Use of triazole compounds as ghrelin receptor agonists

Abstract

The present invention relates to the use of a triazole compound as a ghrelin receptor agonist, and more specifically, to a composition for preventing or treating a disease mediated by a ghrelin receptor, the composition containing a triazole compound that strongly binds to a ghrelin receptor with extremely high specificity. The compound provided by the present invention exhibits a strong binding force to the ghrelin receptor with extremely high specificity, and thus can be very effectively used for preventing or developing a therapeutic agent for a disease mediated by a ghrelin receptor.

Description

Technical Field

[0001] This application claims priority to Korean Patent Application No. 2020-0122540, filed on September 22, 2020, the entire specification of which is incorporated herein by reference.

[0002] The present invention relates to the use of triazole compounds as ghrelin receptor agonists, and more particularly to a composition for preventing or treating diseases mediated by ghrelin receptors, wherein the composition contains a triazole compound that strongly binds to ghrelin receptors with very high specificity. Background Art

[0003] Gastrointestinal stimulant is an endogenous ligand of the growth hormone (GH) secretagogue receptor. Gastrointestinal stimulant, originally purified from the stomach, is a 28 amino acid peptide hormone in which the serine at position 3 is n-octanoylated. Since ghrelin has a potential GH-releasing effect, it is believed to play an important role in maintaining GH release and energy homeostasis (see non-patent document 1). In particular, ghrelin appears to have a potential appetite-enhancing effect. In addition, it is known that ghrelin agonists can be used to treat and / or prevent cancer anorexia / cachexia (see non-patent documents 2, 3 and 4), cachexia and anorexia caused by anticancer drugs (see non-patent documents 4 and 5), hyperalgesia caused by anticancer drugs (see non-patent document 5), COPD / COPD cachexia (see non-patent documents 6 and 7), sarcopenia (see non-patent document 8), and eating disorders and neurogenic eating disorders (see non-patent document 9); inhibit weight loss (see non-patent document 10); treat and / or prevent general weakness after surgery in cancer patients (see non-patent document 11), chronic respiratory tract infections (see non-patent document 7), inflammation (see non-patent document 12), IBD (see non-patent document 12), FD (see non-patent document 4), constipation (see non-patent document 9), diabetic gastroparesis and gastroparesis (see non-patent documents 4 and 13), heart failure (see non-patent documents 14, 15 and 16), myocardial infarction (see non-patent documents 14, 15 and 16), and diabetic neuropathy (see non-patent document 17); diagnosis and treatment of growth hormone deficiency (see non-patent document 18); improving the quality of life of the elderly (see non-patent document 18); and treating and / or preventing defecation disorders in patients with spinal cord injury (see non-patent document 19), postoperative intestinal obstruction (see non-patent documents 4 and 20), acidosis (see non-patent document 1) and morphine-induced intestinal obstruction (see non-patent document 20).

[0004] {Non-patent document 1} Scientifica 2013, Article ID 518909 (http: / / dx.doi.org / 10.1155 / 2013 / 518909), p.25, 2013 {Non-patent document 2} The Oncologist 12, pp.594-600, 2007 {Non-patent document 3} Support Care Cancer 21, pp.2409-2415, 2013 {Non-patent document 4} Neurogastroenterol Motil 20, 177-184, 2008 {Non-patent document 5} Endocrinology 149, pp.455-460, 2008 {Non-patent document 6} BMC Pulmonary Medicine 13, pp.37-46, 2013 {Non-patent document 7} Methods in Enzymology 514, pp.399-407, 2012 {non-patent document 8} Arch Med Sci 9, pp.166-171, 2013 {non-patent document 9} Frontiers in Endocrinology 4, pp.1-27, 2013 {non-patent document 10} Annintern Med 149, pp.601-611, 2008 {non-patent document 11} Gastric Cancer 17, pp.200-205, 2014 {non-patent document 12} Mol Nutr Food Res 52, pp.855-866, 2008 {non-patent document 13} Neurogastroenterol Motil 25, pp.e140-e150, 2013 {non-patent document 14} Journal of Cardiology 59, pp.8-13, 2012 {non-patent document 15} Curr Opin Clin Nutr Metab Care 16, pp.619-624, 2013 {Non-patent document 16} Endocrinology 153, pp.2436-2443, 2012 {Non-patent document 17} Biochemical and Biophysical Research Communications 389, pp.405-408, 2009 {Non-patent document 18} Drug Discovery Today 4, pp.497-506, 1999 {Non-patent document 19} Neurogastroenterol Motil 21, pp.71-77, 2009 {Non-patent document 20} Peptides 26, pp.1598-1601,2005,{Patent reference 1}KR 2014-7036310A.

[0005] It would therefore be desirable to find new compounds that modulate the action of ghrelin receptors. Summary of the invention

[0006] Technical issues

[0007] As a result of intensive studies to develop a ghrelin receptor agonist that binds to the ghrelin receptor with very high specificity, the inventors of the present invention found that a triazole-based compound exhibits such efficacy, and completed the present invention.

[0008] Therefore, an object of the present invention is to provide a pharmaceutical composition for preventing or treating a disease mediated by ghrelin receptor, comprising a compound of the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0009] In addition, an object of the present invention is to provide a pharmaceutical composition for preventing or treating a disease mediated by ghrelin receptor, which is composed of a compound of the following Formula 1 or a pharmaceutically acceptable salt thereof.

[0010] In addition, the present invention aims to provide a pharmaceutical composition for preventing or treating a disease mediated by ghrelin receptor, which is essentially composed of a compound of the following formula 1 or a pharmaceutically acceptable salt thereof:

[0011] [Formula 1]

[0012]

[0013] in

[0014] R1 is hydrogen; a straight chain or branched chain alkyl group having 1 to 15 carbon atoms; or a substituted or unsubstituted alkylcarbonyl group having 1 to 5 carbon atoms, and

[0015] R2 is hydrogen; a straight or branched chain alkyl group having 1 to 15 carbon atoms; an alkenyl group having 2 to 10 carbon atoms; or an alkynyl group having 2 to 10 carbon atoms.

[0016] Another object of the present invention is to provide a food composition for preventing or improving diseases mediated by ghrelin receptor, comprising a compound of the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0017] Another object of the present invention is to provide a food composition for preventing or improving diseases mediated by ghrelin receptor, which is composed of the compound of the following formula 1 or a pharmaceutically acceptable salt thereof.

