WO2014058000A1 - Serotonin 2b receptor antagonist - Google Patents

Serotonin 2b receptor antagonist Download PDF

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WO2014058000A1
WO2014058000A1 PCT/JP2013/077544 JP2013077544W WO2014058000A1 WO 2014058000 A1 WO2014058000 A1 WO 2014058000A1 JP 2013077544 W JP2013077544 W JP 2013077544W WO 2014058000 A1 WO2014058000 A1 WO 2014058000A1
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serotonin
receptor
disease
abnormal
pain
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Japanese (ja)
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隆人 二階堂
美菜子 今井
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大正製薬株式会社
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Definitions

  • the present invention relates to a serotonin 2B receptor antagonist, and more particularly, to prevent serotonin 2B (5-HT2B) receptor antagonistic action and prevent various diseases associated with 5-HT2B receptor signaling abnormality or
  • the present invention relates to a serotonin 2B receptor antagonist useful for treatment.
  • Serotonin is also called 5-hydroxytryptamine (5-HT) and is one of neurotransmitters. Serotonin is widely contained in animals and plants, including humans, and is synthesized from tryptophan as a physiologically active substance that acts on 5-HT receptors both centrally and peripherally. There are currently 14 known subtypes of 5-HT receptors, and there are seven families, 5-HT1 to 5-HT7. Serotonin receptors have different physiological actions depending on their subtypes. For example, 5-HT1A is sleep, eating, temperature regulation, anxiety, 5-HT3 is nervous excitement, anxiety, vomiting, 5-HT4 is gastrointestinal motility, 5-HT6 is long-term memory, neurotrophic factor, etc. -HT7 is known to be associated with the central nervous system, gastrointestinal tract and the like.
  • 5-HT2A Of the seven families of 5-HT receptors, three subtypes of 5-HT2A, 5-HT2B, and 5-HT2C receptors are known in the 5-HT2 family.
  • Compounds that antagonize the 5-HT2B receptor are migraine, myotonic headache, mixed headache, inflammatory pain, nociceptive pain, fibromyalgia, chronic low back pain, visceral pain, gastroesophageal reflux disease (GERD), constipation, diarrhea, functional gastrointestinal disease, irritable bowel syndrome (IBS), asthma, osteoarthritis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, glomerulonephritis, nephritis, dermatitis, hepatitis, Vasculitis, renal ischemia, stroke, myocardial infarction, cerebral ischemia, Alzheimer's disease, reversible airway obstruction, adult respiratory system syndrome, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, idi
  • 5-ethynylpyrazole-3-carboxamide derivatives disclosed in Patent Document 1 are known as compounds that antagonize the serotonin 2B (5-HT2B) receptor.
  • yohimbine and lysergic acid are known.
  • Diethylamide (LSD) is a known degree.
  • the present invention has been made under the above circumstances, and an object of the present invention is to provide a 5-HT2B receptor antagonist that can be used safely without causing any problematic side effects.
  • the present inventors searched for the presence and strength of a serotonin 2B (5-HT2B) receptor antagonistic effect on compounds that have already been used as pharmaceutical ingredients and have been confirmed to be safe.
  • 5-HT2B serotonin 2B
  • antipyretic analgesic activity anti-hyaluronidase activity and anti-exudation activity are known and clinically widely used etenzamide has been found to have an excellent 5-HT2B receptor antagonistic activity. It came to complete.
  • the present invention includes the following contents.
  • a 5-HT2B receptor antagonist characterized by containing etezamide.
  • Diseases associated with abnormal transmission of 5-HT2B receptor include migraine, myotonic headache, mixed headache, inflammatory pain, nociceptive pain, fibromyalgia, chronic low back pain, visceral pain, Gastroesophageal reflux disease (GERD), constipation, diarrhea, functional gastrointestinal disease, irritable bowel syndrome (IBS), asthma, osteoarthritis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, glomerulonephritis, nephritis, Dermatitis, hepatitis, vasculitis, renal ischemia, stroke, myocardial infarction, cerebral ischemia, Alzheimer's disease, reversible airway obstruction, adult respiratory system syndrome, chronic obstructive pulmonary disease
  • etenzamide an active ingredient of the present invention, selectively binds to 5-HT2B receptor and has an antagonistic action against the action of serotonin.
  • etenzaamide is a pharmaceutical that has antipyretic analgesic action and the like, is highly safe, and is widely used clinically
  • the 5-HT2B receptor antagonist of the present invention containing this as an active ingredient is 5 -It is advantageous for the prevention or treatment of diseases associated with abnormal communication of HT2B receptor.
  • 2 is a graph showing the relationship between ethenamide concentration and change in binding rate to 5-HT2B receptor. 2 is a graph showing changes in etezamide concentration and inhibitory activity (antagonistic activity) on 5-HT2B receptor. It is a graph which shows the effect in the rat water avoidance stress model of etenzamid.
  • the 5-HT2B receptor antagonist means a drug that selectively binds to the receptor and can attenuate the action of serotonin or a serotonin receptor agonist.
  • the 5-HT2B receptor antagonist of the present invention is characterized by containing etezamide as an active ingredient.
  • This active ingredient etenzamide (chemical name: 2-ethoxybenzamide, molecular weight: 165.19), is a derivative of salicylamide, and is known to have antipyretic analgesic action, antihyaluronidase action, and anti-exudation action.
  • etenzamide is a component that is already widely used clinically, and is also included in general medicines in general cold drugs and headache drugs for the purpose of antipyretic analgesic action. Therefore, etenzaamide is effective for general antipyretic analgesics.
  • Headache menstrual pain (menstrual pain), toothache, post-extraction pain, low back pain, stiff shoulder pain, muscle pain, joint pain, bruise pain, sprain pain, fracture pain, It is known to be useful for traumatic pain, neuralgia, sore throat, ear pain, and fever which is an effective effect of general cold medicine for general use.
