TW200533337A - Pharmaceutical compositions for prevention or treatment of diseases associated with esophageal dysmotility and use thereof - Google Patents

Abstract

The present invention relates to pharmaceutical compositions comprising as active ingredients aminoethylphenoxyacetic acid derivatives represented by the following general formula (1) or pharmaceutically acceptable salts thereof, which are useful for prevention or treatment of diseases associated with esophageal dysmotility such as esophageal achalasia, esophageal spasm, dysphagia, etc., and the like. In the formula, R1 represents a hydrogen atom. a lower alkyl group or an aralkyl group; R2 represents a hydrogen atom or a halogen atom; a carbon atom marked with (R) represents a carbon atom in R configuration; and a carbon atom marked (S) represents a carbon atom in S configuration.

Description

200533337 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to a pharmaceutical composition and the like that can be used for the prevention or treatment of diseases accompanied by esophageal dyskinesia. More specifically, the present invention relates to

Atom, the carbon atom with (R) is a carbon atom of the (R) configuration, and the carbon atom with (S) is a carbon atom of the (S) configuration] amine ethylphenoxyacetic acid derivative shown in [] Or a pharmacologically acceptable salt thereof as an active ingredient, a pharmaceutical composition that can be used for the prevention or treatment of a disease accompanied by esophageal dyskinesia. [Prior art]

The structure of the esophagus is composed of the upper esophageal sphincter, the esophageal body and the lower esophageal sphincter. The upper part of the esophagus is composed of striated muscles and the lower part is composed of smooth muscles. If dyskinesias such as contraction and excessive tension are caused in these parts, the peristaltic movement of the esophagus and the function of the lower esophageal sphincter are hindered, and dysphagia and chest pain during swallowing are caused. For example, in diseases such as esophageal achalasia and esophageal spasm, the movement of the esophagus and the function of the lower esophagus sphincter are impaired, causing a swallowing disorder. In addition, among these diseases, there are symptoms associated with subswallowing disorder, reverse flu, chest pain, intraoral reflux, weight loss, vomiting blood, chest burns, excessive saliva secretion, cough, and upper abdominal pain (see Non-Patent Literature) 1 ~ 4). 5 312XP / Invention Manual (Supplement) / 94-05 / 94103984 200533337 The treatment of these diseases or symptoms, for example, for the purpose of expanding the lower esophageal sphincter due to potential & and M series stenosis. Insertion under the microscope | & Corpse I Dilation Balloons to improve the forced dilatation through surgery and surgical esophageal incision ^ ^ In addition, the drug therapy includes nitrite-based calcium channel blockers such as nitroglycerin sublingual tablets Nifedipine (Nifedipine) and anticholinergic test $ _ < Octatropine Methylbromide etc. It is said that these drugs are worried about the side effects of lower blood pressure on the circulatory system, so they are eager to develop a safe and effective drug early.

The compound represented by the aforementioned general formula (I) or a pharmacologically acceptable salt thereof has been reported to have selective / 32 and / 33 adrenergic receptor stimulation, and reduce / 3 1 adrenergic receptor stimulation The side effects caused by the action on the circulatory system such as the heart can be used as a pain relief and excretion enhancer for urethral calculi (see Patent Document 1). However, these compounds have not been known to be useful in the treatment of relaxation of the esophagus, esophagus, esophageal spasm, and pharyngeal disorders, and have not been disclosed or suggested. Patent Document 1: International Publication No. 9/0 0 5 0 9 0 Non-Patent Document 1: Fukushima Director Xiu Xiu, Merck Manual 17th edition Japanese version of "esophageal disease", [0 η 1 ine], Wanyou Pharmaceutical Co., Ltd., [Retrieved on February 6, 2015], URL & URL: http: // merckmanual. Banyu. Co. J ρ / > Non-Patent Document 2: Current Medica 1 Diagnosis And Therapy, Nikkei BP, 2003, ρ · 554-555, 570-571 Non-Patent Document 3: Today's Treatment Guide 2004 Edition, Medical College, 2004, ρ 320 6 312XP / Description of the Invention (Supplement) / 94-05 / 94103984 200533337 Non-Patent Document 4: Digestive Disease, Yangtu Company, September 25, 1996, 9-9-10 0 [Content of the Invention] (Inventory) Problem to be Solved) An object of the present invention is to provide a pharmaceutical composition and the like that can be used for the prevention or treatment of diseases associated with esophageal dyskinesia, such as esophageal achalasia. (Means for solving problems)

