TW200803899A - Gastrointestinal function promoter - Google Patents

Abstract

The present invention aims at providing a more effective gastrointestinal function promoter, specifically, an agent for the prophylaxis or improvement of functional gastrointestinal disorders, appetite regulator and the like, and also a screening method for a substance capable of promoting a gastrointestinal function. The present invention provides a gastrointestinal function promoter containing a T1R agonist as an active ingredient and a method of screening for a substance capable of promoting a gastrointestinal function which method uses a cell expressing T1R receptor.

Description

200803899 (1) Description of the Invention [Technical Field of the Invention] The present invention relates to a gastrointestinal function promoting agent, such as an agent for preventing or improving a functional gastrointestinal disease. More specifically, the present invention relates to an agent for preventing or ameliorating functional gastrointestinal diseases (FGID), particularly for upper gastrointestinal dysfunction, such as functional dyspepsia (FD) (eg, abdominal pain, heavy stomach (heavy stomach) ), heartburn and similar diseases), gastroesophageal reflux disease (GERD) and similar diseases. Moreover, the present invention relates to an appetite regulating agent. The invention further relates to a method of screening for a substance capable of promoting gastrointestinal function. [Prior Art] Although there is an advanced endoscope diagnosis, there are many cases in which the discomfort such as upper abdominal pain, discomfort, feelings of stomach after eating, nausea, vomiting, and the like are not fully explained. Among them, the discomfort of the stomach φ intestinal sign, but not any organ disease that is found in general examination (including endoscopy) and without any findings that effectively clarify the sign is called FD (functional dyspepsia: Non-ulcerative digestion does not: Good (NUD): upper abdomen indigestion). According to the American Gastrointestinal Society, ^ FD is defined as an organ disease that is not observed (such as peptic ulcer and cancer symptoms), but the pathology of upper abdominal dyspepsia lasts 4 weeks or longer, such as the retention of contents in the stomach. Abdominal distention, nausea, vomiting, upper abdominal pain, anorexia, abnormal bowel movements and the like. On the other hand, in transcripts, these cases were determined as ~ upper abdominal stomach associated with chronic gastritis -5 - 200803899. (2) Intestinal discomfort, not related to organ discovery, and routine diagnosis in clinical situations For > gastritis or ''chronic gastritis 〃. Current subtypes of FD include ulcer type, gastrointestinal dyskinesia, and non-specific types, including common gastric achalasia, neuropathic dyspepsia, and gastrointestinal dysfunction. Even in cases where organ diseases (reverse esophagus 'peptic ulcer, acute stomach cancer, gastrointestinal cancer, pancreatic cancer, biliary tract disease, etc.) are clearly observed, abdominal pain, abdominal discomfort, and weight after eating are also found. Stomach sensation, φ nausea, vomiting and similar diseases. Therefore, there is a need to urgently improve these discomforts to ensure a better QOL for patients. When FD is combined with dyspepsia in the lower abdomen, such as difficulty in bowel movement due to constipation, uncomfortable feeling after defecation, abdominal pain, bloating and similar diseases, about 30%-50% of the total population of Japan is considered to have experienced some Indigestion, one third of them are said to have actually visited a medical institution. It is believed that the onset of abdominal dyspepsia is affected by gender, age, stress, and excessive weight caused by Western-style foraging, and abdominal dyspepsia is also a disease associated with representative diseases and lifestyles in modern society. These serious φ medical problems are that the pathogen of dyspepsia has only association with various diseases (chronic gastritis, diabetes, overweight, constipation, etc.), and its development mechanism does not exceed the association of only the lower gastrointestinal tract function. In fact, the reduction of gastrointestinal tract function only accounts for 30% of the actual FD patients. It is obvious that the mechanism of FD development has not been fully elucidated. In addition, many patients suffering from progressive degenerative brain diseases (such as Parkinson's disease, Huntington's chorea, olive pons cerebellar atrophy and similar diseases, stroke and similar diseases) Developed gastrointestinal dysfunction. Therefore, QOL has to be 200803899 (3) to improve the function of the gastrointestinal tract. It is believed that these patients include many patients who cannot propose dyspepsia by themselves because of language barriers. Care, dysfunction, and similar disorders. Therefore, care to remove sensory abnormalities (such as dyspepsia and similar diseases) that are performed concurrently with care organ dysfunction should lead to meaningful QOL improvements. Exercise modifiers have been used (eg 5- HT 4 receptor agonists and analogs and analogs are used in the treatment of FD. For example, cisapride and metoclopramide promote gastrointestinal motility and have been used to treat chronic gastritis and bloating. , reflux esophagitis, abdominal dyspepsia and pseudo-colon obstruction and similar diseases, but has been clarified metoclopramide Side effects, including signs of extrapyramidal pathways associated with effects on the dopamine D2 receptor in the central nervous system, and cisapride not only showed Parkinson's symptoms, but also showed side effects on the circulatory system, such as QT prolongation and similar effects. Although mosapride (m 〇sapride) and the like are used, the effect is sometimes insufficient. In addition, φ is now a side effect of bloating, stomach pain and the like. H2 antagonists and Proton pump inhibitors are used to treat gastroesophageal reflux disease (GERD). Regular testing for long-term administration is absolutely necessary because its safety is uncertain. • It is therefore difficult to find therapeutic effects from these existing pharmaceutical agents, while ensuring that they are fully charged. Safety of points. Fenfluramine and phentermine (which acts as a single point on the central nervous system) known as appetite regulators, sibutramine, 吲哚(mazindol) and the like. However, it can be observed as a side effect of dry mouth, constipation, sweating, heart 200803899 (4) 悸 and similar effects, so I hope to have Appetite Modulators with Less Side Effects. At the same time, the signal transduction system that clarifies taste has been implemented in various recipients in recent years. Two G protein-binding receptor families called T1R and T2R have been found as taste receptors in mammals. Body (W02003/001 876, W02005/01 51 5 8 'W02005/04 1 6 84 ). They are especially expressed in the taste cells in the tongue of humans and caries, and involve the sweetness of the five basic tastes. Taste, taste and bitterness. T1R is the body of cognitive sweetness and umami, while T2R forms a family related to bitterness. It is known that T1R1, T1R2 and T1R3 are subunits of T1R. When T1R2 and T1R3 form a heterodimer, they correspond to natural and artificial sweeteners and function as a sweet receptor. When T1R1 is combined with T1R3, they are equivalent to umami substances such as amino acids and the like. By the activation of these taste receptors, unknown transmitters are released from the taste cells, which stimulate the taste nerves and transmit the taste signals to the brain. However, their existence and function in the digestive system are unknown. SUMMARY OF THE INVENTION An object of the present invention is to provide a more effective gastrointestinal tract promoting agent, particularly an agent for preventing or improving functional gastrointestinal diseases, a food regulating agent, a composition containing the same, and the like . Furthermore, it is an object of the present invention to provide a method of screening for substances capable of promoting gastrointestinal function. The present invention has been achieved in view of the above problems. The inventors focused on and studied the T1R receptor. It was found that the T1R receptor is present in the gastric mucosa and the small intestinal mucosa, and the T1R receptor is expressed in gastrointestinal hormone-producing cells, in particular, 200803899 (5) is a gastrin-producing cell. Particularly in the stomach and small intestine, the gastrointestinal tract secreting cells are positive cells. Gastrin with gastrointestinal hormones. Especially positive cells in the vestibular part of the stomach. In the stomach and small intestine _ product, not only the expression of T1R1 mRNA but also the T1R3 mRNA necessary for the functional expression of the taste receptor T1R1+3 were observed. The present inventors found that they can provide a screening T 1 R agonist. And methods of analogs, and further methods for screening for substances capable of gastrointestinal tract function and similar functions by gastrointestinal hormone production of a T1R receptor derived from an animal or animal and using T 1 R As a result of the investigation of the agonist of the body (hereinafter sometimes referred to simply as the medicinal sputum), it was found that the T 1 R receptor agonist promotes gastric clearance (hereinafter sometimes referred to as ''gastric emptying sputum'). Gastric emptying is not controlled by gastric movement, but is also reflected in the digestibility of the duodenum delivered by the contents. In the case of too much fat that resists digestion and absorption, this is obviously a delay in the occurrence of gastric emptying. Therefore, the φ of the present invention can have a gastric emptying-promoting T 1 R agonist to obtain a digestive effect, that is, a gastrointestinal function promoting effect. Promoting gastric emptying reduces the initial abnormal abdominal distension and improves anorexia. Moreover, it promotes the stomach* to accelerate digestion and absorption, which in turn rapidly increases the blood nutrient concentration. w It is expected to increase the satisfaction effect in the early stage after eating. Based on the above, the present inventors have found that T 1 R agonists are effective for promoting gastrointestinal function and knots, and have completed the present invention. In other words, the present invention relates to a method and a method for screening a gastrointestinal tract function promoting agent and an appetite regulating substance which can act to promote gastrointestinal function, and a rapid endogenous cell mucosa. It is based on the receptor to promote the use of self-human cells. The T1R excitatory contents were excluded and the food was found to be less likely to be absorbed. Therefore, it was also found that the appetite T1R agonist, -9 - 200803899 (6) Therefore, the present invention includes at least the following items. [1] A gastrointestinal function promoting agent containing a T1R agonist as an active ingredient. [2] The agent according to the above [1], wherein the promotion of gastrointestinal function is prevention or improvement of a functional gastrointestinal disease. [3] The agent according to [2] above, wherein the functional gastrointestinal disease is upper gastrointestinal dysfunction. [4] The agent of the above [2] wherein the functional gastrointestinal disease is functional dyspepsia or gastroesophageal reflux disease. [5] An appetite regulating agent containing a T 1 R agonist as an active ingredient. [6] The agent according to any one of the above [1] to [5] wherein the T1R agonist is a guanamine derivative or a cyclocamate. [7] The reagent according to the above [6], wherein the decylamine derivative is a compound represented by the following formula (I):

