atoms.

[0026] In the present invention, the term "alkyl" refers to a straight or branched chain hydrocarbon having 1 to 15 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl, and dodecyl.

[0027] As used herein, the term "carbonyl" refers to a -C(O)- group.

[0028] The term "alkylcarbonyl" as used herein refers to an alkyl group bonded to a parent molecular residue via a carbonyl group, as defined above. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-iodopropyl, 2,2-dimethyl-1-iodopropyl, 1-iodobutyl, and 1-iodopentyl.

[0029] In the present invention, when the alkylcarbonyl is a "substituted" alkylcarbonyl, it may be substituted with one or more substituents selected from the group consisting of hydroxy, halogen, cyano, nitro, and amino.

[0030] In the present invention, the term "alkenyl" refers to a straight or branched chain hydrocarbon having 2 to 10 carbon atoms and containing one or more carbon-carbon double bonds formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

[0031] As used herein, the term "alkynyl" refers to a straight or branched chain hydrocarbon group containing 2 to 10 carbon atoms and one or more carbon-carbon triple bonds. Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

[0032] Preferably, in the present invention, R1 is hydrogen or acetyl, and R2 is alkyl having 1 to 15 carbon atoms. More preferably, in the present invention, R1 is hydrogen, and R2 is alkyl having 4 to 15 carbon atoms. Even more preferably, in the present invention, R1 is hydrogen, and R2 is alkyl having 6 to 12 carbon atoms. Most preferably, in the present invention, R1 is hydrogen, and R2 is alkyl having 9 to 12 carbon atoms.

[0033] Specifically, in the present invention, the compound of Chemical Formula 1 is 2-amino-2-(1-hexyl-1H-1,2,3-triazol-4-yl)propane-1,3-diol, 2-amino-2-(1-heptyl-1H-1,2,3-triazol-4-yl)propane-1,3-diol, 2-amino-2-(1-octyl-1H-1,2,3-triazol-4-yl)propane-1,3-diol, 2-amino-2-(1-nonyl 2-amino-2-(1-decyl-1H-1,2,3-triazol-4-yl)propane-1,3-diol, 2-amino-2-(1-undecyl-1H-1,2,3-triazol-4-yl)propane-1,3-diol, or 2-amino-2-(1-dodecyl-1H-1,2,3-triazol-4-yl)propane-1,3-diol.

[0034] According to one embodiment of the present invention, the compound of Chemical Formula 1 has been confirmed to exhibit very strong binding to the ghrelin receptor and very high binding specificity to the ghrelin receptor. Therefore, as a ghrelin receptor agonist, it is expected to exhibit preventive or therapeutic effects on ghrelin receptor-mediated diseases without affecting the activity of other receptors, resulting in minimal side effects.

[0035] The actions of the endogenous ligand ghrelin at the ghrelin receptor have been shown to lead to potential growth hormone-releasing effects, appetite stimulation, gastromotility, acid secretion, beneficent cardiovascular effects, and direct bone formation. Therefore, ghrelin receptor agonists may be beneficial in the treatment of growth hormone deficiency, eating disorders, gastrointestinal diseases, cardiovascular diseases, osteoporosis, aging, and catabolic or chronic wasting syndromes. Ghrelin receptor agonists can also be effective in treating sleep disorders.

[0036] Specific conditions associated with, and therefore mediated by, the ghrelin receptor that may be beneficially affected by ghrelin receptor agonists include obesity and obesity-related risk factors, including, but not limited to, diabetes, diabetes-related complications, metabolic syndromes, and cardiovascular disorders (including atherosclerosis and dyslipidemia).

[0037] Other diseases and / or conditions mediated by the ghrelin receptor include: treatment of growth hormone deficiency, increased muscle mass, increased bone density, treatment of male and female sexual dysfunction, facilitating weight gain, facilitating weight maintenance, and facilitating appetite stimulation (e.g., facilitating weight gain, weight maintenance, or appetite stimulation may be useful for patients with or undergoing treatment for disorders associated with weight loss). Examples of disorders associated with weight loss include anorexia nervosa, bulimia nervosa, cancer cachexia, AIDS, marasmus, cachexia, and frail elderly wasting. Examples of treatments associated with weight loss include chemotherapy, radiation therapy, temporary or permanent immobilization, and dialysis.

[0038] Other diseases or conditions include sleep disorders, congestive heart failure, metabolic disorders, improved memory function, breast cancer, thyroid cancer, and improvement of ischemic nerve or muscle damage.

[0039] Eating disorders include anorexia nervosa, including restrictive, binge eating, and purging subtypes; binge eating disorder, including purging and non-purging subtypes; obesity; compulsive eating disorder; binge eating disorder; and eating disorder not otherwise specified.

[0040] Gastrointestinal disorders for which ghrelin receptor agonists may be effective include gastrointestinal obstruction, gastric ulcers, inflammatory bowel diseases such as Crohn's disease, and ulcerative colitis. The compounds of the present invention are also useful in treating the symptoms associated with esophageal reflux and / or dyspepsia, with or without appetite / metabolism-related cachexia, and in treating constipation-related conditions such as paralytic ileus or pseudo-obstruction and constipation or irritable bowel syndrome.

[0041] The cardiovascular diseases include heart failure and dilated cardiomyopathy.