[0018] In addition, another object of the present invention is to provide a food composition for preventing or improving diseases mediated by ghrelin receptors, which is essentially composed of a compound of the following formula 1 or a pharmaceutically acceptable salt thereof:

[0019] [Formula 1]

[0020]

[0021] in

[0022] R1 is hydrogen; a straight chain or branched chain alkyl group having 1 to 15 carbon atoms; or a substituted or unsubstituted alkylcarbonyl group having 1 to 5 carbon atoms, and

[0023] R2 is hydrogen; a straight or branched chain alkyl group having 1 to 15 carbon atoms; an alkenyl group having 2 to 10 carbon atoms; or an alkynyl group having 2 to 10 carbon atoms.

[0024] Another object of the present invention is to provide a compound of the following formula 2 or a salt thereof:

[0025] [Formula 2]

[0026]

[0027] in

[0028] R1 is hydrogen; a straight chain or branched chain alkyl group having 1 to 15 carbon atoms; or a substituted or unsubstituted alkylcarbonyl group having 1 to 5 carbon atoms.

[0029] Another object of the present invention is to provide use of the compound of formula 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease mediated by ghrelin receptor.

[0030] Another object of the present invention is to provide a method for treating a disease mediated by ghrelin receptor, which comprises 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.

[0031] Solution to the problem

[0032] In order to achieve the above object of the present invention, the present invention provides a pharmaceutical composition for preventing or treating a disease mediated by ghrelin receptor, comprising a compound of the following formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0033] In addition, the present invention provides a pharmaceutical composition for preventing or treating a disease mediated by ghrelin receptor, which is composed of a compound of the following formula 1 or a pharmaceutically acceptable salt thereof.

[0034] In addition, the present invention provides a pharmaceutical composition for preventing or treating a disease mediated by a ghrelin receptor, which is essentially composed of a compound of the following formula 1 or a pharmaceutically acceptable salt thereof:

[0035] [Formula 1]

[0036]

[0037] in

[0038] R1 is hydrogen; a straight chain or branched chain alkyl group having 1 to 15 carbon atoms; or a substituted or unsubstituted alkylcarbonyl group having 1 to 5 carbon atoms, and

[0039] R2 is hydrogen; a straight or branched chain alkyl group having 1 to 15 carbon atoms; an alkenyl group having 2 to 10 carbon atoms; or an alkynyl group having 2 to 10 carbon atoms.

[0040] In order to achieve another object of the present invention, the present invention provides a food composition for preventing or improving diseases mediated by ghrelin receptor, comprising a compound of the following formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0041] In addition, the present invention provides a food composition for preventing or improving a disease mediated by a ghrelin receptor, which is composed of a compound of the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0042] In addition, the present invention provides a food composition for preventing or improving diseases mediated by ghrelin receptors, which is essentially composed of a compound of the following formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

[0043] [Formula 1]

[0044]

[0045] in

[0046] R1 is hydrogen; a straight chain or branched chain alkyl group having 1 to 15 carbon atoms; or a substituted or unsubstituted alkylcarbonyl group having 1 to 5 carbon atoms, and

[0047] R2 is hydrogen; a straight or branched chain alkyl group having 1 to 15 carbon atoms; an alkenyl group having 2 to 10 carbon atoms; or an alkynyl group having 2 to 10 carbon atoms.

[0048] 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:

[0049] [Formula 2]

[0050]

[0051] in

[0052] R1 is hydrogen; a straight chain or branched chain alkyl group having 1 to 15 carbon atoms; or a substituted or unsubstituted alkylcarbonyl group having 1 to 5 carbon atoms.

[0053] In order to achieve another object of the present invention, the present invention provides use of the compound of formula 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease mediated by ghrelin receptor.

[0054] To achieve another object of the present invention, the present invention provides a method for treating a disease mediated by 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.

[0055] Hereinafter, the present invention will be described in detail.

[0056] The present invention provides a pharmaceutical composition for preventing or treating a disease mediated by a ghrelin receptor, comprising a compound of the following formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

[0057] [Formula 1]

[0058]

[0059] in

[0060] R1 is hydrogen; a straight chain or branched chain alkyl group having 1 to 15 carbon atoms; or a substituted or unsubstituted alkylcarbonyl group having 1 to 5 carbon atoms, and

[0061] R2 is hydrogen; a straight or branched chain alkyl group having 1 to 15 carbon atoms; an alkenyl group having 2 to 10 carbon atoms; or an alkynyl group having 2 to 10 carbon atoms.

[0062] In the present invention, "alkyl" refers to a straight or branched hydrocarbon having 1 to 15 carbon atoms. Representative examples of the alkyl group include 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, but the present invention is not limited thereto.

[0063] As used herein, the term "carbonyl" refers to a -C(O)- group.

[0064] In the present invention, "alkylcarbonyl" refers to an alkyl group attached to the parent molecular moiety through a carbonyl group as defined above. Representative examples of alkylcarbonyl include acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl and 1-oxopentyl, but the present invention is not limited thereto.

[0065] In the present invention, when the alkylcarbonyl group is a "substituted" alkylcarbonyl group, it may be substituted with one or more substituents selected from hydroxy, halogen, cyano, nitro and amino.

[0066] In the present invention, "alkenyl" refers to a straight or branched hydrocarbon having 2 to 10 carbon atoms containing at least one carbon-carbon double bond formed by removing two hydrogen atoms. Representative examples of alkenyl include vinyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl and 3-decenyl, but the present invention is not limited thereto.

[0067] In the present invention, "alkynyl" refers to a straight or branched hydrocarbon group having 2 to 10 carbon atoms containing at least one carbon-carbon triple bond. Representative examples of alkynyl include ethynyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl and 1-butynyl, but the present invention is not limited thereto.

[0068] Preferably, in the present invention, R1 may be hydrogen or acetyl, and R2 may be an alkyl group having 1 to 15 carbon atoms. More preferably, in the present invention, R1 may be hydrogen, and R2 may be an alkyl group having 4 to 15 carbon atoms. Even more preferably, in the present invention, R1 may be hydrogen, and R2 may be an alkyl group having 6 to 12 carbon atoms. Most preferably, in the present invention, R1 may be hydrogen, and R2 may be an alkyl group having 9-12 carbon atoms.

[0069] Specifically, in the present invention, the compound of the above formula 1 can be 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-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-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.

[0070] According to one embodiment of the present invention, it is confirmed that the compound of the above formula 1 exhibits very strong binding force to the ghrelin receptor and has very high binding specificity to the ghrelin receptor. Therefore, it can be expected that the compound of the above formula 1 has the effect of preventing or treating diseases mediated by the ghrelin receptor as a ghrelin receptor agonist, and does not affect the activity of other receptors, thereby showing low side effects.