Wherein R1 is an aryl group optionally having a substituent, an aralkyl group optionally having a substituent, an aralkenyl group optionally having a substituent, a heteroaryl group optionally having a substituent, and a heteroaryl group optionally having a substituent An alkyl group, a heteroarylalkenyl group optionally having a substituent, R3-NH-CO- or R3-NH- (R3 is an aryl group optionally having a substituent, an aralkyl group optionally having a substituent, optionally - 10 - V# 200803899 (7) an aralkenyl group having a substituent, optionally having a substituent having a substituent, or optionally having a group), and R2 being an optionally substituted group a C3_25 cycloalkyl group (the cycloalkyl group optionally has an aryl group having a substituent with benzene, optionally a calcining group having a substituent substituted thereon, optionally having a heteroaryl alkane having a substituent thereof Or a pharmaceutically acceptable salt thereof. [8] The agent of the above [6] or [7], wherein the compound of the indoleamine-derived group: (1) 3,6-dichloro ·Ν-(4-ethoxyphenyl)amine, (2) 2,5-dichloro-indole-(4-ethoxyphenyl)benzene £ (3 ) Ν-( 1-ethylpropyl)- And furan (4) Ν-( 1,2,3,4·tetrahydronaphthalen-1-yl)-benzopentene-5-formamide, (5) 4_ethoxy-N-( l-Propanyl)benzamide) (6) 3-(4-methoxyphenyl)-> 1-(1-propylamine. [9] A group containing the above [1] to [8] The test sample [10] - a heteroarylene containing the test heteroaryl group of any of the above [1] to [8], a heteroarylene having a random substituent, optionally having a blending), a Sifangfang base, a random heterofang The heteroarylene of the group and the substituent is a food composition selected from the group consisting of methoxybenzamide, amine, [1,3]dioxane, and butyl) propylene oxime. Or drink-11· 200803899 (8), wherein the active ingredient in the reagent accounts for 食物1_1 00,000 ppm by weight of the food or beverage. - [11] A method of screening for a substance capable of promoting gastrointestinal function using a cell which expresses a T1R receptor. [12] The method according to the above [11], wherein the substance capable of promoting gastrointestinal function is a T 1 R agonist or a T 1 R modulator. [1 3 ] A method for screening a substance capable of promoting gastrointestinal function, wherein φ comprises the following steps (a), (b) and (c): (a) contacting the test substance with a cell expressing a T1R receptor, ( b) determining the activation of the G protein in the cells in contact with the test substance, and comparing with the activation in the control cells not in contact with the test substance, and (c) selecting the comparison result based on the comparison result of the above (b) A substance that promotes gastrointestinal function. [1] The method according to [13] above, wherein the number of φ of the G protein activation is selected from the group consisting of intracellular calcium concentration, intracellular cAMP amount, extracellular proton amount, and intracellular gastrointestinal hormone secretion amount. [1 5] A method for screening a substance capable of promoting gastrointestinal function, comprising: the following steps (a), (b) and (c): ^ (a) allowing the test substance and the T1R receptor to function The ligand is contacted with cells expressing the T 1 R receptor, (b) measuring the amount of ligand bound to the cell membrane of the cell, and comparing with the amount of ligand in the control cell not in contact with the test substance, and (c A substance capable of promoting intestinal function of stomach-12-200803899 (9) is selected based on the comparison result of the above (b). [1 6] A method of promoting gastrointestinal function comprising administering an effective amount of a β T 1 R agonist to a mammal. [17] The method according to the above [16], wherein the promotion of the function of the gastrointestinal tract is prevention or improvement of a functional gastrointestinal disease. [18] The method according to the above [17], wherein the functional gastrointestinal disorder is upper gastrointestinal dysfunction. Φ Π 9] The method according to the above [17], wherein the functional gastrointestinal disease is functional dyspepsia or gastroesophageal reflux disease. [20] A method of regulating appetite comprising administering an effective amount of a T1R agonist to a mammal. [21] The method according to any one of the above [16], wherein the T1R agonist is a guanamine derivative or a cyclohexylamine sulfonate. [22] The method according to the above [21], wherein the decylamine derivative is a compound represented by the following formula (I): wherein R1 is an aryl group optionally having a substituent, and an aralkyl group optionally having a substituent An aralkenyl group optionally having a substituent, a heteroaryl group optionally having a substituent, a heteroarylalkyl group optionally having a substituent, a heteroarylalkenyl group optionally having a substituent, and R3-NH-CO- Or R3-NH- (R3 is an optionally substituted aryl group, optionally substituted aralkyl group, optionally -13-200803899 (10) substituted aralkenyl group, optionally substituted with deuterated a heteroarylalkyl group optionally having a substituent or a heteroarylalkyl group optionally having a substituent, and R2 being a C1 2 alkyl group optionally having a substituent a 25-ring fluorenyl group which has an aryl group having a substituent, optionally has an aralkenyl group having a substituent at a substituent, optionally a heteroarylalkyl group having a substituent intentionally substituted or Optionally having a radical, 'arbitrarily having a benzene condensate', a random aralkyl group, a random aryl group, Substituted acceptable salt group, or the pharmaceutically heteroaralkenyl. [23] The method of the above [21] or [22], wherein the compound of the following group is: # Ψ The guanamine derivative is selected from the group consisting of (1) 3,6-dichloro-indole-(4-ethoxyphenyl-2) -Methoxybenzidine

0.01- -14 - 1 2,5-Dichloro-indole-(4-ethoxyphenyl)benzamide, 2 (3 ) Ν-( 1-ethylpropyl)-benzofuran-2-methyl Amine, 200803899 (11) A food or beverage of the T1R agonist in a ratio of 1 00,000 ppm by weight is administered to a mammal. [26] Use of a T1R agonist for the production of a composition for promoting gastrointestinal function.

I

[27] The use of the above [26] wherein the promotion of the function of the gastrointestinal tract is prevention or improvement of a functional gastrointestinal disease. [28] The use of the above [27] wherein the functional gastrointestinal disorder is upper gastrointestinal dysfunction. [29] The use of the above [27] wherein the functional gastrointestinal disease is functional dyspepsia or gastroesophageal reflux disease. [30] Use of a T1R agonist for the production of a composition for appetite regulation. [31] The use of any one of the above [26] to [3], wherein the T1R agonist is a guanamine derivative or a cyclohexylamine sulfonate. [3 2] The use of the above [3 1] wherein the guanamine derivative is a compound represented by the following formula (I):

(1) wherein R1 is an aryl group optionally having a substituent, an aralkyl group optionally having a substituent, an aralkenyl group optionally having a substituent, a heteroaryl group optionally having a substituent, or a hetero group optionally having a substituent An aralkyl group, a heteroarylalkenyl group optionally having a substituent, R3_NH-CO- or R3-NH- (R3 is optionally -15. 200803899 (12) an aryl group having a substituent, optionally having a substituent a arylalkenyl group, optionally substituted with a heteroarylalkyl group having a substituent or optionally a group; and 4 R2 is a C3 fluorene group optionally having a substituent An aromatic group having a substituent, a aryl group optionally having a substituent Φ, a heteroaryl group optionally having a substituent, or a pharmaceutically acceptable group, or a pharmaceutically acceptable group thereof [33] The use of the above [31] or [32], wherein the compound of the following group: (1) 3,6-dichloro-N-(4-ethoxyphenylamine, • (2) 2,5-Dichloro-N-(4-ethoxyphenyl) (3) N-(l-ethylpropyl)-benzofuran, 2, (4) N- ( 1,2, 3,4 -tetrahydrogen Naphthalen-1-yl)_pentene-5-carbamimidamine, (5) 4-ethoxy-N-(p-propylbutyl) (6) 3-(4-methoxyphenyl)-1^ (1) [34] The pharmaceutical product of any of the above [26] to [33]. The aralkyl group, the heteroaryl group of the random group, the heteroaryl group of the random f substituent, optionally have an affinity a benzene fused), a random aralkyl group, a heteroaryl group of a random substituent, a heteroaryl decylamine derivative having a substituent selected from the group consisting of 1-2-methoxybenzimidamide, _ 醯 ,, 篆 and [1,3] dioxacyclo 3 decylamine, and ... propyl butyl) propylene oxime 'where the composition is -16 -

[038] (13) [35] The use of any one of the above [26] to [33] wherein the composition contains a T1R agonist or a beverage in a ratio of 0.01 to 100, 〇〇〇 by weight ppm. [36] A composition for promoting gastrointestinal function, which comprises an agonist as an active ingredient. [3] The composition of the above [3], wherein the gastrointestinal function promotes the prevention and improvement of the gastrointestinal disease. [3 8] The composition of the above [37], wherein the functional gastrointestinal tract is gastrointestinal dysfunction. [3] The composition of the above [3], wherein the functional gastrointestinal disorder is functional dyspepsia or gastroesophageal reflux disease. [40] A composition for appetite regulation comprising T1R as an active ingredient.

[41] The composition according to any one of the above [36] to [4], wherein the T1R agent is a decylamine derivative or a cyclohexylamine sulfonate. [42] The composition of the above [41], wherein the decylamine derivative is a compound represented by the following formula: (1) wherein R1 is an aryl group optionally having a substituent, optionally having an aralkyl group, optionally having a substitution Aromatic alkenyl group, optionally heteroaryl group having a substituent, heteroarylalkyl group optionally having a substituent, optionally a food T1R is a disease, and the agonist substitution is -17-200803899 ( 14) a heteroaromatic group of a substituent, R3-NH-CO- or R3-NH- (wherein R3 is an aryl group optionally having a substituent, a aryl group optionally having a substituent, optionally having a substituent An alkenyl group, a heteroaryl group optionally having a substituent, a heteroarylalkyl group optionally having a substituent or a heteroaromatic group optionally having a substituent, and 'arbitrarily having a benzene condensate", a random aryl group Alkyl, random heteroaryl, heteroarylene-amine derivatives with substituents

R2 is a Cm ring-based group of a C2_25-institutional radical having a substituent (the ring-based group optionally has an aryl group having a substituent, optionally having an alkene group having a substituent in place of g, optionally a heteroarylalkyl group having a substituent or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, wherein [43] the composition of the above [41] or [42] is a compound of the following group:

(1) 3,6-Dichloro-N-(4-ethoxyphenyl) methoxybenzimidazole, _salamine, $ interesting [1,3]dioxane (2) 2,5-Dichloro-N-(4-ethoxyphenyl(3) N-(1-ethylpropyl)-benzofuran, 2 (4 ) N- ( 1,2,3,4-tetra Hydronaphthalen-1-yl) pentyl-5-cartoamine, (5) 4-ethoxy-N-(1-propylbutyl)benzene~ decylamine, and (6) 3-(4-methoxy Phenyl)-N-(j butyl) propylene oxime is a pharmaceutical product [44] Any of the above [36] to [43] _ _ -18- 200803899 (15)