The present inventors made earnest research in order to find an agent that can be used to prevent or treat a disease accompanied by esophageal dyskinesia, and as a result, found that the compound represented by the aforementioned general formula (I) has an excellent esophageal relaxation effect, and completed the present invention. That is, the present invention relates to: (1) a pharmaceutical composition for the prevention or treatment of a disease accompanied by esophageal dyskinesia, characterized in that it contains an amine ethylphenoxyacetic acid derivative represented by the general formula (I); or The pharmacologically acceptable salt is used as the active ingredient; (2) The pharmaceutical composition as described in (1) above, wherein the active ingredient consists of 2- [3-fluoroyl-4- [2-[[(lS, 2R ) -2 -Hydroxy-2- (4-hydroxyphenyl)-1-fluorenylethyl] amino] ethyl] phenoxy] acetate f-ester, 2- [3-chloro-4-[2- [[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) _1-methylethyl] amino] ethyl] phenoxy] acetic acid, 2- [4- [2-[[ (1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid, 2- [3-enyl-4- [ 2-[[(1S, 2R) -2 -Ethyl-2- (4-Ethyl) -1-amidinoethyl] amino] ethyl] phenoxy] acetic acid and its pharmacological institutes Compounds selected by acceptable salts; (3) The pharmaceutical composition as described in (2) above, wherein the active ingredient is 2-[4-[2 312XP / Invention Specification (Supplement) / 94-05 / 94103984 200533337-[ [(IS, 2R)-2-Ethyl-2- (4-Ethyl) -1 -fluorenylethyl] amine [Ethyl] ethyl] phenoxy] acetic acid or a pharmacologically acceptable salt thereof; (4) The pharmaceutical composition according to any one of (1) to (3) above, wherein the disease is accompanied by a disease of esophageal dyskinesia For esophageal achalasia, esophageal spasm, or the accompanying symptoms thereof; (5) The pharmaceutical composition according to any one of (1) to (4) above, which is intended for esophageal dysphagia, Esophageal spasm, or other symptoms associated with it-used in combination with one or more drugs; Φ (6) the pharmaceutical composition as described in (5) above, wherein the esophageal spasm, esophageal spasm, or their accompanying Other drugs used for each symptom are drugs selected from calcium channel blockers, anticholinergics, nitrite compounds, and xanthine derivatives; (7) — prevention of diseases associated with esophageal dyskinesia or The treatment method is characterized by administering an effective amount of the amine ethylphenoxyacetic acid derivative represented by the aforementioned general formula (I) or a pharmacologically acceptable salt thereof; (8) the prevention according to (7) above or Treatment method, in which the drug is administered by 2-[3

-Fluoro-4-[2-[[(IS, 2R)-2 -Ethyl-2- (4-Ethylphenyl) -1 -methylethyl] amino] ethyl] phenoxy] acetic acid Benzyl ester, 2_ [3 -chloro_ 4-[2-[[(1 S, 2R) -2 -hydroxy-2- (4-hydroxyphenyl) -1-amidinoethyl] amino] ethyl Phenyl] phenoxy] acetic acid, 2- [4- [2-[[(lS, 2R) -2 -Ethyl-2- (4-Ethylphenyl) -1 -fluorenylethyl] amino] ethyl Phenyl] phenoxy] acetic acid, 2- [3-airyl-4- [2-[[((lS, 2R) -2-Cycloyl-2-(4-Cycylphenyl) -1-fluorenylethyl ] Amine] ethyl] phenoxy] acetic acid and other compounds selected from pharmacologically acceptable salts; (9) The method for prevention or treatment as described in (8) above, wherein the drug administered is 2-[ 4-8 312XP / Invention Specification (Supplement) / 94-05 / 94103984