[0042] Catabolic states or chronic wasting syndromes can occur in post-surgical patients and include AIDS-related wasting syndromes and cancer-related wasting syndromes such as cancer cachexia.

[0043] Ghrelin receptor agonists are known to promote gastric acid secretion (KR20147036310A). Therefore, it is clear that the ghrelin receptor agonists of the present invention may be effective in treating various diseases accompanied by low or no gastric acid secretion, even if they are not effective in increasing gastric acid secretion.

[0044] In the present invention, the type of achlorhydria is not particularly limited, and may include, for example, age-related achlorhydria associated with the aging process; chronic gastritis-related achlorhydria; anemic achlorhydria associated with anemia; partial gastrectomy-related achlorhydria; calcium absorption-related achlorhydria; vitamin D absorption-related achlorhydria; calcitonin synthesis-related achlorhydria; and drug-induced achlorhydria.

[0045] In one embodiment of the present invention, the compound of Formula 1 may be effective in preventing or treating a ghrelin receptor-mediated disorder selected from the group consisting of cancer anorexia or cachexia; anticancer drug-induced cachexia or anorexia; anticancer drug-induced hyperalgesia; COPD or COPD cachexia; sarcopenia; eating disorders; weight loss; post-operative general weakness in cancer patients; chronic airway infection; inflammation; IBD; FD; constipation; diabetic gastroparesis; heart failure; myocardial infarction; diabetic neuropathy; growth hormone deficiency; bowel disorders in spinal cord injury patients; post-operative colonic obstruction; achlorhydria; and morphine-induced colonic obstruction.

[0046] Examples of the pharmaceutically acceptable salts in the present invention include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), and salts formed with acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, and the like. The compounds may also be administered in the form of pharmaceutically acceptable quaternary salts known to those skilled in the art, including, among others, chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartarate, ascorbate, cinnamoate, mandeloate, and diphenylacetate).

[0047] The pharmaceutical composition according to the present invention may be formulated into a suitable form together with a pharmaceutically acceptable carrier, and may further contain an excipient or diluent. As used herein, "pharmaceutically acceptable" refers to a non-toxic composition that is physiologically acceptable and does not generally cause allergic reactions such as gastrointestinal disorders or dizziness or similar reactions when administered to humans.

[0048] Pharmaceutically acceptable carriers may further include, for example, carriers for oral administration or carriers for parenteral administration. Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Carriers for parenteral administration may include water, a suitable oil, saline, aqueous glucose, glycol, etc., and may further include stabilizers and preservatives. Suitable stabilizers include antioxidants such as sodium bisulfite, sodium bisulfite, or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. In addition to the above ingredients, the pharmaceutical composition of the present invention may further include lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, etc. Other pharmaceutically acceptable carriers and formulations may be found in those skilled in the art.

[0049] The compositions of the present invention can be administered to mammals, including humans, by any method, for example, orally or parenterally. Parenteral administration may include, but is not limited to, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal administration.

[0050] The pharmaceutical composition of the present invention can be formulated into a preparation for oral or parenteral administration by the administration route as described above.

[0051] In the case of oral administration preparations, the composition of the present invention can be formulated into powder, granules, tablets, pills, sugar-coated tablets, capsules, liquids, gels, syrups, slurries, suspensions, etc., using methods known in the art. For example, oral preparations can be prepared by combining the active ingredient with a solid excipient, crushing the mixture, adding suitable excipients, and then processing the mixture with the granules to obtain tablets or sugar-coated tablets. Examples of suitable excipients include: Sugars including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, and maltitol, as well as corn starch, wheat starch, and rice starch Fillers such as starches including flour and potato starch, celluloses including methylcellulose, sodium carboxymethylcellulose, and hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone, etc. may be included. In addition, disintegrants such as cross-linked polyvinylpyrrolidone, agar, alginic acid, or sodium alginate may be added in some cases. Furthermore, the pharmaceutical composition of the present invention may additionally include an anti-agglomerating agent, a lubricant, a wetting agent, a flavoring, an emulsifier, a preservative, etc.

[0052] For parenteral administration, the formulations may be formulated in the form of injections, creams, lotions, topical ointments, oils, topical emulsions, gels, aerosols, and nasal inhalants by methods known in the art, and these formulations are described in formularies commonly known in all pharmaceutical sciences.

[0053] The total effective amount of the composition of the present invention can be administered to a patient in a single dose or in a fractionated treatment protocol in which multiple doses are administered over a long period of time. The pharmaceutical composition of the present invention may vary in the content of the active ingredient depending on the severity of the disease. Preferably, the total dosage of the pharmaceutical composition of the present invention is approximately 0.01 μg to 10,000 mg per kg of patient body weight per day, most preferably 0.1 μg to 1,000 mg per kg of patient body weight per day. However, the dosage of the pharmaceutical composition is determined by various factors, such as the formulation method, administration route, and treatment frequency, as well as the patient's age, weight, health condition, sex, severity of the disease, diet, and excretion rate. Taking these factors into consideration, a person skilled in the art would be able to determine the appropriate effective dosage of the composition of the present invention. The pharmaceutical composition of the present invention is not particularly limited in its dosage form, administration route, or administration method, as long as it exhibits the effects of the present invention.