[0071] The action of the endogenous ligand ghrelin at the ghrelin receptor has been shown to result in potent growth hormone release, appetite stimulation, gastric motility, gastric acid secretion, positive cardiovascular effects, and direct bone formation. Thus, ghrelin receptor agonists may have good results in the treatment of growth hormone deficiency, eating disorders, gastrointestinal diseases, cardiovascular diseases, osteoporosis, aging, and catabolic or chronic wasting syndromes. Ghrelin receptor agonists may also have beneficial effects in the treatment of sleep disorders.

[0072] Certain diseases associated with and therefore mediated by the ghrelin receptor and for which ghrelin receptor agonists may be beneficial include obesity and obesity-related risk factors. In addition, obesity-related risk factors include diabetes, diabetes-related complications, metabolic syndrome, and cardiovascular abnormalities (e.g., atherosclerosis and dyslipidemia), but the present invention is not limited thereto.

[0073] Other diseases and / or conditions mediated by the ghrelin receptor include: treating growth hormone deficiency, increasing muscle mass, increasing bone density, treating male and female sexual dysfunction, promoting weight gain, promoting weight maintenance, promoting appetite (e.g., promoting weight gain, weight maintenance, or appetite enhancement is useful for patients suffering from or undergoing treatment for a disease associated with weight loss). Examples of diseases or conditions associated with weight loss include anorexia, bulimia, cancer cachexia, AIDS, wasting disease, cachexia, and wasting in frail elderly people. Examples of treatments associated with weight loss include chemotherapy, radiotherapy, temporary or permanent immobilization, and dialysis.

[0074] Other diseases or conditions include improving sleep disorders, congestive heart failure, metabolic disorders, memory loss, breast cancer, thyroid cancer, ischemic nerve or muscle damage.

[0075] Eating disorders include anorexia, including restrictive, binge eating, and eliminative subtypes; bulimia, including eliminative and non-eliminative subtypes; obesity; compulsive eating disorder; binge eating disorder; and other unspecified eating disorders.

[0076] Gastrointestinal disorders that ghrelin receptor agonists are effective in treating include gastric obstruction, gastric ulcers, inflammatory bowel diseases such as Crohn's disease, and ulcerative colitis. The compounds of the present invention are useful in treating symptoms associated with esophageal reflux and / or dyspepsia with or without appetite / metabolic cachexia, and in treating symptoms associated with constipation such as paralytic ileus or pseudo-obstruction and constipation-predominant irritable bowel syndrome.

[0077] Cardiovascular diseases include heart failure and dilated cardiomyopathy.

[0078] Catabolic states or chronic wasting syndromes may occur in postoperative patients and also include AIDS-related wasting syndrome and cancer-related wasting syndromes such as cancer cachexia.

[0079] Ghrelin receptor agonists are known to promote gastric acid secretion (see KR2014-7036310A). Therefore, the effect of enhancing gastric acid secretion indicates that the ghrelin receptor agonist of the present invention can effectively treat various diseases accompanied by low or no gastric acid secretion.

[0080] In the present invention, acidosis is not particularly limited to certain types and may include age-related acidosis accompanying the aging process; acidosis associated with chronic gastritis; anemic hypoxia accompanied by anemic symptoms; hypoxia associated with partial gastrectomy; anemia associated with calcium absorption; acidosis associated with vitamin D absorption; hypoxia associated with calcitonin synthesis; and drug-induced hypoxia.

[0081] In one aspect of the present invention, the compound of Formula 1 above can exhibit the effect of preventing or treating a ghrelin receptor disease selected from the following: cancer anorexia or cachexia; cachexia or anorexia induced by anticancer drugs; hyperalgesia induced by anticancer drugs; COPD or COPD cachexia; sarcopenia; eating disorders; weight loss; general weakness after cancer surgery; chronic respiratory tract infection; inflammation; IBD; FD; constipation; diabetic gastroparesis; heart failure; myocardial infarction; diabetic neuropathy; growth hormone deficiency; defecation disorders in patients with spinal cord injury; postoperative ileus; hypoxia; and morphine-induced intestinal obstruction.

[0082] In the present invention, examples of pharmaceutically acceptable salts include acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid) and salts formed with organic acids (e.g., 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, naphthalenesulfonic acid, naphthalenedisulfonic acid and polygalacturonic acid). The compound may also be administered in the form of pharmaceutically acceptable quaternary ammonium salts known to those skilled in the art, particularly chlorides, bromides, iodides, -O-alkyls, toluenesulfonates, mesylates, sulfonates, phosphates or carboxylates (e.g., benzoates, succinates, acetates, glycolates, maleates, malates, fumarates, citrates, tartrates, ascorbates, cinnamates, mandelates and diphenylacetates), but the present invention is not limited thereto.

[0083] The pharmaceutical composition according to the present invention can be formulated in a suitable form with a pharmaceutically acceptable carrier, and may further comprise an excipient or diluent. In the above, "pharmaceutically acceptable" refers to a non-toxic composition that is physiologically acceptable and does not cause allergic reactions such as gastrointestinal disorders and dizziness or similar reactions when administered to humans.

[0084] 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 and stearic acid. In addition, carriers for parenteral administration may include water, suitable oils, saline, aqueous glucose and ethylene glycol, and additionally include stabilizers and preservatives. Suitable stabilizers include antioxidants such as sodium bisulfite, sodium sulfite and ascorbic acid. Suitable preservatives include benzalkonium chloride, methylparaben or propylparaben and chlorobutanol. The pharmaceutical composition of the present invention may also include lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers and suspending agents in addition to the above-mentioned components. Other pharmaceutically acceptable carriers and agents may refer to those known in the art.

[0085] The composition of the present invention can be administered to mammals including humans by any method. For example, it can be administered orally or parenterally. Parenteral administration methods include intravenous administration, intramuscular administration, intraarterial administration, intramedullary administration, intrathecal administration, intracardiac administration, transdermal administration, subcutaneous administration, intraperitoneal administration, intranasal administration, enteral administration, topical administration, sublingual administration or rectal administration, but the present invention is not limited to these.

[0086] According to the above-mentioned administration route, the pharmaceutical composition of the present invention can be formulated into a preparation for oral administration or parenteral administration.