200533337 [2-[[(1S, 2R) -2-Ethyl-2- (4-Ethylphenyl) -1-fluorenylethyl] phenoxy] acetic acid or a pharmacologically acceptable salt thereof; ( 1 0) The disease associated with esophageal dyskinesia that is prevented or treated as described in any one of (7) to (9) above is the accompanying symptoms of esophageal achalasia, U.S., etc .; (1 1) as described in (7 ) Prevention or treatment of any one of (1) to (1) Administering at least one agent for esophageal achalasia, esophageal spasm, or the like until it is used; (1 2) Prevention or treatment as described in (1 1) above Treatment methods, including # disease, esophageal spasm, or the accompanying symptoms of calcium channel blockers, anticholinergic drugs, and nitrite-selected agents; (13) — the aforementioned general The use of the amine ethylphenoxy represented by formula (I) or a pharmacologically acceptable salt thereof is characterized in that it is used for the prevention or treatment of diseases associated with esophageal dyskinesia (14) as described in (13) The use of which is d-4- [2-[[((lS, 2R) _2-Ethyl-2- (4-Ethyl) -1-Pingyl] ethyl] phenoxy] acetic acid Section S, 2- [3 -Gasyl-4- [2 2R) -2 -hydroxy-2- (4-hydroxyphenyl) -1-fluorenylethyl] amino] acetic acid, 2- [4- [2-[[(lS, 2R) -2-hydroxy-2- (4-methylethyl] amino] ethyl] phenoxy] acetic acid, 2- [3-fluoro [[(1S, 2R)-2-hydroxy-2-(4-hydroxyphenyl) -1- The compound selected from fluorenylethyl J phenoxy] acetic acid or its pharmacological (15) uses as described in (14) above, wherein the drug used is cl 312XP / Invention Specification (Supplement) / 94-05 / 94103984 Ethyl] amino] method, which is accompanied by [convulsions, or its method, which goes one step further. Each symptom f is caused by esophageal relaxation. Other drugs are made from 7, xanthine derivative acetic acid derivative, used to make partners. ? Composition;? 2-[3 -Fluoro7ylethyl] amine-[[(1 S,] ethyl] phenoxyhydroxyphenyl) -1 -yl-4- [2- ^] amino] Ethyl] Permissible salts;!-[4- [2- 9 200533337 [[(IS, 2R) — 2-hydroxy-2-(4-hydroxyphenyl) -1monomethylethyl] amino] ethyl [Phenyl] phenoxy] acetic acid or a pharmacologically acceptable salt thereof; (16) The use according to any one of (13) to (15) above, wherein the disease accompanied by esophageal dyskinesia is esophageal achalasia , Esophageal spasm, or the like Each symptom, (1 7) The use according to any one of (1 3) to (16) above, which further uses at least one other medicament for esophageal achalasia, esophageal spasm, or the accompanying symptoms thereof ;

(18) The use as described in (17) above, wherein the other agents used for esophageal achalasia, esophageal spasm, or the accompanying symptoms thereof are calcium channel blockers, anticholinergics, and nitrite compounds , Selected agents from xanthine derivatives; etc. The esophageal relaxation effect of the compound represented by the aforementioned general formula (I) can be evaluated, for example, by using a mouse to remove the lower esophageal sphincter and reducing the sustained tetanic contraction induced by the Carbachol test (C a b a c h ο 1). As a result, the compound of the general formula (I) has a strong esophageal relaxation effect, and is therefore extremely effective for the prevention or treatment of diseases associated with esophageal dyskinesia such as esophageal achalasia, esophageal spasm, and pharyngeal disorders. Examples of diseases associated with esophageal dyskinesia of the present invention include esophageal achalasia, esophageal spasm, and accompanying pharyngeal disorders, reverse influenza, chest pain, intraoral reflux, weight loss, vomiting, chest burns, excessive saliva secretion, and cough. , Upper abdominal pain, and other symptoms, and the aforementioned general formula (I) compound is particularly suitable for esophageal achalasia, esophageal spasm, and the accompanying pharyngeal disorders. 10 312XP / Invention Specification (Supplement) / 94-05 / 94103984