[0054] The present invention also provides a food composition for preventing or ameliorating a disease mediated by the ghrelin receptor, comprising, as an active ingredient, a compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof: [ka] In the above formula, R1 is hydrogen; straight or branched alkyl having 1 to 10 carbon atoms; or substituted or unsubstituted alkylcarbonyl having 1 to 5 carbon atoms; R2 is hydrogen; or straight or branched chain alkyl having 1 to 15 carbon atoms; alkenyl having 2 to 10 carbon atoms; or alkynyl having 2 to 10 carbon atoms.

[0055] The food composition according to the present invention includes all types of functional foods, nutritional supplements, health foods, food additives, etc. These types can be prepared in various forms by conventional methods known in the art.

[0056] For example, as a health food, the food composition of the present invention itself can be used in tea, juice, and drinks. The food composition of the present invention can be prepared in the form of a composition by mixing it with a known substance or active ingredient known to have the effect of preventing, improving or treating degenerative neurological disorders or depression.

[0057] Furthermore, functional foods can be produced by adding the food composition of the present invention to beverages (including alcoholic beverages), fruits and processed fruits (e.g., canned fruits, bottled fruits, jams, marmalades, etc.), fish, meat and processed fruits (e.g., ham, sausage, corned beef, etc.), breads and noodles (e.g., udon, soba, ramen, spaghetti, macaroni, etc.), fruit juices, various drinks, cookies, candies, dairy products (e.g., butter, cheese, etc.), edible vegetable oils and fats, margarine, vegetable proteins, retort foods, frozen foods, various seasonings (e.g., miso, soy sauce, sauces, etc.), etc.

[0058] The preferred content of the food composition according to the present invention is, but is not limited to, 0.01 to 50 wt % of the total weight of the final food product. To use the food composition according to the present invention as a food additive, it can be prepared in the form of a powder or a concentrated liquid.

[0059] The present invention also provides a compound of Formula 2 or a salt thereof: [ka] In the above formula, R1 is hydrogen; straight or branched chain alkyl having 1 to 15 carbon atoms; or substituted or unsubstituted alkylcarbonyl having 1 to 5 carbon atoms. In the formula, the same applies as described above to alkyl and alkylcarbonyl. Preferably, R1 is hydrogen or acetyl. Most preferably, the compound of Formula 2 is 2-amino-2-(1-decyl-1H-1,2,3-triazol-4-yl)propane-1,3-diol.

[0060] The compound of Formula 2 provided by the present invention acts as a ghrelin receptor-specific efficacious agent and can be used as a preventive or therapeutic agent for diseases mediated by the ghrelin receptor.

[0061] In one aspect of the present invention, the compound of Formula 2 provided by the present invention includes a salt form thereof, and the salt may preferably be in the form of a pharmaceutically acceptable salt.

[0062] Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), as well as acid addition salts formed with acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, etc. alic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid These include salts formed with organic acids such as guanylate, ...

[0063] To achieve another object of the present invention, the present invention provides a use of the compound of Formula 1 or a pharmaceutically acceptable salt thereof for preparing a preparation for treating a disease mediated by the ghrelin receptor.

[0064] To achieve another object of the present invention, the present invention provides a method for treating a disease mediated by the ghrelin receptor, comprising administering an effective amount of a composition comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof to an individual in need thereof.

[0065] The "effective amount" of the present invention refers to an amount that, when administered to an individual, exhibits an effect of improving, treating, preventing, detecting, diagnosing, or suppressing or reducing a ghrelin receptor-mediated disease. The "individual" may be an animal, preferably a mammal, particularly an animal including a human, or may be a cell, tissue, organ, etc. derived from an animal. The individual may be a patient in need of the effect.

[0066] The term "treatment" in the present invention refers to the comprehensive treatment of a ghrelin receptor-mediated disease or the symptoms of the disease, which may include curing, substantially preventing, or ameliorating the condition of the disease, and may include, but is not limited to, alleviating, curing, or preventing one or most of the symptoms associated with the disease.

[0067] As used herein, the term "comprising" is used equivalently to "including" or "characterized by" and does not exclude additional components or method steps not specifically recited in the compositions or methods of the present invention. The term "consisting of" means excluding additional elements, steps, or ingredients not otherwise recited. The term "essentially consisting of" means that the scope of a composition or method may include, in addition to the recited materials or steps, materials or steps that do not substantially affect the basic characteristics of the recited materials or steps. [Effects of the Invention]

[0068] The compounds provided by the present invention exhibit strong binding ability with very high specificity to the ghrelin receptor and can be very useful in the development of preventive or therapeutic agents for diseases mediated by the ghrelin receptor. [Brief explanation of the drawings]