[45] The composition according to any one of the above [36] to [43] which is a food or drink containing an active ingredient in a ratio of 〇〇ι_1 0 0,0 0 by weight p p m . BEST MODE FOR CARRYING OUT THE INVENTION The present invention is explained in detail below. In the present invention, the gastrointestinal function promoting action 〃 represents gastrointestinal tract motility promoting action or digestion and absorption promoting action, which may be any functional promoting action by direct action on the gastrointestinal tract, and by promoting endocrine secretion Secretion (systemic hormones, etc.) in the system, second functional promotion of improved blood flow and the like. For example, it includes various gastrointestinal symptoms which exhibit functional deterioration due to gastrointestinal dysfunction, enhancement of gastrointestinal and intestinal functions in healthy individuals, prevention or improvement of diseases, prevention or improvement of functional gastrointestinal diseases and the like. Thus, the agent for promoting the function of the gastrointestinal tract of the present invention and the composition containing the same (the composition for promoting the function of the gastrointestinal tract) can be used for promoting gastrointestinal function, and can be used for preventing or improving the following indigestion. Reagents, independent of the presence or absence of organ disease. As used herein, a functional gastrointestinal disorder refers to the absence of observed organ diseases (such as peptic ulcers and cancer signs), but the abdominal digestion is not, a good pathology, such as in the gastrointestinal tract (especially in the stomach) Medium) retention and similar phenomena are mainly bloating, nausea, vomiting, abdominal pain, anorexia, acid reflux, abnormal bowel movements (constipation, diarrhea and similar diseases) and similar diseases. This represents a symptom of a repeatable gastrointestinal sign that is not a disease of the gastrointestinal tract but is degraded to the patient's QOL. For example, -19 - 200803899 (16) It includes functional dyspepsia, gastroesophageal reflux disease, diabetic gastroparesis, reflux esophagitis, postoperative gastrointestinal dysfunction and similar diseases. The gastrointestinal tract in the present invention refers to a series of chamber organs that are digested from the esophagus to the anus and can be described, for example, in the esophagus, stomach, small intestine (duodenum, ileum, colon) and large intestine. & upper gastrointestinal tract refers to the esophagus, stomach and duodenum, and ', upper gastrointestinal dysfunction 〃 refers to the above dysfunction in the upper gastrointestinal tract, and includes φ functional dyspepsia, diabetic gastropod paralysis, reflux Esophagitis, postoperative gastrointestinal dysfunction and similar diseases. As used herein, ''functional dyspepsia' refers to a pathology in which no organ disease (eg, peptic ulcer and cancer sign) is observed, but persistent upper abdomen dyspepsia, such as in the stomach and similar organs. Retention and similar phenomena are mainly bloating, nausea, vomiting, upper abdominal pain, anorexia and similar diseases. This represents a symptom of a reproducible gastrointestinal sign that is not a disease of the gastrointestinal tract but is degraded for the patient's QOL. Indigestion • Includes diseases that have been diagnosed as chronic gastritis and gastritis, and often shows signs of abdominal pain, heart ache, heartburn and similar diseases. In recent years, 40-60% of outpatients with licensed physicians have allegedly suffered from functional digestive ‘bad suffering, and treatments to remove Helicobacter pylori tend to increase functionality. Number of indigestions. Furthermore, > Gastroesophageal reflux disease includes reflux esophagitis and is developed by gastric acid reflux, and usually shows special signs of heartburn, up-regulation of stomach acid to the mouth and similar diseases. Moreover, although, swallowing represents swallowing water and food 'but it is not only related to the mouth and pharynx, but also to the movement of the gastrointestinal tract (esophagus and -20-200803899 (17) organs), such as due to adhesion to the esophagus And food groups and analogs similar to I stomach Φ can not be swallowed and vomiting. _ In the present invention, for example, in the case of functional gastrointestinal diseases, special symptoms of dysplasia include, but are not limited to, typical upper stomach, stomach and stomach, such as nausea, vomiting, and morbidity. Heartburn, bloating, heavy stomach, snoring, chest tightness, chest pain, stomach discomfort, anorexia, sputum _ disorder, acid reflux and similar diseases; lower gastrointestinal dyspepsia such as abdominal pain φ pain, constipation, diarrhea and the like Disease; related complaints, such as difficulty breathing, suffocation, low irritation, occlusive pharyngeal esophagus, foreign material sensation (in Chinese medicine, throat foreign body sensation (baikakuki) 、), fatigue, stiff neck, muscle rigidity, Dry mouth (dry mouth, thirst), shortness of breath, burning sensation, cold feeling of desperation, inability to concentrate, irritable, sleep disease, headache, general burnout, palpitations, night sweats, anxiety, dizziness, dizziness, burning sensation, tide Heat, sweating, abdominal pain, constipation, depression and similar diseases. Moreover, in the present invention, the appetite regulating 〃 represents an increase in appetite of an individual suffering from anorexia φ and an individual who is inclined to overeat in eating has a normal eating habit. Use of the gastroesophageal function promoting agent of the present invention, an agent for preventing or improving gastrointestinal gastrointestinal diseases, and an appetite regulating agent as a preventive or improved functional gastrointestinal disease having a QOL degrading which can repeatedly cause a patient to be degraded Reagents, especially for upper gastrointestinal dysfunction, such as functional dyspepsia, gastroesophageal reflux disease and similar diseases. These agents are sometimes referred to as the reagents of the present invention in the following. In the present invention, ''improvement' or 'improving' means "including 'treatment' or treatment, -21 - 200803899 (18) treatment (t r e a t i n g ). The agent of the present invention includes a T 1 R agonist as an active ingredient. In the present invention, the T 1 R agonist 〃 represents a substance which enhances the activity of the T 1 R receptor, which is a substance which directly activates only the T1R receptor by binding to the T1R receptor, and also includes an extended τ 1 R The agonist effect of the T 1 R modulator. Various known T1R receptors and any compound that activates the T1R receptor can be used as the Τ 1 R agonist. Such compounds can be obtained by screening for cells expressing the τ 1 R receptor •. The T1R receptor represents a subunit of T1R1, T1R2 and T1R3, and any subunit or a combination of two or more subunits selected from these variants and any of these subunits or a plurality of subunits may be used. T1R1, T1R2 and T1R3 may be proteins derived from mammals (e.g., humans, monkeys, mice, dogs, cows, and rabbits) or any animal (e.g., birds, fish, and the like), or may be such variants. The sequences of 1'1111, D1112 and Τ1R3 are each registered in Gene Bank under the following names: T1R1 rmRNA Taslrl, mouse NM_03 1 867, rat • XM_3 42986, human NM-1 48697

TlR2: mRNA Tas 1R2, mouse NM - 03 1 8 73 , rat AF 1 27390, human NM - 1 52232 and • T1R3 : mRNA Taslr3, mouse NM - 03 1 872, rat NM - 1 308 1 8, Human XM 327 12 1 0. • 4·-Cyclohexylamine sulfonate (N-cyclohexylamine sulfonic acid) and compounds such as those described in WO2005/041684 are known T1r agonists. Τ 1 R agonist 〃 includes a guanamine derivative (a compound having a partial structure of decylamine)', particularly a compound having a partial structure of, for example, decylamine 22·200803899 (19) represented by the following formula (I) Pharmacologically acceptable salts:

Wherein R1 is an aryl group optionally having a substituent, an aralkyl group optionally having a substituent, an aralkenyl group optionally having a substituent, a heteroaryl group optionally having a substituent, and a heteroaryl group optionally having a substituent An alkyl group, a heteroaryl group optionally having a substituent, R3-NH-CO- or R3-NH- (R3 is an aryl group optionally having a substituent, an aralkyl group optionally having a substituent, optionally having An aralkenyl group of a substituent, a heteroaryl group optionally having a substituent, a heteroarylalkyl group optionally having a substituent or a heteroarylalkenyl group optionally having a substituent, and R2 being a C2_25 optionally having a substituent a Cm-ring fluorenyl group having a substituent, a aryl group optionally substituted with a benzene, a aryl group optionally having a substituent, a aryl group optionally having a substituent, optionally having a substituent An aralkenyl group, a heteroaryl group optionally having a substituent, a heteroarylalkyl group optionally having a substituent or a heteroaromatic having a substituent optionally having an alkyl group of 2 to 25 carbon atoms a linear or branched chain of 2 to 25 carbon atoms (preferably 3 to 10) Mention may be made, for example, of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, di-butyl, pentyl, isopentyl, neopentyl, 1·. Methyl butyl, 2·methyl butyl, 2-ethylpropyl, 1,1-dimethylpropyl, hydrazine-dimethylpropyl, hexa-23-200803899 (20), isohexyl, megyl, 2-methylpentyl, 3-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5- M-hexyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 1-propenyl, octyl, decyl, decyl, undecyl, dodecyl, tetradecyl , tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl 'pentadecyl, eicosyl, icosyl, behenyl, twentieth Trialkyl, tetracosyl, pentadecyl and the like, excellent φ are first selected to be 1-ethylpropyl, 1-propylbutyl and the like. The cycloalkylhydrazine having 3 to 25 carbon atoms is a cycloalkyl group having 3 to 25 carbon atoms (preferably 5 to 10), and may, for example, be a cyclopropyl group, a cyclobutyl group or a cyclopentane group. , cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentadecyl Cyclohexadecyl, cyclohexadecyl, cyclooctadecyl, cyclopentadecyl, cycloecosyl, cyclohexadecyl, cyclotetracosyl, cyclohexadecane The base, cyclotetracosyl, cyclopentadecane φ group and the like are preferably selected from cyclohexyl and the like. The cycloalkyl group can be fused to the benzene ring at any position. As the ring fused to benzene, 1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl and the like are preferred. The ''aryl hydrazine preferably has 6 to 14 carbon atoms and is a monocyclic or polycyclic aromatic hydrocarbon group. In particular, it can be illustrated, for example, by phenyl, naphthyl and the like. The aryl group and the alkyl group are as defined above. The group is one in which one or more hydrogen atoms are substituted by an aryl group. The alkyl moiety is preferably one to three carbon atoms having from -24 to 200803899 (21). Specific aralkyl groups which may be mentioned are, for example, benzyl, phenethyl, 2-naphthylmethyl and the like. > Aromatic alkenyl is a group in which one or more hydrogen atoms of the alkenyl group are substituted by an aryl group, and the aryl group included is as defined by the above aryl group. The alkenyl moiety is preferably from 2 to 3 carbon atoms and may be illustrated, for example, by a vinyl group, an allyl group, and the like. The aralkenyl group can be illustrated, for example, as a styryl group, a cinnamyl group,