[0087] In the case of oral administration preparations, the compositions of the present invention can be formulated into powders, granules, tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions, etc. by using methods known in the art. For example, as oral administration preparations, tablets or dragees can be obtained by mixing active ingredients with solid excipients, grinding the mixture, adding suitable adjuvants thereto and processing the mixture into a granular mixture. The example of suitable excipient includes sugar (for example, lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol), starch (for example, corn starch, wheat starch, rice starch and potato starch), cellulose (for example, cellulose, methylcellulose, sodium carboxymethylcellulose and hydroxypropyl methylcellulose) and fillers such as gelatin and polyvinyl pyrrolidone. In addition, cross-linked polyvinyl pyrrolidone, agar, alginic acid or sodium alginate can be added as disintegrating agents. In addition, the pharmaceutical composition of the present invention can also include anticoagulants, lubricants, wetting agents, flavoring agents, emulsifiers and preservatives.

[0088] In the case of preparations for parenteral administration, they can be formulated in the form of injections, creams, lotions, external ointments, oils, moisturizers, gels, aerosols and nasal inhalants by methods known in the art. These preparations are described in formulations generally known in all pharmaceutical chemistry fields.

[0089] The total effective amount of the composition of the present invention can be applied to the patient in a single dose, or can be applied to the patient by a long-term multiple dose administration composition of the fractionated treatment scheme. The amount of active ingredient contained in the pharmaceutical composition of the present invention can vary according to the severity of the disease. The total dose of the pharmaceutical composition of the present invention can preferably be about 0.01 μg to 10,000 mg per kg of patient body weight per day, most preferably 0.1 μg to 1000 mg. However, the dosage of the pharmaceutical composition is determined by considering the formulation method, route of administration and number of treatments and other various factors (e.g., the patient's age, weight, health status, sex, severity of disease, diet and excretion rate). Therefore, taking this into account, those skilled in the art will be able to determine the appropriate effective dose of the composition of the present invention. As long as the pharmaceutical composition of the present invention shows the effect of the present invention, its preparation, route of administration and method of administration are not particularly limited.

[0090] The present invention also provides a food composition for preventing or improving diseases mediated by ghrelin receptors, comprising a compound of the following formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

[0091] [Formula 1]

[0092]

[0093] in

[0094] R1 is hydrogen; a straight chain or branched chain alkyl group having 1 to 15 carbon atoms; or a substituted or unsubstituted alkylcarbonyl group having 1 to 5 carbon atoms, and

[0095] R2 is hydrogen; a straight or branched chain alkyl group having 1 to 15 carbon atoms; an alkenyl group having 2 to 10 carbon atoms; or an alkynyl group having 2 to 10 carbon atoms.

[0096] The food composition according to the present invention includes all types of functional foods, nutritional supplements, health foods and food additives. The above types can be produced in various forms according to methods conventionally known in the art.

[0097] For example, as health food, food composition of the present invention can be produced in the form of tea to be consumed, fruit juice or beverage, or made into granular, encapsulated or powdered to be consumed. In addition, food composition of the present invention can be produced in the form of composition by mixing with known material or active ingredient having prevention, improvement or treatment of neurodegenerative disease or depression effect.

[0098] In addition, functional foods can be produced by adding the food composition of the present invention to beverages (e.g., alcoholic beverages), fruits and processed foods thereof (e.g., canned fruits, bottled fruits, jams and marmalades), fish, meat and processed foods thereof (e.g., ham and sausage corn beef), bread and noodles (e.g., udon noodles, soba noodles, ramen noodles, pasta and macaroni), fruit juices, various beverages, biscuits, toffees, dairy products (e.g., butter and cheese), edible vegetable oils, margarine, vegetable proteins, retorted foods, frozen foods, various seasonings (e.g., soybean paste, soy sauce and sauces).

[0099] Based on the total weight of the final food, the amount of the food composition of the present invention is preferably 0.01 to 50 weight %, but the present invention is not limited thereto. In order to use the food composition of the present invention in the form of a food additive, it can be produced and used in the form of a powder or a concentrate.

[0100] The present invention also provides a compound of the following formula 2 or a salt thereof:

[0101] [Formula 2]

[0102]

[0103] in

[0104] R1 is hydrogen; a straight chain or branched chain alkyl group having 1 to 15 carbon atoms; or a substituted or unsubstituted alkylcarbonyl group having 1 to 5 carbon atoms.

[0105] In the above formulae, the alkyl group and the alkylcarbonyl group can be used in the same manner as described above.

[0106] Preferably, R1 is hydrogen or acetyl.

[0107] Most preferably, the compound of Formula 2 may be 2-amino-2-(1-decyl-1H-1,2,3-triazol-4-yl)propane-1,3-diol.

[0108] The compound of formula 2 provided by the present invention is characterized in that it is used as a specific agonist of ghrelin receptor and can be used as a preventive or therapeutic agent for diseases mediated by ghrelin receptor.

[0109] 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.

[0110] Examples of these salts include acid addition salts formed from inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid) and salts formed from organic acids (e.g., 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, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid), but the invention is not limited thereto. The compounds may also be administered in the form of pharmaceutically acceptable quaternary ammonium salts known to those skilled in the art, particularly including chlorides, bromides, iodides, -O-alkyls, toluenesulfonates, mesylates, sulfonates, phosphates, or carboxylates (e.g., benzoates, succinates, acetates, glycolates, maleates, malates, fumarates, citrates, tartrates, ascorbates, cinnamates, mandelates, and diphenylacetates).

[0111] In order to achieve another object of the present invention, the present invention provides use of a compound of formula 1 or a pharmaceutically acceptable salt thereof in preparing a medicament for treating a disease mediated by a ghrelin receptor.

[0112] To achieve another object of the present invention, the present invention provides a method for treating a disease mediated by ghrelin receptor, comprising administering an effective amount of a composition comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof to an individual in need thereof.

[0113] The "effective amount" of the present invention refers to an amount that, when administered to an individual, shows the effect of improving, treating, preventing, detecting, diagnosing, inhibiting or reducing diseases mediated by the gastrin receptor, and "individual" refers to animals, preferably mammals, especially animals including humans, and may also be cells, tissues, organs or other substances derived from animals. The individual may be a patient who needs such an effect.

[0114] The "treatment" of the present invention comprehensively refers to improving diseases or disease symptoms mediated by ghrelin receptors, which may include curing, substantially preventing or improving the condition of the disease, or alleviating, curing or preventing one or most symptoms caused by the disease, but the present invention is not limited to these.

[0115] In the present specification, the term "comprising" has the same meaning as "including" or "characterized by", and the composition or method according to the present invention does not exclude additional ingredients or method steps not specifically mentioned. In addition, the term "consisting of..." means excluding additional elements, steps or ingredients not specifically described. The term "consisting essentially of..." means that the composition or method includes the materials or steps, and may include materials or steps that do not substantially affect its basic characteristics.