[0069] [Figure 1] Figure 1 shows the EC50 values ​​for ghrelin and triazole compounds (KARI001, KARI101, and KARI201) at different concentrations to induce 50% intracellular calcium influx in HEK293 (human embryonic kidney 293) cells overexpressing the ghrelin receptor. [Figure 2] Figure 2 shows the changes in ghrelin receptor downstream signaling factors following treatment of ghrelin receptor-overexpressing HEK293 cells with ghrelin and 10 mM triazole compounds (KARI001, KARI101, and KARI201) (n=3, **p<0.01, ***p<0.001). [Figure 3] Figure 3 shows the effect of ghrelin receptor intracellular influx on ghrelin receptor-overexpressing HEK293 cells treated with ghrelin and 10 mM triazole compounds (KARI001, KARI101, and KARI201) (n=6, **p<0.01). [Figure 4a] , [Figure 4b] Figures 4a and 4b are graphs showing the efficacy of a triazole compound (KARI201) as an agonist or antagonist for 170 G-protein coupled receptors, including the ghrelin receptor. [Figure 5a] , [Figure 5b] Figures 5a and 5b show the effect of improving delayed gastric emptying, which can be used to evaluate gastrointestinal motility, after oral administration of a triazole compound (KARI201) at various concentrations in a postoperative ileus (POI) mouse model (n=5-10, *p<0.05, **p<0.01). [Figure 6a] , [Figure 6b]Figures 6a and 6b show the effect of improving delayed gastric emptying, which can be used to evaluate gastrointestinal motility, after oral administration of a triazole compound (KARI101) at various concentrations in a mouse model of postoperative ileus (POI) (n=5, **p<0.01, ***p<0.001). [Figure 7a] , [Figure 7b] , [Figure 7c] , [Figure 7d] Figures 7a to 7d show the colonic transit time (Figure 7a), number and weight of feces (Figure 7b), food intake (Figure 7c), and body weight (Figure 7d), which can be used to evaluate colonic motility after oral administration of 30 mg / kg of a triazole compound (KARI201) to a mouse model of postoperative ileus (POI) (n=4, ***p<0.001, ****p<0.0001). [Figure 8a] , [Figure 8b] , [Figure 8c] , [Figure 8d] Figures 8a to 8d show the colonic transit time (Figure 8a), number and weight of feces (Figure 8b), food intake (Figure 8c), and body weight (Figure 8d), which can be used to evaluate colonic motility after oral administration of 30 mg / kg of a triazole compound (KARI101) to a mouse model of postoperative ileus (POI) (n=4, *p<0.05, **p<0.01, ***p<0.001). [Figure 9a] , [Figure 9b] , [Figure 9c] Figures 9a to 9c show an overview of the experiment conducted to investigate the efficacy of triazole compounds (KARI101, KARI201) in a cancer cachexia mouse model (Figure 9a) and a graph confirming the muscle function improvement effect after oral administration of 10 mg / kg (Figure 9b) (n=7-8, *p<0.05, **p<0.01, ***p<0.001). [Figure 10a] , [Figure 10b] , [Figure 10c] , [Figure 10d] Figures 10a to 10d show the changes in tumor size (Figure 10a), body weight (Figure 10b), food intake (Figure 10c), and average daily food intake (Figure 10d) during oral administration of 10 mg / kg of triazole compounds (KARI101, KARI201) to a cancer cachexia mouse model (n=9, **p<0.01, ****p<0.0001). [Figure 11a] , [Figure 11b] , [Figure 11c] , [Figure 11d] Figures 11a to 11d show the total body fat weight (Figure 11a), visceral fat weight (Figure 11b), subcutaneous fat weight (Figure 11c), and muscle weight (Figure 11d) after oral administration of 10 mg / kg of triazole compounds (KARI101, KARI201) to a cancer cachexia mouse model (n=6-9, *p<0.05, **p<0.01, ****p<0.0001). DETAILED DESCRIPTION OF THE INVENTION

[0070] The present invention will be described in detail below with reference to the following examples, which are provided for illustrative purposes only and are not intended to limit the scope of the present invention.

[0071] <Experimental materials and methods> 0. Compound synthesis The substances KARI001 and KARI201 were manufactured and synthesized based on existing literature (domestic patent, 10-2017324). Ghrelin protein used in the positive control group was purchased from TORIS. KARI001: 2-amino-2-(1-dodecyl-1H-1,2,3-triazol-4-yl)propane-1,3-diol KARI201: 2-amino-2-(1-nonyl-1H-1,2,3-triazol-4-yl)propane-1,3-diol The substance named KARI101, compound name 2-amino-2-(1-decyl-1H-1,2,3-triazol-4-yl)propane-1,3-diol, was prepared through the following series of steps.

[0072] 0-1. Reaction Scheme 1: Synthesis of 1-azidodecane [ka] To synthesize 1-azidodecane of formula 1, sodium azide (4.9 g, 75 mmol, 2 eq) was added to a solution of 1-bromodecane of formula 1 (9.9 g, 37 mmol) in DMF (50 mL). The mixture was stirred at room temperature for 2 days, followed by addition of ice water (200 mL) and extraction with ether. The organic layer was washed with H2O, brine, dried over MgSO4, and concentrated to give 1-azidodecane of formula 2 (6.2 g, 91%). 1 H NMR (400MHz, CDCl3): δ3.28(t, 2H), 1.62(m, 2H, ), 1.40-1.29(m, 14H), 0.91(t, 3H)

[0073] 0-2. Reaction Scheme 2, Synthesis of 2-amino-2-(hydroxymethyl)propane-1,3-diol [ka] To synthesize 2-amino-2-(hydroxymethyl)propane-1,3-diol of Scheme 2, BocO (49.5 g, 1.1 eq) was added to a suspension of tris(hydroxymethyl)amino-methane of Formula 3 (25.0 g, 0.206 mol) in DMF (500 mL). After stirring the mixture at room temperature for 2 hours, 2,2-dimethoxypropane (30.4 mL, 1.2 eq) and p-TsOH.HO (2.0 g, 0.05 eq) were added. The mixture was stirred at room temperature for 18 hours and diluted with EtO (500 mL). The organic layer was washed with saturated NaHCO solution (300 mL) and brine (200 mL). The organic layer was dried over MgSO and concentrated. The residue was crystallized from n-hexane to give tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (4) as a white solid (32.0 g, 59.4%). 1 H NMR (600MHz, CDCl3): δ5.32(s, 1H), 3.86-3.80(m, 4H), 3.73(s, 2H), 3.68(s, 1H), 1.46-1.44(m, 15H)