  • the 5-HT2B receptor antagonist of the present invention is a combination of the above ethenzamide with a known pharmaceutically acceptable carrier, such as liquids, tablets, granules, powders, capsules, dry syrups, chewable tablets, transmucosal agents, etc. It can be prepared by making it into a preparation form for oral or parenteral administration.
  • a known pharmaceutically acceptable carrier such as liquids, tablets, granules, powders, capsules, dry syrups, chewable tablets, transmucosal agents, etc. It can be prepared by making it into a preparation form for oral or parenteral administration.
  • the amount of etenzamide in the preparation is preferably determined according to the dose, and the dose can be appropriately increased or decreased in consideration of age, sex, etc. It can be used in the range of ⁇ 1000 mg, preferably 50 mg to 500 mg.
  • various optional components such as a xanthine derivative, an excipient, a pH adjuster, and a refreshing agent are used within a qualitative and quantitative range that does not impair the effects of the invention.
  • Suspending agent, antifoaming agent, thickening agent, solubilizing agent, disintegrating agent, binder, lubricant, antioxidant, coating agent, coloring agent, flavoring agent, surfactant, plasticizer, fragrance Etc. can be blended.
  • the 5-HT2B receptor antagonist obtained as described above selectively binds to the 5-HT2B receptor as described above, and can attenuate the action of serotonin and serotonin receptor agonists. Therefore, it can be used, for example, as a preventive or therapeutic agent for diseases associated with abnormal signaling of 5-HT2B receptor. Further, it can be used as a positive control group drug, for example, in the case of screening to find a new 5-HT2B receptor antagonist.
  • the disease associated with abnormal transmission of 5-HT2B receptor means, for example, a disease caused by more than normal stimulation of 5-HT2B receptor by serotonin, and the amount of serotonin secreted. And the sensitivity of 5-HT2B receptor to serotonin is renewed from normal.
  • Examples of the diseases associated with abnormal transmission of 5-HT2B receptor include migraine, myotonic headache, mixed headache, inflammatory pain, nociceptive pain, fibromyalgia, chronic low back pain, visceral pain Gastroesophageal reflux disease (GERD), constipation, diarrhea, functional gastrointestinal disease, irritable bowel syndrome (IBS), asthma, osteoarthritis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, glomerulonephritis, nephritis , Dermatitis, hepatitis, vasculitis, renal ischemia, stroke, myocardial infarction, cerebral ischemia, Alzheimer's disease, reversible airway obstruction, adult respiratory system syndrome, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, idiopathic Examples include interstitial pneumonia, bronchitis, liver fibrosis, polypulmonary fibrosis, depression, anxiety, malignant tumor or obesity.
  • GSD Gastroesoph
  • One preferred form of the present invention is a migraine-preventing or treating agent characterized by containing etezamide. It is known that the migraine pathology involves the expansion of the dural blood vessels and the accompanying inflammation around the dura blood vessels, but the 5-HT2B receptor expressed in the dural vascular endothelial cells is vasodilated. Has been reported (Non-patent Document 1). Further, it has been reported that LY202146 having a selective 5-HT2B receptor antagonistic action suppresses protein leakage from dural blood vessels (Non-patent Document 2). Therefore, 5-HT2B receptor antagonists are considered useful for the prevention or treatment of migraine.
  • etenzamide When etenzamide is used as a prophylactic or therapeutic agent for migraine, for example, triptans such as sumatriptan, ergot agents such as ergotamine, calcium antagonists such as romeridine, ⁇ -blockers such as profuranolol, amitriptyline, etc. It can be used in combination with other antidepressants, antiepileptic drugs such as valproic acid, ⁇ -blockers such as clonidine, and other migraine prophylaxis or treatment agents such as magnesium.
  • triptans such as sumatriptan
  • ergot agents such as ergotamine
  • calcium antagonists such as romeridine
  • ⁇ -blockers such as profuranolol, amitriptyline, etc.
  • antiepileptic drugs such as valproic acid
  • ⁇ -blockers such as clonidine
  • treatment agents such as magnesium.
  • Another preferred embodiment of the present invention is an agent for preventing or treating IBS characterized by containing etenzamid.
  • visceral hyperalgesia is involved in the pathology of IBS
  • RS-127445 which has selective 5-HT2B receptor antagonism, attenuates pain due to colon extension stimulation (non- Since Patent Document 3) has been made, it is considered that a 5-HT2B receptor antagonist is useful for the prevention or treatment of IBS.
  • etenzaamide is used as an agent for preventing or treating IBS, for example, an anticholinergic agent such as thikidium, an opioid drug such as trimebbutin, a 5-HT3 receptor antagonist such as ramosetron, a 5-HT4 receptor agonist such as mosapride, It can be used in combination with other preventive or therapeutic agents for IBS such as muscle relaxants such as peppermint oil.
  • an anticholinergic agent such as thikidium
  • an opioid drug such as trimebbutin
  • a 5-HT3 receptor antagonist such as ramosetron
  • a 5-HT4 receptor agonist such as mosapride
  • a disease associated with abnormal 5-HT2B receptor signaling wherein an effective amount of etenzamide is administered to a patient associated with abnormal 5-HT2B receptor signaling
  • an effective amount of etenzamide is administered to a patient associated with abnormal 5-HT2B receptor signaling
  • Example 1 Human 5-HT2B receptor binding test The affinity of etenzamide for the human 5-HT2B receptor binding site was assessed by radioligand binding studies. The specific protocol is as follows.
  • Etenzamide inhibited the binding of 0.2 nM [ 125 I] ( ⁇ ) DOI to the human 5-HT2B receptor in a concentration dependent manner in the range of 10 ⁇ 7 M to 10 ⁇ 3 M.
  • concentration that inhibited 50% of the binding of 0.2 nM [ 125 I] ( ⁇ ) DOI to the human 5-HT2B receptor (IC 50 ) was 2.78 ⁇ M.