200533337 In the present invention, a lower alkyl group is an alkane numbering from 1 to 6 such as fluorenyl, ethyl, propyl, isobutyl, isobutyl, second butyl, third butyl, pentyl, and hexyl. An aralkyl group is an aromatic low-carbon group such as a phenyl group or a naphthyl group, and a halogen atom is an II atom, a gas atom, an atom, or an angstrom atom. Among the compounds represented by the aforementioned general formula (I), preferred compounds may be, for example, 2- [3-fluorofluoro-4- [2-[[(1S, 2R) -2-Cyclo-2-2- (4-Cyclobenzene -1-Aminoethyl] amino] ethyl] phenoxy] benzyl acetate, 2- [3 -Ga # -4_ [2-[[((1S, 2R) -2-hydroxy-2- (4 -Hydroxyphenyl)-1-fluorenylethyl] ethyl] phenoxy] acetic acid, 2-[4_ [2-[[(1S, 2R) -2_Cycloyl-2 hydroxyphenyl) -1 -Fluorenylethyl] amino] ethyl] phenoxy] acetic acid, 2- [3--4- [2- [[((1S, 2R) -2- mesyl-2- (4-hydroxyphenyl ) -1-Aminoethylethyl] ethyl] phenoxy] acetic acid and its pharmacologically acceptable salts. Preferred compounds include 2- [4- [2-[[(lS, 2R) -2-Hydroxy-2- (4-phenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (hereinafter, referred to as Compound 1) and a pharmacologically acceptable salt thereof. Various methods for producing the compound represented by the general formula (I) are known, and methods such as those described in the literature can be easily produced (see the aforementioned Patent Document J 1). The pharmacologically acceptable salts of the compound represented by the aforementioned general formula (I) 1 include salts such as sodium salts, potassium salts, and other inorganic salts, salts with organic amines such as morphine, and hexahydrozolidine, and amines. Base acid salt. The compound represented by the general formula (I) also includes a solvate with a hydrate and a solvent acceptable for pharmaceuticals of B. In addition, in the 3] 2XP / Invention Specification (Supplement) / 94-05 / 94103984 of the present invention, the carbon group is taken from the bromogen enumeration group) group] amine- (4-fluoro) amine and a monohydroxy group The compound 11 200533337, such as hydrazone and XT, also contains crystalline polymorphs (for example, refer to Japanese Patent Laid-Open No. 1 2-2 1 2 1 3 7 and Japanese Patent Laid-Open No. 1 2-2 1 2 1 3 No. 8; JP-A No. 1 2-2 1 2 1 3 9; International Publication No. 0 0/0 4 3 3 5 0).

The compound represented by the general formula (I) may be used in combination with one or more other drugs for esophageal achalasia, esophageal spasm, and other accompanying symptoms. Other drugs that can be used in combination include, for example, calcium channel blockers (nifedipine, diltiazem, etc.), anticholinergics (atropine sulfate, etc.), and nitrite compounds (Nitroglycerin, isosorbide nitrate, etc.), xanthine derivatives (Theophylline, etc.), etc. When the compound represented by the aforementioned general formula (I) is used in combination with one or more other agents, the present invention includes simultaneous administration in a single formulation, and the same or different administration routes in individual formulations. Any one of the administration forms of the simultaneous administration of the compound of the present invention and the administration of the compound of the present invention in combination with other agents described above in any one of the administration forms in the form of an individual preparation through the same or different administration paths at intervals. In the form of administration of the single preparation type as described above and the administration form of combining individual preparations. When the compound represented by the general formula (I) is used in appropriate combination with one or more of the other agents described above, an effective effect greater than the multiplying effect of the above-mentioned disease prevention or treatment can be obtained. In the same manner, the dosage can be reduced more than when used alone, or side effects of the above-mentioned agents can be avoided or alleviated. When the pharmaceutical composition of the present invention is used for actual treatment, various dosage forms can be used according to the usage. Examples of such dosage forms include powders, granules, fine granules, dry syrups, bonding agents, capsules, injections, liquids, ointments 12 312XP / Invention Specification (Supplement) / 94-05 / 94] 03984 200533337 , Suppositories, patches, etc., and can be administered orally or parenterally. Depending on the dosage form, these pharmaceutical compositions can be adjusted by the methods used in science and appropriate excipients, disintegrating agents, adhesives, lubricants, diluents, buffers, isotonicity agents, preservatives, etc. , Humectants, emulsifiers, dispersants, stabilizers, dissolution aids, and other pharmaceutical additives are appropriately mixed, diluted, and dissolved, and can be manufactured by adjusting according to the usual method. In addition, when used in combination with other drugs, the active ingredients can be prepared simultaneously or individually as described above.