[0074] 0-3. Reaction Scheme 3, 2-amino-2-(hydroxymethyl)propane-1,3-diol (2-amino- 2-(hydroxymethyl)propane-1, 3-diol) synthesis [ka] To synthesize tert-butyl 5-pormyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (Scheme 3), a solution of oxalyl chloride (33.4 mL, 3.17 eq) in dry MC (340 mL) was mixed with DMSO (43.7 mL, 5 eq). After stirring the mixture for 15 minutes, tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (32.0 g, 0.123 mol) of Formula 4 in anhydrous MC (340 mL) was added. After stirring the mixture for 2 hours, EtN (171 mL, 10 eq) was added. After stirring the mixture for 10 minutes, the cooling bath was removed and the mixture was allowed to stand at room temperature. The light brown suspension was diluted with EA (300 mL) and washed with 10% NHOH (1,500 mL). The organic layer was concentrated, and the residue was subjected to SiO2 column chromatography eluted with EA / n-hexane = 1 / 10 to obtain tert-butyl 5-pormyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (15.0 g, 47.2%) of Formula 5 as a white solid. 1 H NMR (400 MHz, C D Cl3): δ9.64(s, 1H), 5.56(s, 1H), 4.07(d, 2H, J=12.0Hz), 3.95(d, 2H, J=12.0Hz), 1.47(s, 15H)

[0075] 0-4. Reaction Scheme 4, Synthesis of 2-amino-2-(hydroxymethyl)propane-1,3-diol [ka] To synthesize tert-butyl 5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (Scheme 4), dimethyl-2-iodopropylphosphonate (1.6 g, 1.02 eq) was added to a suspension of KCO (3.0 g, 2.25 eq) and p-toluenesulfonyl azide (14% solution in toluene, 15.8 mL, 1.05 eq) in acetonitrile (50 mL), and the mixture was stirred vigorously at room temperature for 2.5 hours. A solution of tert-butyl 5-pormyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (2.5 g, 9.64 mmol) of Formula 5 in methanol (40 mL) was added to the initial reaction mixture. After adding K2CO3 (2.7 g, 2.06 eq), the mixture was stirred for 1.5 hours, concentrated under reduced pressure, and the remaining water was diluted with MC (200 ml) and H2O (200 ml). The organic layer was washed with H2O (200 ml), dried over MgSO4, and concentrated under reduced pressure. The residue was applied to SiO2 column chromatography eluting with EA / n-hexane = 1 / 9 to give tert-butyl 5-ethynyl-2,2-dimethyl-1,3-dimethyl-1,3-dimethyl-2,4-dimethyl-1,3 ... 3-Dioxan-5-ylcarbamate was obtained as a white solid (2.3 g, 93.4%). 1 H NMR (400MHz, CDCl3): δ5.15(s, 1H), 4.05-3.95(m, 4H), 2.43(s, 1H), 1.48-1.38(m, 15H)

[0076] 0-5. Reaction Scheme 5, Synthesis of 2-amino-2-(1-decyl-1H-1,2,3-triazol-4-yl)propane-1,3-diol (2-amino-2-(1-decyl-1H-1,2,3-triazol-4-yl)propane-1,3-diolhydrochloride) [ka] To synthesize 2-amino-2-(1-decyl-1H-1,2,3-triazol-4-yl)propane-1,3-diol, KARI101 (Scheme 5), CuSO4.5HO (1.56 g, 6 mmol) was added to a solution of tert-butyl 5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (Scheme 6) (4.0 g, 15 mmol), 1-azidodecane (Scheme 1) (3.16 g, 17 mmol), sodium L (4.03 g, 20 mmol), t-BuOH (60 mL), HO (128 mL), and MC (104 mL). The biphasic solution was stirred in air for 18 hours, and the aqueous layer was extracted with MC. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by SiO column chromatography eluting with EA / n-hexane = 1 / 6 to give a solid (6.5 g). The resulting solid was mixed with concentrated HCl (21 ml) and ethanol (210 ml) and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure and recrystallized from acetone to give 2-amino-2-(1-decyl-1H-1,2,3-triazol-4-yl)propane-1,3-diol as a white solid (2.6 g, 52.4%, molecular weight 298.4). 1 H NMR (500MHz, methanol-d4): δ8.06(s, 1H), 4.41(t, 2H), 3.95(dd, J=20Hz, 15Hz, 4H), 1.91(t, 2H), 1.29-1.33(m, 14H), 0.89(t, 3H) 13 C NMR (500MHz, methanol-d4): δ144.9, 124.3, 63.7 (2c, 60.8, 51.5, 33.0, 31.3, 30.6, 30.5, 30.4, 30.1, 27.5, 23.7, 14.4

[0077] 1.Cell culture HEK293 (human embryonic kidney 293) cells were purchased from ATCC and cultured in DMEM medium containing 10% FBS at 37°C and 5% CO2. To overexpress ghrelin receptor, HEK293 cells were transfected with the human ghrelin receptor cDNA vector (hGHSRa-pcDNA3.1+, cDNA Resource Center) and cultured for 48 hours. The cell line was then treated with each of the synthesized triazole compounds and ghrelin to evaluate their efficacy as ghrelin receptor agonists, including intracellular calcium influx, ghrelin receptor downstream signaling factors, and ghrelin receptor intracellular influx.