[0116] Beneficial Effects of the Invention

[0117] The compounds provided by the present invention show strong binding ability to the ghrelin receptor with very high specificity, and therefore, may be very useful for developing preventive or therapeutic agents for diseases mediated by the ghrelin receptor. BRIEF DESCRIPTION OF THE DRAWINGS

[0118] Figure 1 is a graph showing EC50, which may represent 50% of intracellular calcium influx according to the concentration of ghrelin and triazole compounds (KARI001, KARI101, and KARI201) in human embryonic kidney 293 (HEK293) cells overexpressing ghrelin receptor.

[0119] Figure 2 It is a graph showing changes in ghrelin receptor subsignaling factors by treatment with 10 mM ghrelin and triazole compounds (KARI001, KARI101 and KARI201) in ghrelin receptor-overexpressing HEK293 cells (n=3, **p<0.01, ***p<0.001).

[0120] Figure 3 is a graph showing the efficacy of cellular influx of ghrelin receptor by treatment with 10 mM ghrelin and triazole compounds (KARI001, KARI101, and KARI201) in HEK293 cells overexpressing ghrelin receptor (n=6, **p<0.01).

[0121] Figure 4a and Figure 4b is a graph showing the efficacy of a triazole compound (KARI201) as an agonist or antagonist of 170 G protein-coupled receptors including the ghrelin receptor.

[0122] Figure 5a and Figure 5b It is a graph showing the effect of improving delayed gastric emptying, which can evaluate gastric motility in a postoperative ileus (POI) mouse model after oral administration of various concentrations of a triazole compound (KARI 201) (n=5-10, *p<0.05, **p<0.01).

[0123] Figure 6a and Figure 6b It is a graph showing the effect of improving delayed gastric emptying, which can evaluate gastric motility function in a postoperative ileus (POI) mouse model after oral administration of various concentrations of a triazole compound (KARI101) (n=5, **p<0.01, ***p<0.001).

[0124] Figures 7a to 7d It shows the colon transit time of stool ( Figure 7a ), the amount and weight of feces ( Figure 7b ), feed intake ( Figure 7c ) and weight ( Figure 7d ), which can evaluate colonic motility in a postoperative ileus (POI) mouse model after oral administration of 30 mg / kg of a triazole compound (KARI 201) (n=4, ***p<0.001, ****p<0.0001).

[0125] Figures 8a to 8d It shows the colon transit time of stool ( Figure 8a ), the amount and weight of feces ( Figure 8b ), feed intake ( Figure 8c ) and weight ( Figure 8d ), which can evaluate colonic motility in a postoperative ileus (POI) mouse model after oral administration of 30 mg / kg of a triazole compound (KARI 101) (n=4, *p<0.05, **p<0.01, ***p<0.001).

[0126] Figures 9a to 9c To investigate the efficacy of triazole compounds (KARI 101 and KARI 201) in a mouse model of cancer cachexia ( Figure 9a ) and the effect of improving muscle strength and function after oral administration of 10 mg / kg of the compound ( Figure 9b ) (n=7-8, *p<0.05, **p<0.01, ***p<0.001).

[0127] Figures 10a to 10d Figure 2 shows the size of cancer in a mouse model of cancer cachexia over the duration of oral administration of 10 mg / kg of triazole compounds (KARI 101 and KARI 201). Fig.10a ),weight( Fig.10b ), feed intake ( Fig.10c ) and average daily feed intake ( Fig.10d )(n=9, **p<0.01, ****p<0.0001).

[0128] Figures 11a to 11d The total fat weight ( Fig.11a ), visceral fat weight (Table 11b), subcutaneous fat weight ( Fig.11c ) and muscle weight ( Fig.11d ) (n=6-9, *p<0.05, **p<0.01, ****p<0.0001). DETAILED DESCRIPTION

[0129] Hereinafter, the present invention will be described in detail through the following embodiments. However, the following embodiments are only for illustrating the present invention, and the present invention is not limited to these.

[0130] <Experimental Materials and Methods>

[0131] 0. Synthesis of compounds

[0132] According to the existing literature (Korean Patent No. 2017324), substances KARI001 and KARI201 were produced and synthesized. Ghrelin protein used as a positive control was purchased from TORIS.

[0133] KARI001: 2-Amino-2-(1-dodecyl-1H-1,2,3-triazol-4-yl)propane-1,3-diol

[0134] KARI201: 2-amino-2-(1-nonyl-1H-1,2,3-triazol-4-yl)propane-1,3-diol

[0135] The material KARI101, the compound 2-amino-2-(1-decyl-1H-1,2,3-triazol-4-yl)propane-1,3-diol, was prepared by the following series of methods.

[0136] 0-1. Scheme 1: Synthesis of 1-azidodecane

[0137]

[0138] To synthesize 1-azidodecane of Scheme 1, sodium azide (4.9 g, 75 mmol, 2 equivalents) was added to a solution of 1-bromodecane (9.9 g, 37 mmol) of Formula 1 in DMF (50 ml). The mixture was stirred at room temperature for 2 days, and ice water (200 ml) was added thereto to extract with ether. The organic layer was dried with H2O, brine and MgSO4 and concentrated to obtain 1-azidodecane (6.2 g, 91%) of Formula 2.

[0139] 1 H NMR (400MHz, CDCl3): δ3.28(t,2H),1.62(m,2H,),1.40-1.29(m,14H),0.91(t,3H)

[0140] 0-2. Scheme 2: Synthesis of 2-amino-2-(hydroxymethyl)propane-1,3-diol

[0141]

[0142] To synthesize 2-amino-2-(hydroxymethyl)propane-1,3-diol of Scheme 2, Boc2O (49.5 g, 1.1 eq) was added to a suspension of tris(hydroxymethyl)-amino-methane (25.0 g, 0.206 mol) of Formula 3 in DMF (500 ml). After the mixture was stirred at room temperature for 2 hours, 2,2-dimethoxypropane (30.4 ml, 1.2 eq) and p-TsOH.H2O (2.0 g, 0.05 eq) were added thereto. The mixture was stirred at room temperature for 18 hours and diluted with Et2O (500 ml). The organic layer was washed with saturated NaHCO3 solution (300 ml) and brine (200 ml). The organic layer was dried over MgSO4 and concentrated. The residue was crystallized with n-hexane to obtain tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate of Formula 4 (32.0 g, 59.4%) as a white solid.