a heteroaryl 〃 represents preferably 5 to 1 monocyclic or polycyclic aromatic heterocyclic groups, preferably 1 to 4 hetero atoms selected from oxygen atoms, sulfur atoms and nitrogen atoms as ring atoms . Specifically, for example, a pyridyl group, a pyridazinyl group, a pyrimidyl group (=pyrimidinyl), and a pyrazinyl group can be used to illustrate a 6-membered ring group; a furyl group, a thienyl group, a pyrrolyl group, and a hetero- Azolyl, oxazolyl, isothiazolyl, thiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl are illustrated as 5-membered ring groups; Benzo, benzothienyl, fluorenyl, isodecyl, benzoxazolyl (= benzooxazolyl) benzothiazide, benzo-hydrazino Benzimidazolyl) (=benzoimidazolyl), sulphonyl, benzoisoxanyl 11 benzoyl, benzisothiazolyl, benzofurazinyl, benzothiadiazolyl, fluorenyl and benzodiazepine Oxepenyl is illustrated as a 6-5-membered ring group; quinolyl (= quinolinyl), isoquinolinyl, porphyrinyl, pyridazinyl, quinazoline The quinolinol group, pteridinyl group describes a 6-6-membered ring group; and the 5-5-membered ring group is illustrated by imidazoxazolyl, imidazothiazolyl, imidazomidazolyl and the like. -25- 200803899 (22) &heteroarylalkylhydrazine is a group wherein one or more hydrogen atoms of the alkyl group are substituted by a heteroaryl group, and the heteroaryl group and the alkyl group included are as defined above. The alkane moiety is preferably one having 3 to 3 carbon atoms. In particular, it can be illustrated, for example, by 2-pyridinium ethyl, benzofuranmethyl and the like. * " Heteroarylalkenes are groups in which one or more hydrogen atoms of the alkenyl group are substituted by a heteroaryl group, and the heteroaryl and alkenyl groups are as defined above. This can be illustrated, for example, by 2-pyridylethylene and the like. φ These groups may have one or more (1 to 3 preferred) substituents at a replaceable position. When two or more substituents are included, the substituents may be the same or different. For example, a halogen atom (including fluorine, chlorine, bromine, and iodine), a hydroxyl group, a ketone group, an amine group, an alkyl group having 1 to 6 carbon atoms (such as a methyl group, an ethyl group, and the like), having 1 to 7 Alkoxy groups of carbon atoms (such as methoxy, ethoxy, methyldioxy and the like), fluorenyl groups having 2 to 7 carbon atoms (such as carboxyl, ethyl fluorenyl, propyl thiol and the like) a oxyalkylene group having 2 to 7 carbon atoms (e.g., an amine methyl group), an alkylamine methyl group having 2 to 10 carbon atoms, and an arylamine having 7 to 11 carbon atoms Mercapto group, heteroarylamine carbhydryl group having 5 to 11 carbon atoms, aralkylamine-methyl group having 8 to 15 carbon atoms, heteroarylalkylamine having 6 to 15 carbon atoms Mercapto and analogs • Describe substituents. The substituent may further have a substituent at a substitutable position, as described above. An aryl fluorene having a substituent optionally, a aralkyl group optionally having a substituent, a heteroaryl group optionally having a substituent, and the like -26 - 200803899 (23) as R1 Preferably. The aryl group having a substituent and a phenyl group and the like as a substituent of R 1 and optionally having a substituent is preferred. Preferably, a halogen, an alkoxy group having 1 to 7 carbon atoms (1 to 3 is preferred) and the like are used as a substituent, and chlorine, methoxy, ethoxy, methylenedioxy and the like are preferred. Especially good. The arylalkyl group which has a substituent and a styrene group and the like which have a substituent as a random portion of R 1 is preferably a substituent. The alkoxy group having 1 to 7 carbon φ atoms (preferably 1 to 3) and the like are preferable, and a methoxy group and the like are particularly preferable. It is preferred that the benzofuranyl group and the analog having a substituent optionally have a heteroaryl group which has a substituent of R'. Especially 3,6-dichloro-2-methoxyphenyl, 2,5-dichlorophenyl, 5-benzo[1,3]dioxolyl, 4-ethoxyphenyl 2-(4-methoxyphenyl)vinyl, benzofuranyl and the like are preferred as R1. An optionally substituted aryl group, a C2-25 alkyl group optionally substituted with a φ group, a c3-25 alkyl group optionally having a substituent (the cycloalkyl group is optionally fused to a benzene) And the like is preferable as R2. The aryl group which is a substituent having a substituent such as a phenyl group or the like which has a substituent as R2 and which has a substituent. The alkoxy group having 1 to 7 carbon atoms (1 to 3 is preferred) and the like are preferred, and ethoxy groups and the like are particularly preferred. In particular, 4-ethoxyphenyl, 1-ethylpropyl, 1-propenylbutyl, tetrahydronaphthalen-1-yl and the like are preferred as R2. The T1R agonist used in the present invention (particularly the compound represented by the formula (I) -27-200803899 (24)) may have a salt form. Salts which may have inorganic bases, salts with inorganic acids, salts with organic acids, salts with organic bases, and the like are described as such salts, and are not particularly limited as long as they are pharmacologically acceptable Just fine. Alkali metal salts (e.g., sodium, potassium, lithium, and the like), alkaline earth metal salts (e.g., calcium, magnesium, and the like), ammonium salts, and the like can be described as salts having an inorganic base. It may have a salt of a hydrohalic acid (hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.), sulfuric acid, nitric acid, phosphoric acid, and the like, and is described as a salt having an inorganic acid. Salts which may have formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, glutamic acid, aspartic acid, histidine, and the like are described as having a salt of an organic acid class. Salts which may have basic amino acids (arginine, lysine, ornithine, and the like), nucleotides (anthracene derivatives, pyrimidine derivatives, and the like), alkaloids, and the like are described as A salt having an organic base. Further, a substance (compound) which activates the T1R receptor (a known or novel compound obtained from the screening method of the present invention described in detail below) φ and the like can be used as an active ingredient of the present invention, which can promote the gastrointestinal tract. Features. The screening method of the present invention is explained below. The screening method of the present invention is characterized by screening, a substance capable of promoting gastrointestinal function, which is tested by using a cell expressing a T 1 R receptor.

, substance to check for the presence or absence of T1R receptor activation. An agonist or modulator which is a T1R receptor, and a substance capable of promoting gastrointestinal function, which is a substance which modulates the T 1 R receptor activity. Modulators of the T 1 R receptor include substances that extend the activity of the T 1 R receptor agonist. The presence or absence of T1R S activation can be measured by measuring the mass of the substance bound to (with -28-200803899 (25)), suppressing the signal mass of the signal response that regulates T1R receptor activity, and transferring ligand and T1 The R receptor binds to the amount of the signal produced by the (second messenger, etc.) amount and the like to check. For example, T1R receptor activation can be examined by detecting a second messenger produced by the binding of a ligand such as glutamic acid and the like to a 71&receptor. Furthermore, 'T1R receptor activation can also be detected by measuring the binding between the labeled ligand and the T1R receptor using a known labeled ligand. ^ T1R receptor acts on GTP-binding proteins (also known as G proteins: Gs, Gi, Gq, Ggust, etc.) due to ligand binding, and controls various cellular functions via second messengers (such as cAMP) and analogs. . Among these, the intracellular calcium concentration is increased by the activation of G q . In addition, it can be explained by the activation of intracellular enzymes (such as calcitonin, protein kinase C, adenylate cyclase and the like) and the functional regulation of phosphorylation of cytoplasmic membrane proteins in the acute phase. Signaling transduction increases the intracellular calcium concentration downstream. The activation of these intracellular enzymes changes the channel function of φ in the cell membrane. The present inventors have also found that the T1R receptor is expressed in gastrointestinal hormone-producing cells, particularly gastrin-producing cells. Therefore, the presence or absence of detection of the τ 1 R receptor activation of the test substance can be achieved by contacting the test substance with cells expressing the Τ 1 R receptor and using intracellular calcium concentration and accumulation within the cell. cAMP, channel function (eg, extracellular proton production), gastrointestinal hormone secretion, and similar measurements were used as indices to measure G-protein activation. The cells expressing the Τ 1 R receptor used in the screening method of the present invention may be, for example, self-mammals (e.g., mouse, rat, hamster, guinea pig, rabbit, -29 - 200803899 (26) dogs, monkeys, humans, and Analogs), cells derived from birds (such as chickens and the like), and the like. Preferably, the gastrointestinal hormone-producing cells derived from the above animals and the like are used. The test substance used in the screening method of the present invention may be any known compound or novel compound. For example, nucleic acids, carbohydrates, lipids, proteins, peptides, organic low molecular weight compounds, libraries of compounds constructed using combinatorial chemistry techniques, random peptide libraries constructed using solid phase synthesis or phage display methods, or from microorganisms, plants or Description of natural components and analogues derived from animals, marine organisms, and the like. In other words, the screening method of the present invention includes, for example, the following steps (a), (b) and (c): (a) contacting the test substance with cells expressing the T 1 R receptor, and (b) measuring the contact with the test substance. The G-protein activation in the cells is compared with the activation in control cells not in contact with the test substance, and φ (c) selects a substance capable of promoting gastrointestinal function based on the comparison result of the above (b). In the step (a) of the above screening method (hereinafter also referred to as the method < A), the cells expressing the T1R receptor are placed in contact with the test substance. The test substance is contacted with the cells in a culture medium. The culture medium is appropriately selected depending on the cell type and the like to be used. In step (b) of the above screening method, G protein activation in cells expressing the T 1R receptor is first evaluated in the presence of a test substance. The activation is then compared to the activation in the absence of the test substance. -30- 200803899 (27) The intracellular calcium concentration, the intracellular c AMP amount, the extracellular proton amount, the intracellular gastrointestinal hormone secretion amount, and the like can be used as an index for determining the activation of G protein. In the step (c) of the above screening method, for example, the activation is compared based on the significant difference in the presence or absence. As a result of the evaluation, when it is confirmed that the activation is increased/expanded in the presence of the test substance (relative to the absence of the test substance), the test substance can be judged to be a substance capable of promoting gastrointestinal function. When screening for T1R modulators, it is possible to contact the test substance and T1R agonist with cells expressing the T 1 R receptor in step (a) above, in (b) when the T 1 R agonist is in contact with the cell G protein activation upon contact in the presence of the test substance and G protein activation when the T 1 R agonist is contacted with the cell in the absence of the test substance, and selection in (c) will expand the G protein activation The substance acts as a substance (T1R modulator) that promotes gastrointestinal function. φ Moreover, other screening methods of the invention include, for example, the following steps (a), (b), and (〇: (a) the test substance and the ligand acting on the T1R receptor and the table. The T 1 R receptor Cell contact, (b) measuring the amount of ligand bound to the cell membrane of the cell, and comparing the amount of ligand in the control cell not in contact with the test substance, and (c) comparing the results of (b) above A substance capable of promoting gastrointestinal function is selected as a reference. In the step (a) of the above screening method, the fine-31 - 200803899 (28) cell which expresses the T 1R receptor is placed on the test substance and on the T1R receptor. Under the contact of the interacting ligand, the test substance and the ligand acting on the T1R receptor are brought into contact with the cells in the culture medium. The culture medium is appropriately selected depending on the cell type and the like to be used. In the step (b) of the above screening method, the amount of the ligand bound to the cell membrane of the cell expressing the T1R receptor is first evaluated in the presence of the test substance. The amount of the ligand is then made in the absence of the test substance. The amount of ligand is greater than $. The amount of ligand bound can be, for example The ligands and analogs used for radiolabeling are measured. In step (c) of the above screening method, for example, the amount of the ligand is compared based on the significant difference in the presence or absence. The result of the evaluation, when the binding can be determined When the amount of the body is lowered in the presence of the test substance (relative to the absence of the test substance), it can be determined that the test substance is a substance capable of promoting the function of the gastrointestinal tract. Further, a substance which can reduce the amount of ligand binding can be determined by The above φ screening method is determined to be a T1R agonist. Although the ligand acting on T1R is not particularly limited, it can be described, for example, by glutamic acid, nucleic acid, and the like. • For detecting a substance capable of promoting gastrointestinal function The special method # (1) - (6) is shown below, which uses cells that express the T1R receptor (cells that functionally retain the τ 1 R receptor). (1) A method comprising the following steps (3), (1) )) and ((〇): (a) the test substance and cells that have been introduced with calcium-sensitive dyes (eg, Fura-32-200803899 (29) 2, Indo-1, Fluo-3, etc.) expressing T1R receptors Expose for a given period of time (b) measuring the fluorescence intensity (intracellular calcium concentration) in the cells in contact with the test substance, and comparing with the intensity in the control cells not in contact with the test substance, and (c) using the above (b) The comparison results are based on the selection of substances that promote gastrointestinal function. φ In step (a) of the above screening method, the cell line exhibiting the T 1 R receptor in contact with the test substance is a gastrointestinal hormone exhibiting the τ 1 R receptor. It is preferred to generate a cell, for example, the target substance can be searched for by reference to the fluorescence intensity (intracellular calcium intensity) which is changed by the test substance in contact with the gastrointestinal hormone-producing cells into which the calcium-sensitive dye has been introduced for a predetermined period of time. When the Τ 1 R modulator is screened, the test substance and the Τ 1 R agonist can be contacted with cells expressing the T1R receptor which have been introduced with a calcium-sensitive dye (e.g., Fura-2, Indo-1, Fluo-3, etc.). φ In the step (b) of the above screening method, the fluorescence intensity (intracellular calcium intensity) of the cells expressing the T1R receptor in the presence of a change in the test substance was evaluated. In other words, the evaluation was made by comparing the measured fluorescence intensity (intracellular, calcium intensity) with the fluorescence intensity in the absence of the test substance. I Fluorescence intensity can be measured by a method known per se. When screening for Τ 1 R modulators, the fluorescence intensity of the T1R agonist in contact with cells expressing the T1R receptor in the presence of the test substance can be correlated with the Τ 1 R agonist and the cell in the absence of the test substance. Comparison of the fluorescence intensity at the time of contact. In the step (c) of the above screening method, the fluorescence intensity is compared, for example, based on the significant difference in the presence or absence of -33-200803899 (30). As a result of the evaluation of the fluorescence intensity, when it is determined that the intracellular calcium concentration is increased, it is judged that the test substance is a substance capable of promoting gastrointestinal function. When the T1R modulator is screened, a substance which expands the range of the fluorescence intensity shift can be selected as a substance (T 1 R modulator) which can promote the function of the gastrointestinal tract. (2) A method comprising the following steps (a), (b) and (c): ^ (a) contacting the test substance with cells expressing the T 1 R receptor for a predetermined period of time, (b) measuring The amount of cAMP in the cells in contact with the test substance is compared with the amount of cAMP in the control cells not in contact with the test substance, and (c) the substance capable of promoting gastrointestinal function is selected based on the comparison result of the above (b). The execution of steps (a) and (b) above may be, for example, Chaudhari N, • Nat N euro sci 2 0 00 Feb; 3 ( 2 ); 113-9; Flor PJ,