[0078] 2. Intracellular Calcium Influx Experiment HEK293 cells overexpressing ghrelin receptor were treated with Fluo-2AM, a calcium-specific fluorescent dye, and then washed twice with wash buffer containing 20 mM Hepes, 1 mM CaCl2, 1 mM MgCl2, and 0.7 mg / mL probenicid one hour later. After treating the cells with 100 μL of wash buffer, fluorescently labeled intracellular calcium was imaged at an excitation wavelength of 485 nM and an emission wavelength of 520 nM using a laser scanning confocal microscope equipped with temperature and humidity control, with a shutter interval of 10 seconds for 1 minute. Ghrelin and triazole compounds were then added at various concentrations and imaged under the same conditions. The intracellular calcium fluorescence intensity following compound treatment was measured using the same conditions as for the treatment. The fluorescence intensity was quantified based on the fluorescence intensity without treatment.

[0079] 3. Immunofluorescence HEK293 cells overexpressing the ghrelin receptor were treated with 10 mM each of ghrelin and a triazole compound. After 1 hour, the cells were fixed and incubated with anti-ghrelin receptor (rabbit, 1:500, Abcam). One day later, the cells were washed and incubated with anti-rabbit 488 antibody for 1 hour. Analysis was performed using a laser scanning confocal microscope equipped with Fluoview SV1000 imaging software (Olympus FV1000, Japan). The percentage of stained area of ​​ghrelin receptor that had entered the cells was quantified using Metamorph software (Molecular Devices).

[0080] 4. Western Blot Western blotting was used to analyze the protein expression of pAMPK, AMPK, pPI3K, PI3K, pERK, and ERK. Antibodies against pAMPK, AMPK, pPI3K, PI3K, pERK, and ERK (cell signaling) and β-actin (Santa Cruz) were used, and densitometric quantification was performed using ImageJ software (US National Institutes of Health).

[0081] 5. G Protein-Linked Receptor Agonist and Antagonist Analysis The efficacy of triazole compounds (10 mM) as agonists and antagonists against a total of 170 G protein-linked receptors was carried out at Eurofins Discovery.

[0082] 6. Post-surgical Ileus Mouse Model Establishment Six- to eight-week-old mice were fasted for one day and then anesthetized with a mixture of ketamine and xylazine. The abdomen and peritoneum were then incised, and the small intestine was exposed on a sterile gauze pad. A sterile cotton swab was used to manipulate the small intestine from the duodenum to the cecum for five minutes. After surgery, the abdomen was sutured and the mice were allowed to recover for four hours in a cage maintained at 32°C.

[0083] 7. Gastric emptying delay assessment Twenty hours after POI surgery, triazole compounds (10 mg / kg, 20 mg / kg, 30 mg / kg) were orally administered. Four hours later, 1.5% methylcellulose solution and 0.05% phenol red (Sigma) were orally administered. 30 minutes later, the mouse stomachs were removed and homogenized in 2 ml of 0.1 N NaOH solution. 3 ml of 0.1 N NaOH solution was added and centrifuged at 3,000 rpm at 4°C for 10 minutes. 100 ml of 20% trichloroacetic acid was added to the supernatant and centrifuged at 3,000 rpm at 4°C for 10 minutes. 400 ml of 0.5 N NaOH solution was added to 500 ml of the supernatant, and the absorbance was measured at 562 nm. For the baseline control, the stomach was removed immediately after oral administration of 1.5% methylcellulose solution and 0.05% phenol red, and the absorbance of the sample obtained in the above procedure was measured. The percent delayed gastric emptying was calculated as (1-(absorbance of test sample) / (absorbance of baseline control) x 100.

[0084] 8. Colonic Transit Time Assessment To evaluate the colonic transit time of feces, 200 μl of trypan blue dye was injected into the muscle colon after POI surgery before suturing. Four hours after POI surgery, a triazole compound (30 mg / kg) was orally administered. Mice were transferred to metabolic cages and given weighed food. The time to the appearance of the first trypan blue-stained feces was measured over a 24-hour period. At 24 hours, feces were counted and weighed, and the weight of the food consumed and the body weight of the mice were measured.

[0085] 9. Cancer Cachexia Model Establishment To establish the cancer fluid model, CT26 (colon tumor 26 cell line) cells were purchased from ATCC (CRL-2638) and cultured in RPMI1640 medium containing 10% FBS at 37°C and 5% CO2. 6 Each cell was injected subcutaneously into the right flank of a 10-week-old mouse. After measuring the size of the tumor growing in the right flank, body weight, and food intake, 10 mg / kg of a triazole compound was orally administered daily from day 9. On day 18 after cancer cell injection, a grip test and a rota-rod test were performed once each day to evaluate muscle function, and on day 20, the subcutaneous fat, visceral fat, and muscles (thighs and thighs) of the mice were separated and weighed.