  • Example 2 Human 5-HT2B receptor antagonism test Antagonism of etenzamide on the human 5-HT2B receptor was evaluated by a cell functionality test. The specific protocol is as follows.
  • a preparation of a CHO cell membrane transfected with the human 5-HT2B receptor was mixed with 30 nM serotonin and etenzamide in a 96-well plate and allowed to stand at 37 ° C. for 30 minutes.
  • IP1 insitol-1-phosphate
  • the 5-HT2B receptor antagonism of etenzamide was calculated as the inhibition rate with respect to the serotonin agonist activity in the control (no etezamide) as 100%.
  • Etenzamide showed human 5-HT2B receptor antagonism in a concentration-dependent range from 10 ⁇ 7 M to 10 ⁇ 3 M.
  • the concentration at which serotonin agonist activity was inhibited by 50% (IC 50 ) was 38.5 ⁇ M.
  • Example 3 Rat water avoidance stress When water avoidance stress is applied to rats, the number of defecation increases and softening of fecal characteristics is observed, and this phenomenon is very similar to the defecation symptoms of IBS patients when exposed to stress. Is widely used as an IBS model (Gastroenterology. 1993 Mar; 104 (3): 716-23. Neurogastroenterol Motil. 2009 Aug; 21 (8): 856-e59.). Therefore, the effect of etezamide on improving IBS symptoms was examined using the number of defecations in the rat water avoidance stress model as an index.
  • ⁇ Test method> A cylindrical platform having a diameter of 8 cm was placed in a plastic cage filled with water at room temperature so that the upper surface protruded 1 cm above the water surface.
  • the rats were subjected to water avoidance stress by placing the rats on the top surface of the platform for 1 hour.
  • the degree of stress due to the load was evaluated as the number of defecations of rats during a one hour water avoidance stress load. Rats were divided into two groups: a vehicle-administered control group and an etenzamide-administered etenzamide group, and each vehicle or etezamide (200 mg / kg / 5 mL) was orally administered 1 hour before stress loading.
  • a 5-HT2B receptor antagonist containing ethenzamide as an active ingredient.
  • This 5-HT2B receptor antagonist can be used for the prevention or treatment of various diseases associated with abnormal transmission of 5-HT2B receptor signals and associated symptoms.
  • the 5-HT2B receptor antagonist of the present invention includes migraine, myotonic headache, mixed headache, inflammatory pain, nociceptive pain, fibromyalgia, chronic low back pain, visceral pain, stomach Esophageal reflux disease (GERD), constipation, diarrhea, functional gastrointestinal disease, irritable bowel syndrome (IBS), asthma, osteoarthritis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, glomerulonephritis, nephritis, skin Inflammation, hepatitis, vasculitis, renal ischemia, stroke, myocardial infarction, cerebral ischemia, Alzheimer's disease, reversible airway obstruction, adult respiratory system syndrome, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, idiopathic interstitial It can be used for the prevention or treatment of pneumonia, bronchitis, liver fibrosis, polypulmonary fibrosis, depression, anxiety, malignant tumor, obesity, etc.,

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Abstract

The purpose of the present invention is to provide a 5-HT2B receptor antagonist which does not induce problematic adverse side effects or the like and can be used safely. Provided are a serotonin 2B receptor antagonist and a prophylactic or therapeutic agent for diseases associated with abnormal signal transduction from a serotonin 2B receptor, each of which is characterized by comprising ethenzamide.

Description

セロトニン２Ｂ受容体拮抗剤Serotonin 2B receptor antagonist
　本発明は、セロトニン２Ｂ受容体拮抗剤に関し、更に詳細には、セロトニン２Ｂ（５－ＨＴ２Ｂ）受容体に対する拮抗作用を奏し、５－ＨＴ２Ｂ受容体の情報伝達異常と関連した種々の疾患の予防又は治療に有用な、セロトニン２Ｂ受容体拮抗剤に関する。 The present invention relates to a serotonin 2B receptor antagonist, and more particularly, to prevent serotonin 2B (5-HT2B) receptor antagonistic action and prevent various diseases associated with 5-HT2B receptor signaling abnormality or The present invention relates to a serotonin 2B receptor antagonist useful for treatment.
　セロトニンは、５－ヒドロキシトリプタミン（５－ＨＴ）とも称され、神経伝達物質の一つである。セロトニンはヒトを含む動植物に広く含まれ、５－ＨＴ受容体に中枢又は末梢の両方で作用する生理活性物質としてトリプトファンから合成される。５－ＨＴ受容体は、現在１４種類のサブタイプが知られており、７つのファミリー、５－ＨＴ１から５－ＨＴ７が存在する。セロトニン受容体はそのサブタイプの違いにより、発現する生理作用が異なる。例えば、５－ＨＴ１Ａは睡眠、摂食、体温調節、不安など、５－ＨＴ３は神経興奮、不安、嘔吐など、５－ＨＴ４は胃腸運動など、５－ＨＴ６は長期記憶、神経栄養因子など、５－ＨＴ７は中枢神経系、消化管などとの関連が知られている。 Serotonin is also called 5-hydroxytryptamine (5-HT) and is one of neurotransmitters. Serotonin is widely contained in animals and plants, including humans, and is synthesized from tryptophan as a physiologically active substance that acts on 5-HT receptors both centrally and peripherally. There are currently 14 known subtypes of 5-HT receptors, and there are seven families, 5-HT1 to 5-HT7. Serotonin receptors have different physiological actions depending on their subtypes. For example, 5-HT1A is sleep, eating, temperature regulation, anxiety, 5-HT3 is nervous excitement, anxiety, vomiting, 5-HT4 is gastrointestinal motility, 5-HT6 is long-term memory, neurotrophic factor, etc. -HT7 is known to be associated with the central nervous system, gastrointestinal tract and the like.