The description of Neuropharmacology 1995 Feb; 34 (2): 149-55 is based. ^ The amount of cAMP can be measured using a commercially available assay kit. In the step (a) of the above screening method, when the T1R modulator is screened, the test substance and the T1R agonist can be brought into contact with cells expressing the T1R receptor. In step (b) of the above screening method, when the T1R modulator is screened, the T 1 R agonist can be contacted with the cell expressing the T 1 R receptor in the presence of the test substance -34-200803899 (31). The amount of cAMP at the time is compared to the amount of cAMP when the T1R agonist is in contact with the cell in the absence of the test substance. In the step (c) of the above screening method, the amount of cAMP is compared based on, for example, a significant difference in the presence or absence. As a result of the evaluation of the amount of cAMP, when it is determined that the amount of cAMP is increased, it is judged that the test substance is a substance capable of promoting gastrointestinal function. When the T 1 R modulator is screened, a substance which enhances the increase in the amount of cAMP can be selected as a substance (T 1 R modulator) capable of promoting gastrointestinal function. (3) A method comprising the following steps (a), (b) and (c): (a) a test substance and a known ligand acting on the T1R receptor (eg glutamic acid, nucleic acid) Etching) contact with cells expressing the T 1 R receptor for a predetermined period of time, (b) measuring the amount of ligand bound to the cell membrane of the cell, and comparing the amount of ligand to the control cell not in contact with the test substance And (e) selecting a substance capable of promoting gastrointestinal function based on the comparison result of the above (b). The above steps (a) and (b) can be performed, for example, by Naples MA, Neuropharmacology 200 1; 40(2); 170-7; Thomsen C,

The description of Neuropharmacology 1 997 Jan; 3 6 ( 1 ) : 2 1 -3 0 is the basis. It is known that the amount of the ligand can be measured by labeling a portion of the substance with radioactivity and measuring the amount of radioactivity bound to the cell membrane. In step (c) of the above screening method, the amount of ligand is compared, for example, based on the significant difference in the presence or absence of -35-200803899 (32). As a result of the evaluation of the amount of the ligand, when it is determined that the amount of the ligand to be bound is increased, it is judged that the test substance is a substance capable of promoting the function of the gastrointestinal tract. (4) A method comprising the following steps (a), (b) and (c): (a) contacting the test substance with a cell exhibiting a T1R receptor into which a cAMP-sensitive fluorescent protein (e.g., FICRhR, etc.) has been introduced. For a predetermined period of time, (b) determine the fluorescence intensity (intracellular cAMP concentration) in the cells in contact with the test substance, and compare the intensity with the control cells not in contact with the test substance, and (c) (b) The comparison results are based on the selection of substances that promote gastrointestinal function. The execution of the above steps (a) and (b) can be based, for example, on the description of Adams SR, Nature 1 99 1 Feb 2 1 ; 349 (63 1 1 ): 694-7. The cell line which expresses the T 1 R receptor is preferably a gastrointestinal stimulating cell which expresses the T 1 R receptor. In step (a) of the above screening method, when the T1R modulator is screened, the test substance and the T1R agonist can be expressed as a T 1 R receptor having introduced a cAMP-sensitive fluorescent protein (for example, F 1 CRhR, etc.). Cell contact. In step (b) of the above screening method, when the T1R modulator is screened, the fluorescence intensity (intracellular cAMP concentration) and the T1R agonist when the T1R agonist is contacted with the cell in the presence of the test substance can be used. The fluorescence intensity of the cells when contacted in the absence of the test substance was compared. -36- 200803899 (33) In the step (c) of the above screening method, for example, the fluorescence intensity is compared based on a significant difference in presence or absence. As a result of the evaluation of the fluorescence intensity, when it is determined that the fluorescence intensity is increased, it is judged that the test substance is a substance capable of promoting the function of the gastrointestinal tract. When the T 1 R modulator is screened, a substance which enhances the increase in fluorescence intensity can be selected as a substance (T 1 R modulator) capable of promoting gastrointestinal function. (5) A method comprising the following steps (a), (b) and (c): (a) contacting the test substance with cells expressing the T 1 R receptor for a predetermined period of time, (b) measuring The amount of extracellular proton production in the cells in contact with the test substance, and the amount of extracellular proton production in the control cells not in contact with the test substance, and (c) the selection based on the comparison result of the above (b) A substance that promotes gastrointestinal function. φ The execution of steps (a), (b) and (c) above may be for example

McConnell ΗM5 Science 1 9 9 2 Sep 25; 257 ( 5078) : 1906- 1 2 is based on the description. A cell line exhibiting a T1R receptor is preferably a gastrointestinal stimulating cell which expresses a T1R receptor, and is, for example, measured for contact with a τ 1 R receptor agonist and a test substance in contact with a gastrointestinal hormone cell exhibiting a T1R receptor. The amount of extracellular proton produced at a given time, and the target substance can be detected using an amount of protons as an index. The amount of proton generated is measured by a position sensor. In the step (a) of the above screening method, when the T1R modulator -37-200803899 (34) is screened, the test substance and the T1R agonist can be brought into contact with cells expressing the T1R receptor. In step (b) of the above screening method, when the T1R modulator is screened, the amount of extracellular proton produced when the T 1 R agonist is contacted with the cell exhibiting the τ 1 R receptor in the presence of the test substance Comparison with the amount of proton produced when the T1R agonist is in contact with the cell in the absence of the test substance. I In the step (c) of the above screening method, for example, the amount of proton formation is compared based on a significant difference in presence or absence. As a result of the evaluation of the amount of proton production, when it is determined that the amount of extracellular proton production is increased, it is judged that the test substance is a substance capable of promoting gastrointestinal function. When the Τ 1 R modulator is screened, a substance which enhances the increase in extracellular proton production may be selected as a substance capable of promoting gastrointestinal function (Τ 1 R modulator). (6) a species comprising the following steps (a), (b) and ((the method of 〇: φ (a) causes the test substance to contact the cells exhibiting the Τ 1 R receptor for a predetermined period of time, (b) the measurement is in The amount of gastrointestinal hormones secreted in the cells in contact with the test substance, and compared with the amount of gastrointestinal tract hormone secretion in the control cells not in contact with the test substance, and (c) based on the comparison result of the above (b) A substance capable of promoting gastrointestinal function. A cell line exhibiting R 1 R receptor is preferably a gastrointestinal hormone-producing cell expressing a Τ 1 R receptor, and is, for example, measured at a T 1 R receptor agonist and a test substance-38- 200803899 (35) The amount of gastrointestinal hormone secretion in contact with gastrointestinal hormone-producing cells expressing T1R receptor for a given period of time, and the target substance can be searched using the amount of gastrointestinal hormone secretion as an index. Gastrointestinal hormone secretion can be Using a commercially available assay kit measurement. In step (a) of the above screening method, when the T1R modulator is screened, the test substance and the T 1 R agonist can be brought into contact with cells expressing the τ 1 R receptor. In the above sieve In the step (b) of the selection method, when the Τ1R modulator is screened, the amount of gastrointestinal hormone secretion when the T1R agonist is contacted with the cell exhibiting the T1R receptor in the presence of the test substance can be compared with the T1R agonist. Comparison of the amount of gastrointestinal hormone secretion when the cells are contacted in the absence of the test substance. In the step (c) of the above screening method, for example, the amount of gastrointestinal hormone secretion is compared based on the significant difference in the presence or absence. Gastrointestinal hormone The results of the evaluation of the secretion amount, when it can be determined that the amount of gastrointestinal hormone secretion changes, then φ can determine that the test substance is a substance that can promote the function of the gastrointestinal tract. When screening the T1R modulator, the amount of gastrointestinal hormone secretion can be selected. A range-expanding substance is used as a substance capable of promoting gastrointestinal function (Τ 1 R regulating agent). The agent of the present invention can be used as a pharmaceutical agent, food and tart, and the like, and is administered to a subject such as a mammal (e.g., human). , mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, etc.) and the like. Moreover, according to the present invention, it is provided for production for promoting gastrointestinal Use of T1R agonists for function and appetite control 'and promotion of gastrointestinal function and control - 39-200803899 (36) Method for appetite preparation - comprising administering an effective amount of a T 1 R agonist to a sputum milk. When the agent is included in the pharmaceutical composition, the pharmaceutical composition usually includes a T 1 R agonist and a carrier. Although the carrier is not particularly limited as long as it is acceptable as a pharmaceutical agent, and may be, for example, the following substances (for example, The agent, the solvent, etc. are used. As used herein, although the administration mode of the reagent or the pharmaceutical composition of the present invention (also referred to as a pharmaceutical agent under φ) is not particularly limited, a general administration route can be generally used. For example, oral administration, rectal administration, injection or infusion administration, and the like. Dosage forms for oral administration include granules, fine granules, powders, coated tablets, troches, suppositories, powders, (micro)capsules, chewable tablets, syrups, juices, liquids, suspensions, lotions, and the like. A general dosage form of a pharmaceutical preparation can be used for injection, such as a direct intravenous injection, a drip infusion, a preparation for prolonging the release of the active substance, and the like. φ These pharmaceutical agents can be formulated according to conventional methods. When it is desired to formulate, various pharmaceutically acceptable substances (as adjuvants) for the preparation may be added. Although the substance for the preparation may be appropriately selected depending on the dosage form of the preparation, it includes, for example, excipients, diluents, additives, disintegrating agents, binding agents, coating agents, lubricants, slip agents, lubricants. , flavoring agents, sweeteners, solubilizers, solvents and the like. Specific examples of materials for use in the preparation include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, polyethylene glycol and solvents, Such as sterile water and unit or polyol-40-200803899 (37) (such as glycerin and the like). Although the dosage of the pharmaceutical agent of the present invention for oral administration is changed according to the symptoms and the age and administration method of the patient to be administered, it is used for the active ingredient of the adult (6 kg body weight). The daily dose is usually about 0.001 mg to 1 g, preferably about 0.01 mg to 1 g, and more preferably about 0.1 mg to 1 g. The dose of parenteral administration (intake) in the form of drip infusion, injection (intravenous administration) and the like is about 1/10 of the above-mentioned preferred dose (intake) for oral administration. To 1/20. Combinations of the pharmaceutical agents of the present invention with other pharmaceutical agents can be used. For example, acid secretion inhibitors (such as Η2 receptor antagonists, proton pump inhibitors and the like), motor function improvers (such as 5-quinone receptor agonists, D2 antagonists and the like), and antacids can be used ( Such as muscarinic receptor antagonists, anti-gastrin drugs, anticholinergic drugs and analogues), mucosal protective agents (such as teprenone, plaunotol, ornoprost) Lu (ornoprostil), enprostil, misoprostol, rebamipide, sucralfate, polaprezinc, azulene , B, Sodium, glutamate, glutenic acid, aldioxa, gefarnate, ecabet sodium, and the like, inflammatory bowel disease treatment Agents such as sulfasalazine, 5-ASA formulation, steroids, remicade and the like are used as such pharmaceutical agents. One or more of these categories may be included. -41 - 200803899 (38) The reagent of the present invention may be included in food or dips. When it is included in foods or beverages, any conventional dietary form may be used as long as it includes the active ingredient of the present invention. For example, a suitable flavoring agent can be added to obtain a drink, such as a refreshing drink and a powdered drink. For example, it can be mixed and preserved especially with juice, milk, cakes, jellies and the like. It is also possible to provide foods such as foods with health claims (including food and drinks) as defined by the Ministry of Health (Labour and Welfare) and φ beverages, especially for designated health foods, with nutrition Functionally claimed foods and the like, showing the use of the present invention for promoting gastrointestinal function and appetite regulation and the like. Moreover, it is also possible to add the reagent of the present invention to a concentrated liquid foraging or to use it as a foraging supplement. For example, it can be formed into tablets, capsules, powders, granules, suspensions, chewable tablets, syrups and the like for use as a foraging supplement. In addition to those that obtain supplements from food, the dietary supplements of the present invention include those that are obtained for the purpose of replenishing nutrients, φ which include nutritional supplements, supplements (especially foraging supplements), and the like. When the agent of the present invention is included in a food or a dip, the daily intake of the active ingredient of the adult is usually about 0.001 mg to 1 g, preferably about 0.01 mg to 1 g, and about 1 mg to 1 g. The gram is better. When the agent of the present invention is included in a food or beverage, the amount of the active ingredient in the food or beverage is usually from about 0. 01 to about 10,000,000 ppm by weight, preferably from about 0.01 to about 10,000 ppm by weight, and about 0.01 to about 1 000 ppm by weight is more preferred. - 42- 200803899 (39) [Embodiment] The present invention is explained in more detail by reference to examples and experimental examples, which are not to be construed as limiting the invention. Example 1: Confirmation of position of TIR1 receptor by immunostaining <1> Preparation of sliced samples of stomach and small intestine of rats After incision of right atrial appendage under ether anesthesia, rats (Sprague-Dawley, male rats, 3 50 -400 grams) sacrificed by bloodletting, and immediately get the stomach and small intestine. The pyloric vestibular part of the stomach was obtained, in which many gastric gut hormone-producing cells were distributed, and a small intestine portion 5 cm from the stomach pylorus was obtained. When a large amount of digestate remains in the gastrointestinal tract, the intestine is washed with saline. The removed stomach and intestines were cut, nailed to cork board and shaken in 4% p-formaldehyde (4 ° C) for 1 day to be dipped and fixed. They were then cryopreserved in immersion φ in 20% sucrose-PBS for 3-4 days, embedded in an embedding agent (OCT compound, trademark: Tissue-Tek, Sakura Seiki Co., Ltd.) and extremely cold. The thermostat was cut to 5-7 microns. The sections were dried at room temperature and stored at 4 ° C until used for different staining. <2> Immunostaining using anti-T1R1 receptor antibody immunostaining The sections were immunostained according to the method described in the known publication (Drengk et al. J. Auto. Ner v. S ys. 78:1 09- 1 1 2, 2000; Mi amp amb a & Sharkey, J. Auto·N er v. Sys· 77:1 40- 1 5 1, -43- 200803899 (40) 1999)° Wash the slices with PBS and Treatment with 3% hydrogen peroxide and methanol for 5 minutes to avoid endogenous peroxidase reaction. The sections were then washed with PBS and blocked with 1% bovine serum albumin (1% BSA-PBS) supplemented with PBS containing 10% normal horse serum for 1 hour. The sections were washed again with PBS and reacted with a primary antibody (Table 1) diluted with 1% BSA-PBS containing 1% normal horse serum for 2 nights at 4 °C. The sections were then washed with PBS and reacted with a secondary antibody diluted in 1% BSA-PBS (Table 1) for 1 hour at room temperature. Finally, the ABC (Avidin-Biotin Complex) reaction was carried out using a Vectorstain elite kit (Vector) and treated with 0.025% diaminobenzidine to develop color. After the completion of the reaction, the sections were washed with PB S, dehydrated with ethanol·xylene, encapsulated and observed under a microscope. A section containing no primary antibody was used as a negative control group. The types and dilution rates of the primary and secondary antibodies used are shown in Table 1. Primary antibody primary antibody dilution rate secondary antibody secondary antibody dilution rate anti-rat hri antibody, rabbit antibody, polyclonal antibody, US Alpha Diagnostic International, catalog #TR11-A 100 biotinylated goat anti-rabbit antibody IgG (Pennsyl West Grove's Jackson ImmunoResarch) 500