[0143] 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)

[0144] 0-3. Scheme 3: Synthesis of 2-amino-2-(hydroxymethyl)propane-1,3-diol

[0145]

[0146] In order to synthesize 5-formyl-2,2-dimethyl-1,3-dioxane-5-ylcarbamic acid tert-butyl ester of scheme 3, a solution of oxalyl chloride (33.4ml, 3.17 equivalents) in anhydrous MC (340ml) was mixed with DMSO (43.7ml, 5 equivalents). The mixture was stirred for 15 minutes and then mixed with 5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-5-ylcarbamic acid tert-butyl ester (32.0g, 0.123mol) of formula 4 in anhydrous MC (340ml). After the mixture was stirred for 2 hours, Et3N (171ml, 10 equivalents) was added thereto. The mixture was stirred for 10 minutes, then the cooling bath was removed and the mixture was placed at room temperature. The light brown suspension was diluted with EA (300ml) and washed with 10% NH4OH (1,500ml). The organic layer was concentrated and applied to SiO2 column chromatography, and the residue was eluted by EA / n-hexane = 1 / 10 to obtain tert-butyl 5-formyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate of Formula 5 (15.0 g, 47.2%) as a white solid.

[0147] 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)

[0148] 0-4. Scheme 4: Synthesis of 2-amino-2-(hydroxymethyl)propane-1,3-diol

[0149]

[0150] To synthesize tert-butyl 5-ethynyl-2,2-dimethyl-1,3-dioxane-5-ylcarbamate of Scheme 4, dimethyl-2-oxopropyl-phosphonate (1.6 g, 1.02 eq) was added to a suspension of acetonitrile (50 ml) containing K2CO3 (3.0 g, 2.25 eq) and p-toluenesulfonyl azide (14% solution in toluene, 15.8 ml, 1.05 eq), and the mixture was vigorously stirred at room temperature for 2.5 hours. A solution of tert-butyl 5-formyl-2,2-dimethyl-1,3-dioxane-5-ylcarbamate (2.5 g, 9.64 mmol) of Formula 5 contained in methanol (40 ml) was added to the first reaction mixture. After adding K2CO3 (2.7g, 2.06 equivalents), the mixture was stirred for 1.5 hours and concentrated under reduced pressure, and the residue was diluted with MC (200ml) and H2O (200ml). The organic layer was washed with H2O (200ml), dried with MgSO4, and concentrated under reduced pressure. The residue was eluted by EA / n-hexane=1 / 9 and applied to SiO2 column chromatography to obtain 5-ethynyl-2,2-dimethyl-1,3-dioxane-5-ylcarbamic acid tert-butyl ester (2.3g, 93.4%) of formula 6 as a white solid.

[0151] 1 H NMR (400 MHz, C D Cl3): δ5.15(s,1H),4.05-3.95(m,4H),2.43(s,1H),1.48-1.38(m,15H)

[0152] 0-5. Scheme 5: Synthesis of 2-amino-2-(1-decyl-1H-1,2,3-triazol-4-yl)propane-1,3-diol hydrochloride

[0153]

[0154] To synthesize 2-amino-2-(1-decyl-1H-1,2,3-triazol-4-yl)propane-1,3-diol (which is KARI101 of Scheme 5), CuSO4.5H2O (1.56 g, 6 mmol) was added to a solution of tert-butyl 5-ethynyl-2,2-dimethyl-1,3-dioxane-5-ylcarbamate (4.0 g, 15 mmol), 1-azidodecane (3.16 g, 17 mmol) of Scheme 1, sodium L-ascorbate (4.03 g, 20 mmol), t-BuOH (60 ml), H2O (128 ml) and MC (104 ml). The two-phase 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 eluted by EA / n-hexane = 1 / 6 and applied to SiO2 column chromatography to obtain a solid (6.5 g). The obtained 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 obtain 2-amino-2-(1-decyl-1H-1,2,3-triazol-4-yl)propane-1,3-diol (2.6 g, 52.4%, molecular weight 298.4) as a white solid.

[0155] 1 H NMR (500 MHz, methanol-d4): δ8.06 (s, 1H), 4.41 (t, 2H), 3.95 (dd, J=20 Hz, 15 Hz, 4H), 1.91 (t, 2H), 1.29-1.33 (m, 14H), 0.89 (t, 3H)

[0156] 13 C NMR (500 MHz, methanol-d4): δ 144.9, 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

[0157] 1. Cell Culture

[0158] Human embryonic kidney 293 (HEK293) 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 infected with human ghrelin receptor cDNA vector (hGHSRa-pcDNA3.1+, cDNA Resource Center) and cultured for 48 hours. Thereafter, each triazole compound synthesized in the cell line and ghrelin were treated to evaluate the efficacy as a ghrelin receptor agonist in terms of intracellular calcium influx, ghrelin receptor subsignaling factors, and ghrelin receptor cellular influx.

[0159] 2. Intracellular calcium influx experiment

[0160] HEK293 cells overexpressing ghrelin receptors were treated with Fluo-2AM (a calcium-specific fluorescent factor) and washed twice with a wash buffer containing 20mM Hepes, 1mM CaCl2, 1mM MgCl2 and 0.7mg / mL probenecid after 1 hour. After treating the cells with 100ul of wash buffer, the fluorescently labeled intracellular calcium was imaged for 1 minute at an excitation wavelength of 485nm and an emission wavelength of 520nm with a shutter interval of 10 seconds under a laser scanning confocal microscope equipped with temperature and humidity control equipment. Thereafter, ghrelin and triazole compounds were added for each concentration and then imaged under the same conditions. Based on the fluorescence intensity when not treated with the compound, it was quantified by calculating the fluorescence intensity of intracellular calcium treated with the compound.

[0161] 3. Immunofluorescence

[0162] HEK293 cells overexpressing ghrelin receptor were treated with 10 mM ghrelin and triazole compounds, respectively, and after 1 hour, the cells were fixed and cultured with anti-ghrelin receptor for ghrelin receptor (rabbit, 1:500, abcam). One day later, the cells were washed and cultured with anti-rabbit 488 antibody for 1 hour and analyzed by using a laser scanning confocal microscope equipped with Fluoview SV1000 imaging software (Olympus FV1000, Japan). Metamorph software (Molecular Devices) was used to quantify the area percentage of the stained area of ​​ghrelin receptor introduced into the cells.