[0086] 10. Grip test and Rota-rod test for assessing muscle function To assess muscle function, the grip test involved having the mouse grasp a metal grid mounted on a grip strength measuring machine, then pulling the tail horizontally backward. The force applied to the grid just before the mouse lost its grip was recorded in g as the maximum tension. The test was performed nine times per animal, and the average was recorded. The rota-rod test (Ugo Basile, Comerio, VA, Italy) involved performing rota-rod exercise at a rotation speed of 4 rpm on a machine equipped with a 3 cm diameter rod appropriately machined to provide a grip. The endurance time of the experimental animals was measured in seconds, and the average was recorded. Each rota-rod behavioral test did not exceed 5 minutes.

[0087] 11. Statistical analysis For comparisons of multiple groups, Tukey's honestly significant difference test and repeated measures analysis of variance test were performed according to the SAS statistical package (release 9.1; SAS Institute Inc., Cary, NC). *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 were considered significant.

[0088] <Experimental Results> 1. Confirmation of its effect as a ghrelin receptor agonist through increasing intracellular calcium influx To confirm the efficacy of the triazole compounds as ghrelin receptor agonists, we first measured changes in intracellular calcium influx, a key function of ghrelin. HEK293 cells overexpressing the human ghrelin receptor were incubated with a calcium-labeled fluorescent dye for one hour and then treated with ghrelin and the triazole compounds KARI001, KARI101, and KARI201 at varying concentrations. We confirmed that intracellular calcium influx increased with increasing concentrations of the three triazole compounds (Figure 1). The EC50 values, or the concentrations required to induce 50% intracellular calcium influx, were ghrelin = 39.45 nM, KARI001 = 128.3 nM, KARI101 = 188.5 nM, and KARI201 = 272.9 nM. That is, it was confirmed that the three triazole compounds can induce intracellular calcium influx as ghrelin receptor agonists.

[0089] 2. Ghrelin receptor agonist through regulation of G protein-dependent downstream factors of the ghrelin receptor The ghrelin receptor is a G protein-coupled receptor, and when ghrelin binds to it, it regulates the activity of downstream signaling factors, each of which is dependent on three major G proteins. For example, Gaq-dependent signaling increases intracellular calcium influx and increases AMPK phosphorylation, Gai / o-dependent signaling increases PI3K phosphorylation, and B-arrestin-dependent signaling increases ERK phosphorylation or induces ghrelin receptor influx into cells (FASEB J. 2019;33(1):518-531). First, we investigated whether the three triazole compounds could modulate the phosphorylation of G protein-dependent signaling subfactors of the ghrelin receptor. HEK293 cells overexpressing the human ghrelin receptor were treated with ghrelin and 10 mM of the three triazole compounds. After 1 hour, cell proteins were extracted and the phosphorylation of the subfactors was examined by Western blot analysis. We found that the three triazole compounds increased the phosphorylation of AMPK (Figure 2). Additionally, to confirm the intracellular influx effect of ghrelin receptor, human ghrelin receptor was overexpressed. HEK293 cells were treated with 10 mM ghrelin and the three triazole compounds, and then incubated with ghrelin receptor antibody for 1 hour to examine the expression of intracellular ghrelin receptors. Cells not treated with ghrelin or the three triazoles expressed ghrelin receptors in the plasma membrane, whereas cells treated with ghrelin or the three triazoles expressed ghrelin receptors in the perinuclear cytoplasm (Figure 3). In other words, the three triazole compounds were found to be effective as agents capable of regulating Gaq-dependent signaling and B-arrestin-dependent signaling of the ghrelin receptor.

[0090] 3. Triazole compounds act as ghrelin receptor-specific agonists The G protein-linked receptor family includes many receptors, including the ghrelin receptor. We investigated whether triazole compounds act as agonists or antagonists of other G protein-linked receptors. Cell lines expressing a total of 170 G protein-linked receptors, including the ghrelin receptor, were treated with 10 mM of the triazole compound KARI201 alone (agonist effect) or together with the ligands for each receptor (antagonist effect). As a result, KARI201 was confirmed to exhibit 83.7% ghrelin receptor agonist activity (Figures 4a and 4b). In other words, these results demonstrate that the KARI201 triazole compound is effective as a ghrelin receptor-specific agonist.

[0091] 4. Triazole compounds improve gastric emptying delay To confirm the gastric motility-promoting effect, one of the major physiological effects of ghrelin, a ghrelin receptor, we used postoperative ileus (POI) mice. POI mice with ileus induced showed delayed gastric emptying compared to normal mice. POI mice administered KARI201 and KARI101 20 hours after POI surgery showed significant improvements in delayed gastric emptying due to the increased concentrations of KARI201 and KARI101 (Figures 5a and 5b, 6a and 6b). In other words, it was found that the triazole compounds KARI201 and KARI101 act as ghrelin receptor agonists, improving gastric motility and slowing gastric emptying.

[0092] 5. Triazole compounds improve colonic motility Based on the gastric emptying delay effect of the triazole compounds KARI201 and KARI101, we investigated whether they could improve the colonic transit time of feces in POI mice. While mice administered PBS 4 hours after POI surgery had a prolonged colonic transit time, mice administered 30 mg / kg of KARI201 or KARI101 had a significantly decreased colonic transit time (Figures 7a and 8a). The number and weight of feces also increased with KARI201 administration (Figures 7b and 8b). Feed intake was also increased compared to PBS-administered POI mice, with no significant changes in body weight (Figures 7c, 7d, 8c, 8d). In other words, the triazole compounds KARI201 and KARI101, which act as ghrelin receptor agonists, were found to improve colonic motility and reduce bowel evacuation time. Therefore, triazole compounds can be used effectively as preventive or therapeutic agents for diseases mediated by the ghrelin receptor.