<3> Hematoxylin staining The sections were washed with water. The core was stained with Mayer's hematoxylin 44. 200803899 (41) (Wako Pure Chemical Industries, Ltd.), and after color development, dehydration and application were carried out. Envelope. < 4 > Results The results of immunostaining are shown in Fig. 1. In the stomach (Fig. 1A) and the small intestine (Fig. 1B), cells scattered in the gastrointestinal mucosa were stained by an anti-T1R1 receptor antibody. From the upper end of the positive cells toward the morphological characteristics of the intestinal chamber in both the stomach and the small intestine, the cells are considered to be gastrointestinal hormone producing cells. The expression of the T1R1 receptor in gastrointestinal hormone producing cells has not been known so far. Since the T1R1 receptor is expressed in gastrointestinal hormone-producing cells, it associates with the functional relationship of endocrine regulation of gastrointestinal hormones. The anti-T1R1 receptor antibody was determined to stain the taste cells of the taste bud (Fig. 1C). Example 2: Confirmation of the position of the TIR1 receptor and gastrin by double immunostaining <1> The double staining of the anti-11 & 1 receptor antibody and the anti-gastrin antibody allows the stomach slice to receive the anti-T1R1 receptor antibody and the anti-T1R1 receptor antibody Double staining of gastrin antibodies. The sections were first washed with PBS and blocked with 1% bovine serum albumin (1% BSA-PBS) containing PBS containing 10% normal horse serum for 1 hour. The sections were washed again with PBS, and a mixture of primary antibodies diluted in 1% BSA-PBS containing 1% normal horse serum (Table 2) was reacted at 4 ° C for 2 nights. The sections were then washed with PBS and reacted with a secondary antibody diluted in 1% BSA-PBS (Table 2) for 2 hours at room temperature. After completion of the reaction, the sections were washed with PBS, dehydrated with ethanol dimethyl-45-200803899 (42), and included and observed with a conjugated-focus laser microscope (LSM 5 10 of Zeiss, Germany). A section containing no primary antibody was used as a negative control group. The types and dilution rates of the primary and secondary antibodies used are shown in Table 2. Table 2 - Grade Antibody Mixture Composition (1) + (2) - Grade Antibody Dilution Rate Secondary Antibody Mixture Composition (3) + (4) Secondary Antibody Dilution Rate (1) Anti-rat T1R1 Antibody, Rabbit Antibody, Multiple Antibody, (USA) Alpha Diagnostic International 5 Table of Contents #TR11-A) 100 (3) Cy34ated anti-rabbit antibody IgG 100 (2) anti-gastrin antibody, goat antibody, multi-drug antibody Santa Cruz Biotechnology Inc.) 200 or 400 (4) to Alexa Fluoro 488 labeled anti-goat antibody IgG 100 < 2 > Results The results of immunostaining observed in the same range with a conjugated focal laser microscope are shown in Fig. 2. Cells scattered in the gastric mucosa were stained with anti-T1R1 receptor antibody (Fig. 2A) and anti-gastrin antibody (Fig. 2B). In the overlay of Fig. 2A and Fig. 2B (Fig. 2C), the dyed images are in mutual agreement. This clarifies that the .T1R1 positive cells in the stomach produce cells for gastrin (one of the gastrointestinal hormones). Since T 1 R 1 is expressed in gastrin-forming cells, it associates with the functional relationship of gastrin endocrine regulation. Example 3: Detection of TIR1 mRNA expression in the stomach by molecular biological method <1>TIR1 mRNA partial sequence 歹[| amplification -46-200803899 (43) Removal of the glandular stomach from the stomach of rats (Sprague-Dawley) The mucosa of the vestibular part of the pylorus. The braided mastoids including the taste buds and the tasteless bud tissue are taken out from the tongue. Total RNA extracted from each part of the stomach and tongue samples was used as a template and SuperScrip reverse transcriptase (Invitrogen, California, USA) for reverse transcription. Using the obtained cDNA as a template, T1R1 was amplified using the following gene-specific primers and LA taq (TaKaRa). The gene-specific primer used is shown below. Sequence ID: 1 : T1R1-824 Forward 5'-AGGACCACCGTGGTCGTGGTCTT-3' SEQ ID NO: 2: T1R1-2163 Reverse 5'-GCACTCAAGAATCACCAGATGGG-3, < 2 > Results Samples derived from the gastric pyloric vestibular mucosa (Fig. 3, lane 5) and the tongue. sacral papilla (Fig. 3, lane 2) obtained PCR products of the same size. Sequence analysis reveals these? The product of €11 has the same sequence as T1R1 derived from taste cells. On the other hand, the PCR product was not obtained from the samples derived from the gastric glandular mucosa φ (Fig. 3, lane 4) and the tongue. tasteless bud tissue (Fig. 3, lane 3). Further, the p CR product was not obtained from the sample which was not subjected to the amplification reaction by reverse transcriptase (Fig. 3, lanes 6, 7). - The stomach pyloric vestibular site is especially known as the part of the distribution of gastrin-producing cells. By this example, T1R1 expression in the mucosa of the gastric pyloric vestibular site was established not only by immunohistochemistry but also by molecular biologic methods. Example 4: Gastric contents emptying test using T1R agonist <Experimental method> • 47-200803899 (44) Gastric emptying method in mice ICR male mice were used. 5% of Compound 1 (1 ppm by weight and 1 〇 ppm by weight) containing 0.05% phenol red and the test drug (3.5 mM cyclohexylamine sulfonate, 3.7 mM MSG (monosodium glutamate), the following Production Example 1) The casein liquid diet (0.5 ml) was administered orally and the chest was opened and the stomach was separated after 30 minutes. The stomach was placed in 0.1 N sodium hydroxide (14 ml), homogenized and left at room temperature. i hours. Add 20% trichloroacetic acid (0.5 ml) to 5 ml of the supernatant and centrifuge the mixture (3 000 rpm, 20 minutes). Add 0.5 N sodium hydroxide (4 ml) to the supernatant. The absorption enthalpy was measured by an absorption spectrometer (560 nm). The gastric emptying rate was determined by the following formula: Gastric emptying speed (%) = (1 - absorption of test sample / absorption of standard sample値) X 1 0 0 Regarding the absorption enthalpy of the standard sample, the stomach immediately after administration of the 〇.〇5 % phenol red solution was used. Example 5: Gastrointestinal exercise test using T1R agonist <Experimental method> The method of monitoring the movement of the gastrointestinal tract by a vigilant dog makes the Migru bitch fasting for 1 night at 1.0%. Abdominal surgery under anesthesia with isoflurane; sew the sensor used to measure gastrointestinal motility on the stomach that allows measurement of the contraction of the annular muscle; -48- 200803899 (45) and suture the abdomen. Within the week, gastrointestinal motility was measured after 1 day of fasting; and the test compound described in the following production examples was orally administered 10 to 20 minutes after completion of the fasting-strong contraction exercise of stage III ( T1R agonist) 3, 5 or 6 (10 ppm by weight, respectively) of 300 ml of concentrated liquid foraging (A ji η 〇m 〇 to C 〇. I ne ·, '' MEDIEF BAG") (each Test group n = l). Calculate the exercise index from the reference line and the surface I product surrounded by the 60-90 minute contraction fluctuation line after oral ingestion, and provide a concentrated fluid with no compound relative to oral administration only. The percentage of the control group of the diet is expressed. <Experimental Results> The results are shown in Figure 6. As the data showed, the test group showed an increase in gastrointestinal motility compared with the control group. Example 6: Using a T 1 R agonist Empty stomach contents Test φ <Experimental method> The gastric emptying method of mice uses ICR male mice. It will contain 0.05% phenol red and the test drug, (3.5 mM cyclohexylamine sulfonate, 3.7 mM MSG (monosodium glutamate) ), the following compound 2, 3, 4 or 5 (10 ppm by weight, respectively) of 5% casein liquid diet (0.5 ml) was orally administered, and after 30 minutes, the chest was opened and The stomach is separated. The stomach was placed in 氢氧化钠·1Ν sodium hydroxide (14 ml), homogenized and left at room temperature for 1 hour. 20% trichloroacetic acid (〇. 5 ml) was added to 5 ml of the supernatant and the mixed -49-200803899 (46) was centrifuged (3000 rpm, 20 minutes). 〇.5N sodium hydroxide (4 ml) was added to the supernatant, and the absorption enthalpy was measured by an absorption spectrometer (56 Å nanometer). The gastric emptying speed is determined by the following formula. Gastric emptying rate (%) = (absorption enthalpy of test sample / absorption enthalpy of standard sample) X 1 0 0 Regarding the absorption enthalpy of the standard sample, the stomach immediately after administration of 〇.〇5 % phenol red solution was used. <Persistent Results> The results are shown in Fig. 7, in which the vertical axis shows the gastric emptying speed (%). It is understood from the figure that Compound 2 - 5 promotes gastric emptying. Production Examples Compounds -6 as described in the following Table 3 were synthesized by the methods described in the following examples. However, the synthesis of these compounds is not limited to the following examples. The structures of the compounds synthesized in the following examples were confirmed by nuclear magnetic resonance spectroscopy (Bruker AVANCE 400 (400 MHz)) and mass spectrometry (Thermo Quest TSQ700). Production Example 1: Synthesis of 3,6-dichloro-indole-(4-ethoxyphenyl)-2-methoxybenzamide (Compound 1) 3,6·Dichloro-2-methyl Oxybenzoic acid (1.68 g, 7.60 mmol 50 -