For example, the powder is a compound represented by the aforementioned general formula (I), and if necessary, appropriate excipients, lubricants, etc. are added and thoroughly mixed to form a powder. For example, a tablet is a compound represented by the aforementioned general formula (I), and if necessary, appropriate excipients, disintegrating agents, binders, lubricants, etc. are added and tableted by conventional methods to form a tablet. Lozenges can be made into film-coated tablets, sugar-coated tablets, enteric-coated tablets, etc. by coating if necessary. For example, a capsule is a compound represented by the aforementioned general formula (I), and if necessary, an appropriate excipient, lubricant, etc. are added and mixed thoroughly, and then filled into an appropriate capsule to form a capsule. In addition, granules can be made into fine particles by conventional methods and then filled. When the pharmaceutical composition of the present invention is used in actual treatment, the dosage of the compound represented by the general formula (I) as an active ingredient is appropriately determined according to the patient's weight, age, gender, disease, and degree of treatment. When administered orally, adults range from 1 to 100 mg per day, and when administered orally, adults range from 0.1 to 1 mg per day, Appropriate for one or several rounds. When used in combination with other drugs, 13 312XP / Invention Manual (Supplement) / 94-05 / 94103984

200533337 The administration amount of the compound represented by the aforementioned general formula (I) can be reduced according to the 'administration amount'. (Effects of the Invention) The pharmaceutical composition of the present invention exhibits excellent esophageal pine. The present invention can be used for the prevention or treatment of esophageal dyskinesia diseases accompanied by esophageal achalasia, lower disorders, and the like. [Embodiment] The effect of the present invention (Example 1) on extracting the lower esophageal sphincter of a rat will be described in more detail with reference to the following examples. After the rats were bled to death and laparotomy, the lower esophagus bracket specimen was removed. The specimen was draped in an organ bath filled with 95% 0 2 and 37 ° C of air and 10 ml of K rebs solution (0r and an initial load of about 0.3 g. The lower esophageal sphincter sensor passed through The pressure pump was derived with isometric properties and recorded. After inducing tonic contraction with 1 // Μ carbachol, sex was added to the organ bath. Add 1 0 // Μ Forskolin (F for maximum relaxation response. Set the shrinkage height before the drug addition to 1 0 // The shrinkage height after the addition of M Forsgalin is set to 0%, and the shrinkage height in the concentration is expressed as a percentage (mean of 6 cases ± marked. The results are shown in Figure 1 As mentioned above, the compound of the general formula (I) described above is strong against carbachol-induced contraction of the sphincter muscle, showing a strong and 312XP / Invention Specification (Supplement) / 9105/94103984 'other drugs' relaxation effect. According to esophageal spasm The contents of the drug composition of the pharynx. About muscles, making tubes 5% C 0 2 mixed ganbath), muscle contraction is written by Zhang Yubi to record the accumulation of the test drug (orskol ine) 44 is 100%, each test drug is Quasi-error) calculate the concentration-dependent 14 200 of the lower esophagus of rats 533337 Reduce effect. (Industrial Applicability) The pharmaceutical composition of the present invention exhibits an excellent esophageal relaxation effect. Therefore, according to the present invention, it is possible to provide a pharmaceutical composition and the like which are extremely useful for diseases associated with esophageal dyskinesia such as esophageal achalasia and esophageal spasm. [Brief Description of the Drawings] Figure 1 shows the esophageal relaxation effect of the aforementioned compound 1 using the lower esophageal sphincter of the mouse. The horizontal axis represents the drug concentration (1 ogM), and the vertical axis represents the concentration before the drug was set to 100%, and 10 // cubic forskolin (? 〇131 ^ 〇1 丨 116) was set to 0% when added. High shrinkage (%). -·-Represents the compound 1 additive group of the aforementioned compound of the present invention. 15 312XP / Invention Specification (Supplement) / 94-05 / 94103984

Claims (1)