[0093] 6. Triazole compounds have the effect of improving muscle strength and function Cancer cachexia mice were used to confirm the increased food intake and subsequent improvement of fat and muscle loss, which are other physiological effects of ghrelin, a ghrelin receptor. To establish a cancer cachexia mouse model, CT26 cancer cells were injected subcutaneously into the right flank of 10-week-old mice. Nine days after cell injection, cancer cell growth in the right flank was confirmed, and KARI101 or KARI201 (10 mg / kg) was orally administered once daily. On day 18, grip and rota-rod tests were performed to evaluate muscle strength (Figure 9a). Vehicle-injected cancer cachexia mice showed reduced muscle strength, while KARI101 or KARI201-injected cancer cachexia mice maintained muscle strength. A significant improvement was confirmed (Fig. 9b and Fig. 9c).

[0094] 7. Triazole compounds improve food intake, fat loss, and muscle loss We evaluated the effects of the triazole compounds KARI101 and KARI201 on improving muscle function in a cancer cachexia mouse model, assessing tumor size, body weight, and food intake. Administration of KARI101 and KARI201 did not affect tumor size (Figure 10a) or body weight (Figure 10b) in cancer cachexia mice, but increased daily food intake compared to vehicle-administered mice (Figures 10c and 10d). Furthermore, administration of KARI101 and KARI201 increased the decreased total fat mass (Figure 11a), visceral fat mass (Figure 11b), and subcutaneous fat mass (Figure 11c) compared to vehicle-administered cancer cachexia mice, and also increased the decreased muscle mass (Figure 11d). In other words, the triazole compounds KARI201 and KARI101, as ghrelin receptor agonists, can increase the reduced food intake in cancer cachexia mice, thereby improving reduced fat and muscle mass, as well as muscle strength and function. [Industrial Applicability]

[0095] As described above, according to the present invention, the compounds provided by the present invention exhibit strong binding affinity with very high specificity to the ghrelin receptor and can be very useful in the development of preventive or therapeutic agents for diseases mediated by the ghrelin receptor, and therefore have high industrial applicability.

Claims

1. The following chemical formula 1: 【Chemistry 1】 (In the formula, R １ is hydrogen and R ２ is a linear alkyl having 6 to 12 carbon atoms; or a pharmaceutically acceptable salt thereof, The pharmaceutical composition is characterized in that the disease mediated by the ghrelin receptor is selected from the group consisting of eating disorders; cancer anorexia or cachexia; cachexia or anorexia induced by anticancer drugs; anticancer drug-induced hyperalgesia; COPD (chronic obstructive pulmonary disease) or COPD-cachexia; sarcopenia; eating disorders; weight loss; post-operative general weakness in cancer patients; chronic airway infections; inflammation; inflammatory bowel disease (IBD); functional dyspepsia (FD); constipation; diabetic gastroparesis; heart failure; myocardial infarction; diabetic neuropathy; growth hormone deficiency; bowel disorders in spinal cord injury patients; post-operative colonic obstruction; achlorhydria; and morphine-induced colonic obstruction.

2. The following chemical formula 1: 【Chemistry 2】 (In the formula, R １ is hydrogen and R ２ is a linear alkyl having 6 to 12 carbon atoms.) or a pharmaceutically acceptable salt thereof as an active ingredient. The food composition is characterized in that the disease mediated by the ghrelin receptor is selected from the group consisting of eating disorders; cancer anorexia or cachexia; cachexia or anorexia induced by anticancer drugs; anticancer drug-induced hyperalgesia; COPD (chronic obstructive pulmonary disease) or COPD-cachexia; sarcopenia; eating disorders; weight loss; general weakness after surgery in cancer patients; chronic airway infections; inflammation; inflammatory bowel disease (IBD); functional dyspepsia (FD); constipation; diabetic gastroparesis; heart failure; myocardial infarction; diabetic neuropathy; growth hormone deficiency; bowel disorders in spinal cord injury patients; postoperative colonic obstruction; achlorhydria; and morphine-induced colonic obstruction.

3. 2-amino-2-(1-decyl-1H-1,2,3-triazol-4-yl)propane-1,3-diol or a salt thereof.

4. 1: 【Transformation 3】 (In the formula, R １ is hydrogen and R ２ is a linear alkyl having 6 to 12 carbon atoms, or a pharmaceutically acceptable salt thereof, The use is characterized by being selected from the group consisting of eating disorders; cancer anorexia or cachexia; cachexia or anorexia induced by anticancer drugs; anticancer drug-induced hyperalgesia; COPD (chronic obstructive pulmonary disease) or COPD-cachexia; sarcopenia; eating disorders; weight loss; general weakness after surgery in cancer patients; chronic respiratory tract infections; inflammation; inflammatory bowel disease (IBD); functional dyspepsia (FD); constipation; diabetic gastroparesis; heart failure; myocardial infarction; diabetic neuropathy; growth hormone deficiency; bowel disorders in spinal cord injury patients; postoperative colonic obstruction; achlorhydria; and morphine-induced colonic obstruction.

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