　５－ＨＴ受容体の７つのファミリーのうち、５－ＨＴ２ファミリーには５－ＨＴ２Ａ、５－ＨＴ２Ｂ、５－ＨＴ２Ｃ受容体の３つのサブタイプが知られている。そして、５－ＨＴ２Ｂ受容体を拮抗する化合物は、片頭痛、筋緊張型頭痛、混合型頭痛、炎症性疼痛、侵害受容性疼痛、線維筋痛症、慢性腰痛、内臓痛、胃食道逆流性疾患（ＧＥＲＤ）、便秘、下痢、機能性胃腸疾患、過敏性腸症候群（ＩＢＳ）、喘息、変形性関節炎、リウマチ性関節炎、クローン病、潰瘍性大腸炎、糸球体腎炎、腎炎、皮膚炎、肝炎、血管炎、腎虚血、脳卒中、心筋梗塞、脳虚血、アルツハイマー症、可逆的気道閉塞、成人呼吸器系統症候群、慢性閉塞性肺疾患（ＣＯＰＤ）、肺高血圧、突発性間質性肺炎、気管支炎、肝線維症、多肺線維症、抑うつ症、不安神経症、悪性腫瘍、肥満を含む多種の疾患の予防又は治療に有用であることが知られている（特許文献１）。 Of the seven families of 5-HT receptors, three subtypes of 5-HT2A, 5-HT2B, and 5-HT2C receptors are known in the 5-HT2 family. Compounds that antagonize the 5-HT2B receptor are migraine, myotonic headache, mixed headache, inflammatory pain, nociceptive pain, fibromyalgia, chronic low back pain, visceral pain, gastroesophageal reflux disease (GERD), constipation, diarrhea, functional gastrointestinal disease, irritable bowel syndrome (IBS), asthma, osteoarthritis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, glomerulonephritis, nephritis, dermatitis, hepatitis, Vasculitis, renal ischemia, stroke, myocardial infarction, cerebral ischemia, Alzheimer's disease, reversible airway obstruction, adult respiratory system syndrome, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, idiopathic interstitial pneumonia, bronchitis It is known to be useful for the prevention or treatment of various diseases including hepatic fibrosis, polypulmonary fibrosis, depression, anxiety, malignant tumor, obesity (Patent Document 1).
　現在、セロトニン２Ｂ（５－ＨＴ２Ｂ）受容体を拮抗する化合物としては、上記特許文献１に開示の５－エチニルピラゾール－３－カルボキサミド誘導体が知られているが、それ以外には、ヨヒンビンやリゼルグ酸ジエチルアミド（ＬＳＤ）が知られている程度である。 Currently, 5-ethynylpyrazole-3-carboxamide derivatives disclosed in Patent Document 1 are known as compounds that antagonize the serotonin 2B (5-HT2B) receptor. Other than that, yohimbine and lysergic acid are known. Diethylamide (LSD) is a known degree.
　しかしながら、後二者は、何れも主作用としてコントロールの難しい薬効を有し、利用範囲が限定されるため、５－ＨＴ２Ｂ受容体拮抗剤として使用するには問題があった。そこで、安全性が高く、広く一般的に使用できる化合物を有効成分とする５－ＨＴ２Ｂ受容体拮抗剤の開発が求められていた。 However, both of the latter two have problems in use as 5-HT2B receptor antagonists because both have medicinal effects that are difficult to control as main effects and the range of use is limited. Accordingly, there has been a demand for the development of 5-HT2B receptor antagonists that contain highly safe and widely usable compounds as active ingredients.
特開２０１０－１５５８０２JP 2010-155802 A
　本発明は、上記状況下においてなされたものであり、問題となるような副作用等を惹起することがなく、安全に利用できる５－ＨＴ２Ｂ受容体拮抗剤の提供をその課題とするものである。 The present invention has been made under the above circumstances, and an object of the present invention is to provide a 5-HT2B receptor antagonist that can be used safely without causing any problematic side effects.
　本発明者らは、上記課題を解決するため、既に医薬品成分として使用され、安全性が認められている化合物について、セロトニン２Ｂ（５－ＨＴ２Ｂ）受容体に対する拮抗作用の有無およびその強度について検索を行っていたところ、解熱鎮痛作用のほか、抗ヒアルロニダーゼ作用、抗滲出性作用が知られ、臨床的に広く用いられているエテンザミドが優れた５－ＨＴ２Ｂ受容体拮抗作用を有することを見出し、本発明を完成するに至った。 In order to solve the above-mentioned problems, the present inventors searched for the presence and strength of a serotonin 2B (5-HT2B) receptor antagonistic effect on compounds that have already been used as pharmaceutical ingredients and have been confirmed to be safe. As a result, in addition to antipyretic analgesic activity, anti-hyaluronidase activity and anti-exudation activity are known and clinically widely used etenzamide has been found to have an excellent 5-HT2B receptor antagonistic activity. It came to complete.
　すなわち本発明は、次の内容を含むものである。
（１）エテンザミドを含有することを特徴とする５－ＨＴ２Ｂ受容体拮抗剤。
（２）エテンザミドを含有することを特徴とする５－ＨＴ２Ｂ受容体の情報伝達異常と関連した疾患の予防又は治療剤。
（３）５－ＨＴ２Ｂ受容体の情報伝達異常と関連した疾患が、片頭痛、筋緊張型頭痛、混合型頭痛、炎症性疼痛、侵害受容性疼痛、線維筋痛症、慢性腰痛、内臓痛、胃食道逆流性疾患（ＧＥＲＤ）、便秘、下痢、機能性胃腸疾患、過敏性腸症候群（ＩＢＳ）、喘息、変形性関節炎、リウマチ性関節炎、クローン病、潰瘍性大腸炎、糸球体腎炎、腎炎、皮膚炎、肝炎、血管炎、腎虚血、脳卒中、心筋梗塞、脳虚血、アルツハイマー症、可逆的気道閉塞、成人呼吸器系統症候群、慢性閉塞性肺疾患（ＣＯＰＤ）、肺高血圧、突発性間質性肺炎、気管支炎、肝線維症、多肺線維症、抑うつ症、不安神経症、悪性腫瘍又は肥満である、上記（２）に記載の予防又は治療剤。 That is, the present invention includes the following contents.