[0163] 4. Western Blot

[0164] Protein expression of pAMPK, AMPK, pPI3K, PI3K, pERK and ERK was analyzed by Western blotting. Antibodies to pAMPK, AMPK, pPI3K, PI3K, pERK, ERK (cell signaling) and β-actin (Santa Cruz) were used and density quantification was performed using ImageJ software (US National Institutes of Health).

[0165] 5. Analysis of G protein-coupled receptor agonists and antagonists

[0166] The efficacy of triazole compounds (10 mM) as agonists and antagonists against a total of 170 types of G protein-coupled receptors was performed by Eurofins Discovery.

[0167] 6. Establishment of a mouse model of postoperative intestinal obstruction

[0168] Mice aged 6-8 weeks were fasted for one day and then anesthetized with a mixture of ketamine and xylazine. The abdomen and peritoneum were then cut open and the small intestine was exposed on a sterile gauze pad. A sterile cotton swab was used to operate from the duodenum to the cecum for 5 minutes. After the operation, the abdomen was sutured and the mice were allowed to recover for 4 hours in a cage maintained at 32 degrees.

[0169] 7. Assessment of delayed gastric emptying

[0170] Triazole compounds (10 mg / kg, 20 mg / kg and 30 mg / kg) were orally administered 20 hours after POI surgery. 4 hours later, 1.5% methylcellulose aqueous solution and 0.05% phenol red (Sigma) were orally administered. 30 minutes later, the stomach of the mouse was removed and homogenized in 2ml of 0.1N NaOH solution. 3ml of 0.1N NaOH solution was added and centrifuged at 3000rpm for 10 minutes at 4 degrees. After adding 100ml of 20% trichloroacetic acid to the supernatant, the mixture was centrifuged at 3000rpm for 10 minutes at 4 degrees. After adding 400ml of 0.5N NaOH solution to 500ml of supernatant, the absorbance was measured at 562nm. For baseline control, the stomach was removed immediately after oral administration of 1.5% methylcellulose aqueous solution and 0.05% phenol red, and the absorbance in the obtained sample was measured by the above method. The percentage of delayed gastric emptying was calculated by (1-(absorbance of test sample) / (absorbance of baseline control)×100.

[0171] 8. Assessment of Colonic Transit Time

[0172] In order to evaluate the colonic transit time of feces, 200ul trypan blue dye was injected into the proximal colon after POI surgery and before suturing. Triazole compounds (30mg / kg) were orally administered 4 hours after POI surgery. Mice were transferred to metabolic cages, and the weighed feed was administered to them, and the time of the first feces appearance with trypan blue dyeing was measured within 24 hours. At the 24th hour, the quantity and weight of feces were measured, and the weight of the consumed feed and the body weight of mice were measured.

[0173] 9. Establishment of Cancer Cachexia Model

[0174] To establish the cancer acinar 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. 6Cells were injected subcutaneously into the right side of the abdomen of 10-week-old mice. After cell injection, the size of the cancer growing in the right abdomen, body weight and feed intake were measured once each time, and 10 mg / kg of triazole compound was orally administered every day from the 9th day. On the 18th day after cancer cell injection, a 1-day grip strength test and a rotating rod test were performed to evaluate muscle function. On the 20th day, the subcutaneous fat, visceral fat and muscles (femur, calf) of the mice were separated and weighed.

[0175] 10. Grip strength test and rotarod test for assessing muscle function

[0176] In order to evaluate muscle function, grip strength test is carried out by making mice grasp, and method is to make mice grasp the metal grid connected on the grip strength meter, grab the tail of mice, and pull it horizontally from the back.The force applied to the metal grid before losing grasp is recorded in the measuring instrument as the maximum pulling force in g, and the whole process is carried out 9 times to record the mean value for each individual.In the rotarod test (Ugo Basile, Comerio, VA, Italy), at least three rotarod movements are carried out with a rotating speed of 4rpm by using a machine equipped with a rod with a diameter of 3cm of suitable processing, so as to provide grasping to measure the tolerance time of the tested animal in seconds and record the mean value.Each rotarod behavior experiment is no more than 5 minutes at a time.

[0177] 11. Statistical Analysis

[0178] Tukey's HSD test and repeated measures analysis of variance test were performed according to the SAS statistical software package (version 9.1; SAS Institute Inc., Cary, NC) for comparison of multiple groups. *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001 were considered significant.

[0179] <Experimental Results>

[0180] 1. Confirmation of its action as a ghrelin receptor agonist based on the increase in intracellular calcium influx

[0181] To confirm the efficacy of the triazole compounds as ghrelin receptor agonists, changes in intracellular calcium influx, which is the main function of ghrelin, were first measured. HEK293 cells overexpressing human ghrelin receptor were reacted with a calcium-labeled fluorescent factor for 1 hour and then treated with each concentration of ghrelin and the triazole compounds KARI001, KARI101, and KARI201. As a result, it was confirmed that intracellular calcium influx increased with increasing concentrations of the three triazole compounds (see Figure 1). EC50, i.e., the concentration capable of inducing 50% of intracellular calcium influx, was determined to be ghrelin = 39.45 nM, KARI001 = 128.3 nM, KARI101 = 188.5 nM, and KARI201 = 272.9 nM.

[0182] That is, it has been confirmed that these three triazole compounds can act as ghrelin receptor agonists to induce intracellular calcium influx.

[0183] 2. Acts as a ghrelin receptor agonist by regulating the G protein-dependent subtype of the ghrelin receptor

[0184] It is known in the art that the ghrelin receptor is a G protein-coupled receptor, and when ghrelin binds to the ghrelin receptor, the activity of different sub-signaling factors is regulated according to three main types of G proteins. For example, Gaq-dependent signaling increases intracellular calcium influx, thereby increasing AMPK factor phosphorylation, and Gai / o-dependent signaling increases PI3K factor phosphorylation. B-arrestin-dependent signaling increases ERK factor phosphorylation or induces intracellular influx of ghrelin receptor (FASEB J. 2019; 33(1): 518-531).

[0185] First, it was examined whether these three triazole compounds can regulate the phosphorylation of the G protein-dependent signal transduction sub-factor of the ghrelin receptor. HEK293 cells overexpressing the human ghrelin receptor were treated with 10 mM ghrelin and the three triazole compounds, and after 1 hour, the cell proteins were extracted and examined by using Western blotting whether the sub-factor was phosphorylated. As a result, it was observed that these three triazole compounds could increase the phosphorylation of the AMPK factor (see Figure 2 ).