200803899 (47) Ear) and p-ethoxyaniline (1·〇4 g, 7.60 mmol) in nitrile (30 ml). 1H-benzotriazole-(dimethylamino) hexafluorophosphate (BOP, 3.21 g, 7.60 mmol) diisopropylethylamine (DIEA, 4.0 mL, 23.5 mmol) force [should mixture The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. ethyl acetate (1 mL) was evaporated. The organic layer was washed with water (50 ml) aqueous chloric acid (50 mL), brine (50 mL of saturated aqueous sodium hydrogen sulfate (50 mL) and brine) and dry. The magnesium sulfate was filtered and concentrated under reduced pressure. The residue obtained was recrystallized twice from ethyl acetate to give the title compound (g, 3.26 m. W-NMR (CDC13, (5): 1.44 (t, J = 7.0Hz, 3H), (s, 3H), 4.03 (q, J = 7.0Hz, 2H) 5 6·90 ( d, J = 9.0Hz 7·15 ( d, J = 8.6 Hz, lH), 7·40 (br.s'lH), 7.36 (d5 1H ), 7·50 ( d, J = 9.〇Hz, 2H ). ESI-MS : 340.2, 342.2 ( M + H ) +. Production Example 2: Synthesis of 2,5-dichloro-N-(4-ethoxyphenyl)benzeneate 2). Same as Production Example L In the manner obtained as a white compound (yield 6 6.8 %), except for the use of 2,5-dichlorobenzene 3,6-dichloro-2-methoxybenzoic acid. Add ethoxy group to N, N- Inclusion of this reaction will be carried out into the residual, 2N-hydrogen'), carbon (50 milligrams will be filtered - n-hexane 1. 1 1 male 3.99, 2H), J = 8 · 6 Η z, amine (standard acid of the chemical body) Substitute -51 - 200803899 (48) !H-NMR (CDC13, 5): 1.42 (t, J = 7.0Hz, 3H), 4·04 (q, J = 7.0Hz, 2H), 6.90 (d, J = 10_2Hz, 2H), 7.38 (S, 2H), 7.51 ( d, J = 10.2Hz, 2H ), 7.74 ( s, lH ), 7.78 ( br.s, lH ). ESI-MS·· 310.2, 312.2 ( M + H) +. Production Example 3: N-(1-ethylpropyl)-benzofuran-2-carboxamide Compound 3) synthesis

The title compound (yield 75.1%) was obtained as white crystals in the same manner as in Production Example 1, except that benzofuran-2-carboxylic acid was used instead of 3,6-dichloro-2-methoxybenzoic acid and - Aminopentane in place of p-ethoxyaniline. 'H-NMR (CDC13?(5) : 1.03 (t?J = 7.4Hz56H) 5 1.48- 1.59 (m, 2H), 1.64-1.75 (m, 2H), 3.98-4.07 (m, lH), 6· 35 ( br.d,lH),7·26·7·3 1 ( m,lH),7.3 8-7.43 ( m,lH), 7·46 ( s,lH) , 7.50 ( d,J = 8.4Hz , lH), 7·68 (d, J = 8.4 Hz, 1H) 〇ESI-MS: 232.0 (M + H) +. Production Example 4: N-( 1,2,3,4-tetrahydronaphthalene-1 -Synthesis of benzo[l,3]dioxol-5·carboxamide (Compound 4) The title compound was obtained as white crystals in the same manner as in Production Example 1 (yield 74.7%) In addition to the use of geranic acid instead of 3,6-dichloromethoxybenzoic acid and the use of I,2,3,4-tetrahydro-1-naphthylamine in place of p-ethoxyaniline. -52- 200803899 (49) 'H-NMR ( CDC135(5 ) : 1.84-1.96 ( m?3H) 5 2.10-2.17 (m,lH ), 2.76-2.8 8 ( m,2H ),5.3 3 -5.3 7 ( m,lH ), 6.01 (s, 2H), 6.20 (br.d, lH), 6.80 (d, J = 8.5 Hz 5lH), 7.12 - 7.33 (m, 6H). ESI-MS: 296.0 (M + H) +. Example 5: Synthesis of 4-ethoxy-N-(1-propylbutyl)benzamide (Compound | 5) 4-Ethoxybenzene Formic acid (1.66 g, 10.0 mmol) and 4-heptylamine (1·15 g, 10.0 mmol) were added to dichloromethane (30 mL) and the solution was maintained at 0 ° C in an ice bath. 1-Hydroxybenzotriazole (HOBt, 1.68 g, 11.0 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC, 2.11)克克, 1 1 · 0 mmol) was added to the reaction mixture, and the mixture was removed from the ice-bath and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and ethyl acetate <RTIgt; Add the residue and stir the mixture. The organic layer is water (50 ml), 5% aqueous citric acid (50 ml x 2), saturated brine (50 ml), 5% aqueous sodium hydrogen carbonate (50 ml, x2) The mixture was washed with brine (50 ml) and dried over anhydrous magnesium sulfate. The residue obtained was recrystallized twice from ethyl acetate to give the title compound (663 mg, 2.52 mmol, 25.2%). W-NMR ( CDC13,5 ) : 0.90 ( t, 7.1 Hz, 6H), 1·33-1·65 (m, 15H) 5 4.07 ( q, J = 7,0Hz, 2H) , 4.10-4.20 ( m , lH), -53- 200803899 (50) 5·65-5·75 (m, lH), 6.90 (d, J = 8.8 Hz, 2H), 7·71 (d, J = 8.8 Hz, 2H). E S I - M S : 2 6 4 · 0 ( Μ + Η ) +. Production Example 6: Synthesis of 3-(4-methoxyphenyl)-N-(1-propenylbutyl)propene oxime (Compound 6)

The title compound (yield 41.4%) which became white crystals was obtained in the same manner as in Production Example 5 except that 4-methoxy cinnamic acid was used instead of 4-ethoxybenzoic acid. iH-NMRCCDClhHUOCnJW.OHzJH), ^-1.55 (m, 12H), 3.82 (s, 3H), 4.05-4_15 (m, lH), 5.35-5.55 (m, lH), 6.27 (d, J = 15.5 Hz, lH), 6·87 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 15.5 Hz, lH). ESI-MS: 276.1 (M + H) +.

-54- 200803899 (51) Table 3 Structure name Compound 1 3,6·Dichloro-indole-(4-ethoxyphenyl)-2·methoxybenzamide compound 2 2,5-Dichloro· Ν-(4-ethoxyphenyl)benzamide compound 3 0 S hepta-(l-ethylpropyl)-benzofuran-2-carboxamide compound 4 0 N-(l,2,3 ,4-tetrahydronaphthalen-1·yl)-benzo[1,3]dioxol-5-formamide compound 5 4-ethoxypropylbutyl)benzamide compound 6 3-( 4-methoxyphenyl)-indole-(1-propenyl) acrylamide industrial application According to the present invention, it is possible to provide a pharmaceutical, food or drink for promoting gastrointestinal function, which is useful for preventing or improving, for example, functional gastrointestinal tract Diseases, especially upper gastrointestinal dysfunction, such as functional dyspepsia, gastroesophageal reflux disease and the like. The use of the composition of the present invention can safely and effectively achieve prevention or improvement of dyspepsia associated with gastrointestinal dysfunction, such as FD and the like, without inducing side effects. Further, the screening method of the present invention is used to detect an active ingredient to be incorporated into the above-mentioned pharmaceutical agent, food or drink of the present invention and an experiment which can be used in the field of physiology and biochemistry. The present application is hereby incorporated by reference in its entirety in its entirety in its entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 shows the results of immunostaining using an anti-T1R1 antibody, wherein the arrow shows stained cells, (A) is a gastric pyloric vestibular site, (B) is a small intestine, and (C) is a taste bud of taste buds. Figure 2 shows the results of double immunostaining using an anti-T1R1 antibody and an anti-gastrin antibody in the same range, wherein (A) is a T1R1 staining image, (B) is a gastrin staining image, and (C) is ( A) and (B) overlapping images. Figure 3 shows the results of electrophoresis of PCR products derived from each tissue, wherein the left end is an RNA marker, lanes 2-5 from the left are amplification reaction products in the presence of reverse transcriptase and lanes 6-7 are in the absence of a Reaction product in the presence of transcriptase (left end: RNA marker, lane 2: tongue, sputum-like mastoid, lane 3 · tongue, tasteless bud tissue, lane 4: stomach. glandular gastric mucosa, φ lane 5: stomach pyloric vestibule Part of the mucosa). Figure 4 shows the rate of gastric emptying when cyclohexylamine sulfonate and MSG were administered. Figure 5 shows the gastric emptying rate when Compound 1 was administered (1 ppm by weight and 1 〇 by weight ppm). Figure 6 shows the results of a gastrointestinal motility test in which compounds 4, 5 and 6 (10 ppm by weight, respectively) were administered. Figure 7 shows the gastric emptying rate when Compounds 2, 3, 4 and 5 were administered (1 重量 by weight ppm, respectively). -56·