(1) A 5-HT2B receptor antagonist characterized by containing etezamide.
(2) A preventive or therapeutic agent for a disease associated with abnormal signaling of 5-HT2B receptor, comprising etezamide.
(3) Diseases associated with abnormal transmission of 5-HT2B receptor include migraine, myotonic headache, mixed headache, inflammatory pain, nociceptive pain, fibromyalgia, chronic low back pain, visceral pain, Gastroesophageal reflux disease (GERD), constipation, diarrhea, functional gastrointestinal disease, irritable bowel syndrome (IBS), asthma, osteoarthritis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, glomerulonephritis, nephritis, Dermatitis, hepatitis, vasculitis, renal ischemia, stroke, myocardial infarction, cerebral ischemia, Alzheimer's disease, reversible airway obstruction, adult respiratory system syndrome, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, idiopathic stroma The prophylactic or therapeutic agent according to (2) above, which is pneumonia, bronchitis, liver fibrosis, polypulmonary fibrosis, depression, anxiety, malignant tumor or obesity.
　本発明の有効成分であるエテンザミドは、選択的に５－ＨＴ２Ｂ受容体に結合し、セロトニンの作用に対して拮抗作用を有することが見いだされた。そして、エテンザミドは、解熱鎮痛作用等を有し、安全性が高く、臨床的に広く用いられている医薬品であるため、これを有効成分とする本発明の５－ＨＴ２Ｂ受容体拮抗剤は、５－ＨＴ２Ｂ受容体の情報伝達異常と関連した疾患の予防又は治療に有利なものである。 It was found that etenzamide, an active ingredient of the present invention, selectively binds to 5-HT2B receptor and has an antagonistic action against the action of serotonin. And since etenzaamide is a pharmaceutical that has antipyretic analgesic action and the like, is highly safe, and is widely used clinically, the 5-HT2B receptor antagonist of the present invention containing this as an active ingredient is 5 -It is advantageous for the prevention or treatment of diseases associated with abnormal communication of HT2B receptor.
エテンザミドの濃度と、５－ＨＴ２Ｂ受容体に対する結合率の変化の関係を示すグラフである。2 is a graph showing the relationship between ethenamide concentration and change in binding rate to 5-HT2B receptor. エテンザミドの濃度と、５－ＨＴ２Ｂ受容体に対する阻害活性（拮抗活性）の変化を示すグラフである。2 is a graph showing changes in etezamide concentration and inhibitory activity (antagonistic activity) on 5-HT2B receptor. エテンザミドのラット水回避ストレスモデルにおける効果を示すグラフである。It is a graph which shows the effect in the rat water avoidance stress model of etenzamid.
　本明細書中において５－ＨＴ２Ｂ受容体拮抗剤とは、当該受容体に対して選択的に結合し、セロトニンやセロトニン受容体作動薬の作用を減弱させることができる薬剤を意味する。 In the present specification, the 5-HT2B receptor antagonist means a drug that selectively binds to the receptor and can attenuate the action of serotonin or a serotonin receptor agonist.
　本発明の５－ＨＴ２Ｂ受容体拮抗剤は、有効成分としてエテンザミドを含有することを特徴とするものである。この有効成分であるエテンザミド（化学名：２－エトキシベンザミド、分子量：１６５．１９）は、サリチルアミドの誘導体であり、解熱鎮痛作用のほか、抗ヒアルロニダーゼ作用、抗滲出性作用が知られている化合物である。エテンザミドは既に臨床的に広く用いられる成分であり、一般用医薬品においても、解熱鎮痛作用を目的に総合感冒薬や頭痛薬に配合されている。従ってエテンザミドが、一般用解熱鎮痛薬の効能効果にある頭痛・月経痛（生理痛）・歯痛・抜歯後の疼痛・腰痛・肩こり痛・筋肉痛・関節痛・打撲痛・ねんざ痛・骨折痛・外傷痛・神経痛・咽喉痛・耳痛や、一般用総合感冒薬の効能効果にある発熱に対し有用であることは公知である。 The 5-HT2B receptor antagonist of the present invention is characterized by containing etezamide as an active ingredient. This active ingredient, etenzamide (chemical name: 2-ethoxybenzamide, molecular weight: 165.19), is a derivative of salicylamide, and is known to have antipyretic analgesic action, antihyaluronidase action, and anti-exudation action. A compound. Ethenzamide is a component that is already widely used clinically, and is also included in general medicines in general cold drugs and headache drugs for the purpose of antipyretic analgesic action. Therefore, etenzaamide is effective for general antipyretic analgesics. Headache, menstrual pain (menstrual pain), toothache, post-extraction pain, low back pain, stiff shoulder pain, muscle pain, joint pain, bruise pain, sprain pain, fracture pain, It is known to be useful for traumatic pain, neuralgia, sore throat, ear pain, and fever which is an effective effect of general cold medicine for general use.
　本発明の５－ＨＴ２Ｂ受容体拮抗剤は、上記エテンザミドを公知の薬学的に許容される担体と組み合わせ、液剤、錠剤、顆粒剤、散剤、カプセル剤、ドライシロップ剤、チュアブル錠、経粘膜剤などの経口又は非経口投与の製剤形態とすることで調製することができる。 The 5-HT2B receptor antagonist of the present invention is a combination of the above ethenzamide with a known pharmaceutically acceptable carrier, such as liquids, tablets, granules, powders, capsules, dry syrups, chewable tablets, transmucosal agents, etc. It can be prepared by making it into a preparation form for oral or parenteral administration.