200533337 10. Scope of patent application: 1. A pharmaceutical composition for the prevention or treatment of diseases associated with esophageal dyskinesia, characterized in that it contains the general formula XOOR [Wherein R1 is a hydrogen atom, a lower alkyl group or an aralkyl group, R2 is a hydrogen atom or a halogen atom, the carbon atom with (R) is a carbon atom of the (R) configuration, and the carbon with (S) An amine ethylphenoxyacetic acid derivative represented by an atom having a (S) configuration] or a pharmacologically acceptable salt thereof is used as an active ingredient. 2. The pharmaceutical composition according to item 1 of the scope of patent application, wherein the active ingredient is 2- [3_1 group_4-[2-[[(1S, 2R) -2 -Ceto-2- (4-Ceto ) -1-Aminoethyl] amino] ethyl] phenoxy] benzyl acetate, 2- [3-chloro-4-[2-[[(lS, 2R) -2 -hydroxy-2 -(4-hydroxyphenyl)-1-fluorenylethyl] amino] ethyl] phenoxy] acetic acid, 2- [4- [2-[[((S, 2R) -2_hydroxy-2- (4-hydroxyphenyl) -l-fluorenylethyl] amino] ethyl] phenoxy] acetic acid, 2- [3-Fluoro-4-[2-[[((1S, 2R)-2- Selected compounds of hydroxy-2- (4-hydroxyphenyl) -1-amidinoethyl] amino] ethyl] phenoxy] acetic acid and its pharmacologically acceptable salts. 3. The pharmaceutical composition according to item 2 of the patent application scope, wherein the active ingredient is 2- [4- [2-[[(13,21〇-2-hydroxy-2- (4-hydroxyphenyl) -1- Methylethyl] amino] ethyl] phenoxy] acetic acid or a pharmacologically acceptable salt thereof 4. The pharmaceutical composition according to any one of claims 1 to 3 of the scope of patent application, wherein The diseases of esophageal dyskinesia are esophageal achalasia, esophageal spasm 16 312XP / Instruction Manual (Supplements) / 94-05 / 94103984 200533337, or any symptoms accompanying it. 5. If the scope of patent application is 1 to 3 The pharmaceutical composition according to any one of clauses, wherein one or more other drugs used for esophageal achalasia, esophageal spasm, or the accompanying symptoms thereof are used in combination. 6. The pharmaceutical composition according to item 5 of the scope of patent application, wherein the other drugs used for esophageal achalasia, esophageal spasm, or the accompanying symptoms are calcium channel blockers and anticholinergic drugs , Nitrite compounds, Xanthine derivatives. 7. The use of an aminoethylphenoxyacetic acid derivative represented by the general formula or a pharmacologically acceptable salt thereof, which is characterized in that it is used for the prevention or treatment of diseases associated with esophageal dyskinesia. Pharmaceutical composition [Wherein R1 is a hydrogen atom, a lower alkyl group or an aralkyl group, R2 is a hydrogen atom or a halogen atom, the carbon atom with (R) is a carbon atom of the (R) configuration, and the carbon with (S) The atom is a carbon atom in the (S) configuration]. 8. The use according to item 7 of the scope of patent application, wherein the drug used is from 2- [3-fluorofluoro-4- [2-[[((1S, 2R) -2-hydroxy-2- 2- (4-hydroxybenzene ) -1-Amidinoethyl] amino] ethyl] phenoxy] benzyl acetate, 2- [3-chloro-4- [2-[[((lS, 2R)-2 -hydroxy-2 -(4-hydroxyphenyl)-;!-Fluorenylethyl] amino] ethyl] phenoxy] acetic acid, 2- [4- [2-[[(lS, 2R) -2 -hydroxy-2 -(4-hydroxyphenyl) -1-fluorenylethyl] amino] ethyl] phenoxy] acetic acid, 2- [3-fluorofluoro 17 312XP / Invention Specification (Supplement) / 94 · 05/94103984 200533337-Compound selected from 4- [2-[[(lS, 2R) -2 -Ethyl-2-(4-Ethylphenyl-methylethyl] amino] ethyl] phenoxy] acetic acid or Its pharmacologically acceptable salt. 9. The use of item 8 in the scope of the patent application, wherein the drug used is 2- [4_ [2-[[(1S, 2R) -2- Jingji-2- (4 -Phenyl) -1-amidinoethyl] amino] ethyl] phenoxy] acetic acid or a pharmacologically acceptable salt thereof, 10. As in any of claims 7 to 9 of the scope of patent application Use of items, in which: • diseases associated with esophageal dyskinesia are esophageal achalasia, esophageal spasm, or β or the like Each symptom. 1 1. The patent uses any one of a range of 7 to 9, wherein, for further use Achalasia esophagus, esophageal spasm, or at least one other agent, and other associated symptoms of the used. 12. The use of item 11 in the scope of patent application, wherein the other agents used for esophageal achalasia, esophageal spasm, or the accompanying symptoms are calcium channel blockers, anticholinergic drugs, It is selected from nitrite compounds and xanthine derivatives. 18 312XP / Invention Specification (Supplement) / 94-05 / 94103984