Claims (1)

200803899 (1) X. Patent application scope 1 · A gastrointestinal function promoting agent comprising a T 1 R component. 2. The agent according to the first application of the patent application can promote the prevention or improvement of functional gastrointestinal diseases. 3. According to the reagent of the second application of the patent application, the intestinal disease is upper gastrointestinal dysfunction. 4. According to the reagent of claim 2, the intestinal disease is functional dyspepsia or gastroesophageal reflux disease. 5. An appetite regulating agent comprising a T 1 R agonist. 6. The T1R agonist according to any one of claims 1 to 5 is a guanamine derivative or a cyclamate. 7. The reagent according to item 6 of the patent application, wherein the blood is a compound represented by the following formula (I): (1) R1 wherein R1 is an optionally substituted aryl group, a random aralkyl group, optionally has a substituent An aralkenyl group, a heteroaryl group with a heteroaryl group, a heteroarylalkenyl group optionally substituted with a heteroarylalkyl group, an R3-NH-CO- or an R3-NH-agonist as a living gastrointestinal tract In the functional stomach, the functional gastric agent is an active ingredient agent, and the 3-amine sulfonate in the 3-amine sulfonate has a substituent which is intentionally substituted and optionally has: R3 is optionally -57- 200803899 (2) an aryl group having a substituent, an aryl group optionally having a substituent, an aralkenyl group optionally having a substituent, a heteroaryl group optionally having a substituent of a month, and a heteroaryl group optionally having a substituent a base or a random heteroaryl group having a substituent, and R2 is a c3_25 cycloalkyl group of a c2 substituent optionally having a substituent (the cycloalkyl group having an aryl group having a substituent, optionally having an aromatic group having a substituent, optionally having a substituent a heteroarylalkyl group or a random group, 25 院, optionally condensed with benzene, a random substituent of an aralkyl group, a random substituent having a heteroaryl group, and an oxime I h ^ gastric substituent a heteroarylene or a pharmaceutically acceptable salt thereof. 8 · According to item 7 of the scope of application, it is a compound selected from the group consisting of: guanamine derivatives (1) 3,6-^Chloro-N- (4-Ethoxy tomb stupid &amp; }Methoxybenzidine (2) 2,5-monochloro-N- ( 4 - 乙 j 基 ( (3) Ν-(1·ethylpropyl)-benzofuran (4) Ν· ( 1,2,3,4 - tetrahydronaphthalene-1, pentylene-5-formamide, base) lean to carbamide, I' amide, ), benzo[1,3]diox 4-Ethoxy-N-(1-propenyl)% Benzene-3-(4-methoxyphenyl), (L芮 Butyl) propylene oxime 9. A reagent of any one of the pharmaceutical compositions. The invention includes the patents of the first to fifth items - 58 ^ 200803899 (3) ίο - a food or beverage comprising the reagent of any one of claims 1 to 5 wherein the activity in the reagent The ingredient comprises from 0.01 to 10,000,000 ppm by weight of the food or beverage. 11 A method of screening for a substance capable of promoting gastrointestinal function, which uses a cell exhibiting a τ 1 R receptor. 1 2 . The substance capable of promoting gastrointestinal function according to the method of claim i1, wherein the substance is a Τ 1 R agonist or a τ 1 R modulator. Φ 1 3 · A method for screening a substance capable of promoting gastrointestinal function, comprising the following steps (a), (b) and (〇): (a) contacting a test substance with a cell expressing a Τ 1 R receptor, (b) determining G-protein activation in cells in contact with the test substance, and comparing with activation in control cells not in contact with the test substance, and (c) comparing the results of (b) above Choose substances that promote gastrointestinal function. Φ 14. The method of claim 13, wherein the index for determining G-protein activation is selected from the group consisting of intracellular calcium concentration, intracellular cAMP amount, extracellular proton amount, and intracellular gastrointestinal hormone secretion. I 1 5 . A method for screening a substance capable of promoting gastrointestinal function, which comprises the following steps (a), (b) and (c): (a) a test substance and a ligand acting on a T1R receptor Contact with cells expressing the T1R receptor' (b) measuring the amount of ligand bound to the cell membrane of the cell' and comparing it with the amount of ligand in the control cell not in contact with the test substance, and -59-200803899 (4 (c) a substance that compares colonic function with the above (b). 16. A T 1 R agonist that promotes gastrointestinal function is administered to mammals. 17. Promotion according to the 16th function of the patent application for functional gastrointestinal diseases 18. According to the patent application scope 1 7 φ Gastrointestinal diseases for upper gastrointestinal dysfunction 19. According to the patent application scope 17 gastrointestinal diseases for function Sexual dyspepsia or 20. A method of regulating appetite, 3 drugs are administered to mammals. 2 1. According to the scope of patent application No. 16- T1R agonist is sulfamate: (cyclamate). Φ 22. According to the scope of the patent application, the compound represented by the following formula (I): R1 Wherein R 1 is an optionally substituted arylalkyl group, optionally a heteroaryl group having a substituent group, optionally having a substitutional fruit as a reference for promoting a gastric method, comprising an effective amount of a method wherein the gastrointestinal tract Prevention or improvement of the Tao. The method of the item, wherein the method of functional 〇, wherein the functional gastroesophageal reflux disease. And a method comprising the method of any one of an effective amount of T 1 R, wherein the indoleamine is derived from (1) an aryl group, optionally substituted with an aralene. Heteroaryl group optionally having a heteroaryl group, optionally having a heteroaryl group of #-60-200803899 (5) 13-&gt;^-(:〇- or R3_nh an aryl group having a substituent, a aryl group optionally having a substituent: an aralkenyl group having a substituent, a heteroaryl group optionally having a substituent, optionally a heteroaryl group having a substituent or a heteroarylalkenyl group optionally having a substituent, and R 2 is a C 2 25 alkyl group optionally having a substituent, and a Cm cycloalkyl group optionally having a substituent (the cycloalkyl group) Arbitrarily condensed with benzene), optionally Φ-substituted aryl group, optionally substituted aryl group, optionally 'substituted aralkenyl group, optionally substituted heteroaryl group, optionally A heteroarylalkyl group having a substituent or a heteroaryl M group optionally having a substituent, or a pharmaceutically acceptable salt thereof. 2 3. The method according to item 22 of the patent application, wherein the guanamine derivative is a compound selected from the group consisting of: (1) 3,6-dichloro-N-(4.ethoxyphenyl)- 2_Methoxybenzamide' (2) 2,5-Dichloro·Ν·(4·ethoxyphenyl)benzamide, (3) N-(l-ethylpropyl)· Benzopyran-2-carbamide, (4) &gt; 1-(1,2,3,4-tetrahydronaphthalenyl-buyl)-benzo[1,3]dioxane-5 - formic acid amine, (5) 4-ethoxy-N-(1-propbutylbutyl)benzamide, and (6) 3-(4-methoxyphenyl)-N-(κ-propylbutyl)propene Guanamine. The method according to any one of claims 16 to 20, wherein -61 * 200803899 (6) comprises administering a pharmaceutical composition comprising the T 1 R agonist and a carrier to the mammal. The method according to any one of claims 16 to 20, which comprises administering a food or drink containing the T1R agonist in a ratio of 〇.〇1-1〇〇, 〇〇〇ppm by weight to mammals . 26. Use of a T1R agonist for the production of a composition for promoting gastrointestinal function. I 27. The use according to claim 26, wherein the promotion of gastrointestinal function is prevention or improvement of a functional gastrointestinal disease. 28. The use according to claim 27, wherein the functional gastrointestinal disorder is upper gastrointestinal dysfunction. 2 9. The use according to item 27 of the patent application scope, wherein the functional gastrointestinal disease is functional dyspepsia or gastroesophageal reflux disease. 3 〇. The use of T 1 R agonist in the production of appetite regulation, composition The use of animal husbandry 1. Φ 3 1. The use according to any one of claims 26 to 30, wherein the T1R agonist is a guanamine derivative or a cycloamine compound 〇, _ (cyclamate) 〇, 32. According to claim 31 The use thereof, wherein the guanamine &amp; $ is a compound represented by the following formula (I): -62- 200803899 (7) wherein R1 is an optionally substituted aryl group, optionally substituted aralkyl group, optionally substituted aralkenyl group, optionally substituted heteroaryl group, optionally a heteroarylalkyl group having a substituent, an anthracene group optionally having a substituent, R3-NH-CO- or R3-NH- (wherein R3 is an aryl group optionally having a substituent, optionally having a substituent An aralkyl group, an optionally substituted aryl aryl group, a heteroaryl group having a substituent in the oxime, a heteroarylalkyl group optionally having a substituent or a heteroarylene optionally having a substituent a fused aromatic, a random aralkyl group, a random heteroaryl group, a heteroarylene with a substituent, wherein the decylamine is derivatized into a C1_25 decyl group having a substituent, a C2_25 ring of a substituent An alkyl group (the cycloalkyl group optionally has an aryl group having a substituent on the benzene group, an aralkenyl group having a substituent optionally having a substituent, a heteroarylalkyl group optionally having a substituent and optionally having a substituent or optionally The ground has a radical, ' or a pharmaceutically acceptable salt thereof. 33. The use according to item 32 of the scope of the patent application is a compound selected from the group below. (3 _ ethoxyphenyl * 2-methoxybenzimidone) benzamide, meglumine, - benzo[1,3]dioxetane, and -63 - 1 2,5_Dichloro-Ν·(4_ethoxyphenyl(2) Ν-(1-ethylpropyl)-benzofuran·2 2 (3 ) Ν· ( 1,2,3,4- Tetrahydronaphthalen-1-yl) 3 pentene-5, formamide, 200803899 (8) (6) 3-(4-methoxyphenyl)-N- (1-propylamine. 34. According to the scope of application Items 26 to 30, wherein the composition is a pharmaceutical product. 35. According to the scope of the patent application No. 26 to 30, wherein the composition contains 〇.〇1-1〇〇, 〇〇〇 weight T 1 R A food or beverage of an agonist. A ratio of ppm used in any one of butyl) acrylonitrile -64- 200803899 Sequence Listing &lt;110&gt; AJINOMOTO CO., INC. <120> Gastrointestinal Function Promoter &lt;130> 09972 &lt;150> JP 2005-320827 &lt;151>2005-n-04 &lt;160> 2 &lt;170&gt; Patentln version 3.1 &lt;210> 1 &lt;211> 23 &lt;212> DNA &lt;213&gt; <220> <223>Introduction &lt;400> 1 23 aggaccaccg tggtcgtggt ctt 200803899 &lt;210> 2 &lt;211> 23 &lt;212&gt; DNA <213>artificial &lt;220> &lt;223〉弓一子 &lt;400〉 2 23 gcactcaaga atcaccagat ggg