　製剤中でのエテンザミドの量は、その投与量に応じて決定することが好ましく、また投与量は、年齢、性別などを考慮して、適宜増減することができるが、通常成人で１回、１０ｍｇ～１０００ｍｇの範囲で用いることができ、好ましくは、５０ｍｇ～５００ｍｇである。 The amount of etenzamide in the preparation is preferably determined according to the dose, and the dose can be appropriately increased or decreased in consideration of age, sex, etc. It can be used in the range of ˜1000 mg, preferably 50 mg to 500 mg.
　本発明の５－ＨＴ２Ｂ受容体拮抗剤の調製においては、発明の効果を損なわない質的及び量的範囲で、各種の任意成分、例えば、キサンチン誘導体、賦形剤、ｐＨ調整剤、清涼化剤、懸濁化剤、消泡剤、粘稠剤、溶解補助剤、崩壊剤、結合剤、滑沢剤、抗酸化剤、コーティング剤、着色剤、矯味矯臭剤、界面活性剤、可塑剤、香料などを配合することができる。 In the preparation of the 5-HT2B receptor antagonist of the present invention, various optional components such as a xanthine derivative, an excipient, a pH adjuster, and a refreshing agent are used within a qualitative and quantitative range that does not impair the effects of the invention. , Suspending agent, antifoaming agent, thickening agent, solubilizing agent, disintegrating agent, binder, lubricant, antioxidant, coating agent, coloring agent, flavoring agent, surfactant, plasticizer, fragrance Etc. can be blended.
　以上のようにして得られた、５－ＨＴ２Ｂ受容体拮抗剤は、上記したように５－ＨＴ２Ｂ受容体に対して選択的に結合し、セロトニンやセロトニン受容体作動薬の作用を減弱させることができるので、例えば５－ＨＴ２Ｂ受容体の情報伝達異常と関連した疾患の予防又は治療剤として使用することが可能である。また、例えば新たな５－ＨＴ２Ｂ受容体拮抗薬を見いだすためにスクリーニングする場合の、陽性対照群の薬剤として使用することが可能である。 The 5-HT2B receptor antagonist obtained as described above selectively binds to the 5-HT2B receptor as described above, and can attenuate the action of serotonin and serotonin receptor agonists. Therefore, it can be used, for example, as a preventive or therapeutic agent for diseases associated with abnormal signaling of 5-HT2B receptor. Further, it can be used as a positive control group drug, for example, in the case of screening to find a new 5-HT2B receptor antagonist.
　ここで、５－ＨＴ２Ｂ受容体の情報伝達異常と関連した疾患とは、例えばセロトニンにより５－ＨＴ２Ｂ受容体への刺激が通常より多く伝達されることにより生じる疾患等を意味し、セロトニンの分泌量が正常より亢進している場合や、５－ＨＴ２Ｂ受容体のセロトニンへの感受性が正常より更新している場合などがあげられる。上述の５－ＨＴ２Ｂ受容体の情報伝達異常と関連した疾患としては、例えば片頭痛、筋緊張型頭痛、混合型頭痛、炎症性疼痛、侵害受容性疼痛、線維筋痛症、慢性腰痛、内臓痛、胃食道逆流性疾患（ＧＥＲＤ）、便秘、下痢、機能性胃腸疾患、過敏性腸症候群（ＩＢＳ）、喘息、変形性関節炎、リウマチ性関節炎、クローン病、潰瘍性大腸炎、糸球体腎炎、腎炎、皮膚炎、肝炎、血管炎、腎虚血、脳卒中、心筋梗塞、脳虚血、アルツハイマー症、可逆的気道閉塞、成人呼吸器系統症候群、慢性閉塞性肺疾患（ＣＯＰＤ）、肺高血圧、突発性間質性肺炎、気管支炎、肝線維症、多肺線維症、抑うつ症、不安神経症、悪性腫瘍又は肥満等が挙げられる。 Here, the disease associated with abnormal transmission of 5-HT2B receptor means, for example, a disease caused by more than normal stimulation of 5-HT2B receptor by serotonin, and the amount of serotonin secreted. And the sensitivity of 5-HT2B receptor to serotonin is renewed from normal. Examples of the diseases associated with abnormal transmission of 5-HT2B receptor include migraine, myotonic headache, mixed headache, inflammatory pain, nociceptive pain, fibromyalgia, chronic low back pain, visceral pain Gastroesophageal reflux disease (GERD), constipation, diarrhea, functional gastrointestinal disease, irritable bowel syndrome (IBS), asthma, osteoarthritis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, glomerulonephritis, nephritis , Dermatitis, hepatitis, vasculitis, renal ischemia, stroke, myocardial infarction, cerebral ischemia, Alzheimer's disease, reversible airway obstruction, adult respiratory system syndrome, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, idiopathic Examples include interstitial pneumonia, bronchitis, liver fibrosis, polypulmonary fibrosis, depression, anxiety, malignant tumor or obesity.
　本発明の１つの好ましい形態は、エテンザミドを含有することを特徴とする片頭痛の予防又は治療剤である。片頭痛の病態には、硬膜血管の拡張及びそれに伴う硬膜血管周囲の炎症が関与していることが知られているが、硬膜血管内皮細胞に発現する５－ＨＴ２Ｂ受容体が血管拡張を惹起するとの報告がある（非特許文献１）。また、選択的５－ＨＴ２Ｂ受容体拮抗作用を有するＬＹ２０２１４６が硬膜血管からの蛋白漏出を抑制するとの報告（非特許文献２）がなされている。したがって、５－ＨＴ２Ｂ受容体拮抗剤は片頭痛の予防又は治療に有用であると考えられる。 One preferred form of the present invention is a migraine-preventing or treating agent characterized by containing etezamide. It is known that the migraine pathology involves the expansion of the dural blood vessels and the accompanying inflammation around the dura blood vessels, but the 5-HT2B receptor expressed in the dural vascular endothelial cells is vasodilated. Has been reported (Non-patent Document 1). Further, it has been reported that LY202146 having a selective 5-HT2B receptor antagonistic action suppresses protein leakage from dural blood vessels (Non-patent Document 2). Therefore, 5-HT2B receptor antagonists are considered useful for the prevention or treatment of migraine.