[0186] Furthermore, to confirm the role of ghrelin receptor in cellular influx, HEK293 cells overexpressing human ghrelin receptor were treated with 10 mM ghrelin and the three triazole compounds, and ghrelin receptor was cultured 1 hour later to examine whether it expressed intracellular ghrelin receptor. As a result, it was observed that cells not treated with ghrelin and the three triazoles expressed ghrelin receptor in the cell membrane, whereas cells treated with ghrelin and the three triazoles expressed ghrelin receptor in the perinuclear cytoplasm (see Figure 3 ).

[0187] That is, these three triazole compounds were found to be effective as agonists that were able to modulate both Gaq-dependent signaling and B-arrestin-dependent signaling of the ghrelin receptor.

[0188] 3. Effects of triazole compounds as ghrelin receptor-specific agonists

[0189] The G protein-coupled receptor family includes many types of receptors, including the ghrelin receptor. It was examined whether triazole compounds have efficacy as agonists or antagonists of different types of G protein-coupled receptors. Different cell lines expressing a total of 170 G protein-coupled receptors (including the ghrelin receptor) were treated with 10 mM of the triazole compound KARI201 alone (agonist effect) or together with the ligand of each receptor (antagonist effect). As a result, it was confirmed that KARI201 exhibited 83.7% efficacy as a ghrelin receptor agonist only (see Figure 4a and Figure 4b ).

[0190] That is, from this result, it was found that the KARI201 triazole compound is effective as a ghrelin receptor-specific agonist.

[0191] 4. Effect of triazole compounds on improving delayed gastric emptying

[0192] To confirm the gastric motility promoting effect, which is one of the representative physiological effects of ghrelin as a ghrelin receptor, postoperative ileus (POI) mice were used. POI mice induced with ileus showed delayed gastric emptying effect compared with normal mice, and POI mice administered with KARI201 and KARI101 20 hours after POI surgery showed significant improvement in delayed gastric emptying with increasing concentrations (see Figure 5a , Figure 5b , Figure 6a and Figure 6b ).

[0193] That is, it was found that the triazole compounds KARI201 and KARI101 are ghrelin receptor agonists and are effective in improving delayed gastric emptying by improving gastric motility.

[0194] 5. Triazole compounds improve colonic motility

[0195] Based on the effects of the triazole compounds KARI201 and KARI101 in delaying gastric emptying, we examined whether they could improve the colonic transit time of feces in POI mice. Mice administered PBS 4 hours after POI surgery showed a prolonged colonic transit time of feces, whereas mice administered 30 mg / kg of KARI201 or KARI101 showed a significant decrease in the colonic transit time of feces (see Figure 7a and Figure 8a The amount and weight of stools were also increased by administration of KARI201 (see Figure 7b and Figure 8b ). Food intake also increased compared to POI mice administered PBS, whereas their body weight did not change (see Figure 7c , Figure 7d , Figure 8c and Figure 8d ).

[0196] That is, it was found that the triazole compounds KARI201 and KARI101, as ghrelin receptor agonists, also improve colonic motility, thereby effectively improving stool excretion time. Therefore, it was found that the triazole compounds can be very useful as preventive or therapeutic agents for ghrelin receptor-mediated diseases.

[0197] 6. Effect of triazole compounds on improving strength and function

[0198] Cancer cachexia mice were used to confirm the increase in feed intake, another physiological effect of ghrelin on ghrelin receptors, and thereby improve fat and muscle loss. To establish a cancer cachexia mouse model, CT26 cancer cells were subcutaneously injected into the right abdominal layer of 10-week-old mice. On day 9 after cell injection, cancer cell growth in the right abdomen was confirmed, and 10 mg / kg KARI101 and KARI201 were orally administered once a day. On day 18, grip strength test and rotarod test were performed to evaluate muscle strength function (see Figure 9a It has been confirmed that the muscle strength function of cancer cachexia mice injected with a vehicle is reduced, while the muscle strength function of cancer cachexia mice administered with KARI101 or KARI201 is significantly improved (see Figure 9b and Fig.9c ).

[0199] 7. Effects of triazole compounds on improving feed intake and fat and muscle loss

[0200] Based on the effects of the triazole compounds KARI101 and KARI201 on improving muscle strength and function in a mouse model of cancer cachexia, cancer size, body weight, and feed intake were evaluated. Administration of KARI101 and KARI201 did not affect cancer size in mice with cancer cachexia compared to mice with cancer cachexia treated with vehicle (see Fig.10a ) and weight (see Fig.10b ), but increased daily feed intake (see Fig.10c and Fig.10d In addition, KARI101 and KARI201 administration increased the reduced total fat mass compared to vehicle-administered cancer cachexia mice ( Fig.11a ), visceral fat (see Fig.11b ) and subcutaneous fat (see Fig.11c ), and increased the reduced muscle mass (see Fig.11d ).

[0201] That is, it was found that the triazole compounds KARI201 and KARI101, which are ghrelin receptor agonists, can increase the reduced feed intake of cancer cachexia mice, thereby effectively improving the reduced fat and muscle mass and muscle strength function.

[0202] Industrial availability

[0203] The compound provided by the present invention exhibits a very strong binding ability with extremely high specificity to the ghrelin receptor, and therefore is very useful for preventing or developing a preventive or therapeutic agent for a disease mediated by the ghrelin receptor, and has high industrial applicability.

Claims

1. Use of a compound of the following formula 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease mediated by a ghrelin receptor: [Formula 1] in R1 is hydrogen; or a straight or branched chain alkyl group having 1 to 15 carbon atoms; and R2 is hydrogen; or a straight or branched chain alkyl group having 1 to 15 carbon atoms; The disease mediated by the gastrin receptor is selected from: eating disorders; cancer anorexia or cachexia; cachexia or anorexia induced by anticancer drugs; hyperalgesia induced by anticancer drugs; chronic obstructive pulmonary disease (COPD) or COPD cachexia; sarcopenia; weight loss; general weakness in cancer patients after surgery; chronic respiratory tract infection; inflammation; inflammatory bowel disease (IBD); functional dyspepsia (FD); constipation; diabetic gastroparesis; heart failure; myocardial infarction; diabetic neuropathy; growth hormone deficiency; defecation disorders in patients with spinal cord injury; postoperative intestinal obstruction; and morphine-induced intestinal obstruction.

2. The method according to claim 1, wherein R1 is hydrogen.

3. The method according to claim 1, wherein R2 is a straight or branched alkyl group having 1 to 15 carbon atoms.

4. The use according to claim 1, wherein the compound of 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-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-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.

5. The use according to claim 1, wherein the compound of formula 1 is a ghrelin receptor agonist.

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