　エテンザミドを上記片頭痛の予防又は治療剤として使用する場合には、例えばスマトリプタン等のトリプタン系薬剤、エルゴタミン等の麦角剤、ロメリジン等のカルシウム拮抗剤、プロフラノロール等のβ遮断薬、アミトリプチリン等の抗うつ薬、バルプロ酸等の抗てんかん薬、クロニジン等のα遮断薬、マグネシウム等の他の片頭痛の予防又は治療剤と組み合わせて使用することが可能である。 When etenzamide is used as a prophylactic or therapeutic agent for migraine, for example, triptans such as sumatriptan, ergot agents such as ergotamine, calcium antagonists such as romeridine, β-blockers such as profuranolol, amitriptyline, etc. It can be used in combination with other antidepressants, antiepileptic drugs such as valproic acid, α-blockers such as clonidine, and other migraine prophylaxis or treatment agents such as magnesium.
　また、本発明の他の好ましい態様は、エテンザミドを含有することを特徴とするＩＢＳの予防又は治療剤である。ＩＢＳの病態には、内臓痛覚過敏が関与していることが知られているが、選択的５－ＨＴ２Ｂ受容体拮抗作用を有するＲＳ－１２７４４５が、結腸伸展刺激による痛みを減弱するとの報告（非特許文献３）がなされていることから、５－ＨＴ２Ｂ受容体拮抗剤はＩＢＳの予防又は治療に有用であると考えられる。 Another preferred embodiment of the present invention is an agent for preventing or treating IBS characterized by containing etenzamid. Although it is known that visceral hyperalgesia is involved in the pathology of IBS, it has been reported that RS-127445, which has selective 5-HT2B receptor antagonism, attenuates pain due to colon extension stimulation (non- Since Patent Document 3) has been made, it is considered that a 5-HT2B receptor antagonist is useful for the prevention or treatment of IBS.
　エテンザミドをＩＢＳの予防又は治療剤として使用する場合、例えばチキジウム等の抗コリン剤、トリメブチン等のオピオイド系薬剤、ラモセトロン等の５－ＨＴ３受容体拮抗剤、モサプリド等の５－ＨＴ４受容体作動薬、ペパーミントオイル等の筋弛緩剤等の他のＩＢＳの予防又は治療剤と組み合わせて使用することが可能である。 When etenzaamide is used as an agent for preventing or treating IBS, for example, an anticholinergic agent such as thikidium, an opioid drug such as trimebbutin, a 5-HT3 receptor antagonist such as ramosetron, a 5-HT4 receptor agonist such as mosapride, It can be used in combination with other preventive or therapeutic agents for IBS such as muscle relaxants such as peppermint oil.
　更に、本発明の治療方法に関する態様として、５－ＨＴ２Ｂ受容体の情報伝達異常と関連した疾患の患者に対し、有効量のエテンザミドを投与する、５－ＨＴ２Ｂ受容体の情報伝達異常と関連した疾患の予防又は治療方法が挙げられる。 Further, as an embodiment relating to the therapeutic method of the present invention, a disease associated with abnormal 5-HT2B receptor signaling, wherein an effective amount of etenzamide is administered to a patient associated with abnormal 5-HT2B receptor signaling The prevention or treatment method of this is mentioned.
　更にまた、本発明の別の態様としては、エテンザミドの５－ＨＴ２Ｂ受容体の情報伝達異常と関連した疾患の治療のための使用が挙げられる。 Furthermore, as another aspect of the present invention, use of ethenamide for the treatment of diseases associated with abnormal transmission of 5-HT2B receptor information can be mentioned.
　以下に実施例をあげ、本発明をさらに具体的に説明するが、本発明はこれら実施例に何ら制約されるものではない。 Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.
実　施　例　１
　　　ヒト５－ＨＴ２Ｂ受容体結合試験：
　ヒト５－ＨＴ２Ｂ受容体結合部位に対するエテンザミドの親和性を、放射性リガンド結合試験により評価した。具体的なプロトコールは以下の通りである。 Example 1
Human 5-HT2B receptor binding test:
The affinity of etenzamide for the human 5-HT2B receptor binding site was assessed by radioligand binding studies. The specific protocol is as follows.
（１）ヒト５－ＨＴ２Ｂ受容体をトランスフェクトしたＣＨＯ細胞膜の調製物（１０μｇ)を、０．２ｎＭ　[125Ｉ](±)ＤＯＩ（５－ＨＴ２Ａ、２Ｂ、２Ｃ受容体アゴニスト）及びエテンザミドと共に９６ウェルプレートで混合し（２００μＬ）、室温にて６０分間放置した。
（２）その後、それぞれの反応液をガラス繊維フィルタにより迅速に濾過した。
（３）フィルタを乾燥し、フィルタに吸着した０．２ｎＭ　[125Ｉ](±)ＤＯＩの放射活性をシンチレーションカウンタを用いて測定した。
（４）エテンザミドの５－ＨＴ２Ｂ受容体結合率は、コントロール（エテンザミド無し）における０．２ｎＭ　[125Ｉ](±)ＤＯＩの結合率を１００％とし、これに対する阻害率として算出した。 (1) A preparation of CHO cell membrane (10 μg) transfected with human 5-HT2B receptor was added 96 μg together with 0.2 nM [ 125 I] (±) DOI (5-HT2A, 2B, 2C receptor agonist) and etenzaamide. Mixed in a well plate (200 μL) and left at room temperature for 60 minutes.
(2) Thereafter, each reaction solution was quickly filtered through a glass fiber filter.
(3) The filter was dried, and the radioactivity of 0.2 nM [ 125 I] (±) DOI adsorbed on the filter was measured using a scintillation counter.
(4) The 5-HT2B receptor binding rate of etenzamide was calculated as the inhibition rate relative to 0.2% [ 125 I] (±) DOI binding rate in the control (no etezamide).
＜試験結果＞
　エテンザミドは、１０-7Ｍから１０-3Ｍの範囲で濃度依存的に０．２ｎＭ　[125Ｉ](±)ＤＯＩのヒト５－ＨＴ２Ｂ受容体への結合を阻害した。０．２ｎＭ　[125Ｉ](±)ＤＯＩのヒト５－ＨＴ２Ｂ受容体への結合を５０％阻害する濃度（ＩＣ50）は２．７８μMであった。 <Test results>
Etenzamide inhibited the binding of 0.2 nM [ 125 I] (±) DOI to the human 5-HT2B receptor in a concentration dependent manner in the range of 10 −7 M to 10 −3 M. The concentration that inhibited 50% of the binding of 0.2 nM [ 125 I] (±) DOI to the human 5-HT2B receptor (IC 50 ) was 2.78 μM.
　なお、同様の試験を５－ＨＴ１Ａ、１Ｂ、１Ｄ、２Ａ、２Ｃ、４ｅ、５ａ、６及び７受容体においても実施したが、エテンザミドは１０-7Ｍ及び１０-6Ｍにおいてこれらの受容体にほとんど結合親和性を示さなかった。 Similar tests were also conducted on 5-HT1A, 1B, 1D, 2A, 2C, 4e, 5a, 6 and 7 receptors, but etenzamide was observed at these receptors at 10 -7 M and 10 -6 M. It showed little binding affinity.
実　施　例　２
　　　ヒト５－ＨＴ２Ｂ受容体拮抗試験：
　ヒト５－ＨＴ２Ｂ受容体対するエテンザミドの拮抗作用を、細胞機能性試験により評価した。具体的なプロトコールは以下の通りである。 Example 2
Human 5-HT2B receptor antagonism test:
Antagonism of etenzamide on the human 5-HT2B receptor was evaluated by a cell functionality test. The specific protocol is as follows.
（１）ヒト５－ＨＴ２Ｂ受容体をトランスフェクトしたＣＨＯ細胞膜の調製物を、３０ｎＭセロトニン及びエテンザミドと共に９６ウェルプレートで混合し、３７℃にて３０分間放置した。
（２）その後、それぞれの反応液中のＩＰ１（insitol-1-phosphate）量を、ＨＴＲＦ法（homogeneous　time　resolved　fluorescence　assay）により測定した。
（３）エテンザミドの５－ＨＴ２Ｂ受容拮抗作用は、コントロール（エテンザミド無し）におけるセロトニンのアゴニスト活性を１００％とし、これに対する阻害率として算出した。 (1) A preparation of a CHO cell membrane transfected with the human 5-HT2B receptor was mixed with 30 nM serotonin and etenzamide in a 96-well plate and allowed to stand at 37 ° C. for 30 minutes.
(2) Thereafter, the amount of IP1 (insitol-1-phosphate) in each reaction solution was measured by the HTRF method (homogeneous time resolved fluorescence assay).
(3) The 5-HT2B receptor antagonism of etenzamide was calculated as the inhibition rate with respect to the serotonin agonist activity in the control (no etezamide) as 100%.
　＜試験結果＞
　エテンザミドは１０-7Ｍから１０-3Ｍの範囲で濃度依存的にヒト５－ＨＴ２Ｂ受容体拮抗作用を示した。セロトニンのアゴニスト活性を５０％阻害する濃度（ＩＣ50）は、３８．５μMであった。 <Test results>
Etenzamide showed human 5-HT2B receptor antagonism in a concentration-dependent range from 10 −7 M to 10 −3 M. The concentration at which serotonin agonist activity was inhibited by 50% (IC 50 ) was 38.5 μM.
実　施　例　３
　　ラット水回避ストレス：
　ラットに水回避ストレスを負荷することにより排便数の増加や便性状の軟化が認められ、この現象がストレスに曝された際のＩＢＳ患者の排便症状と酷似していることから、ラット水回避ストレスはＩＢＳモデルとして広く用いられている（Gastroenterology.1993　Mar;104(3):716-23.　Neurogastroenterol　Motil.　2009　Aug;21(8):856-e59.）。従ってラット水回避ストレスモデルの排便数を指標とし、エテンザミドのＩＢＳ症状改善作用について検討した。 Example 3
Rat water avoidance stress:
When water avoidance stress is applied to rats, the number of defecation increases and softening of fecal characteristics is observed, and this phenomenon is very similar to the defecation symptoms of IBS patients when exposed to stress. Is widely used as an IBS model (Gastroenterology. 1993 Mar; 104 (3): 716-23. Neurogastroenterol Motil. 2009 Aug; 21 (8): 856-e59.). Therefore, the effect of etezamide on improving IBS symptoms was examined using the number of defecations in the rat water avoidance stress model as an index.
＜試験方法＞
室温の水で満たしたプラスティックケージの中に、直径８ｃｍの円柱形プラットホームを上面が水面より１ｃｍ上に出るように設置した。そのプラットホーム上面にラットを１時間置くことによりラットに水回避ストレスを負荷した。当該負荷によるストレスの程度は、１時間の水回避ストレス負荷中のラットの排便数として評価した。ラットを媒体投与の対照群及びエテンザミド投与のエテンザミド群の２群に分け、それぞれストレス負荷の１時間前に媒体又はエテンザミド（２００ｍｇ/ｋｇ/５ｍＬ）を経口投与した。 <Test method>
A cylindrical platform having a diameter of 8 cm was placed in a plastic cage filled with water at room temperature so that the upper surface protruded 1 cm above the water surface. The rats were subjected to water avoidance stress by placing the rats on the top surface of the platform for 1 hour. The degree of stress due to the load was evaluated as the number of defecations of rats during a one hour water avoidance stress load. Rats were divided into two groups: a vehicle-administered control group and an etenzamide-administered etenzamide group, and each vehicle or etezamide (200 mg / kg / 5 mL) was orally administered 1 hour before stress loading.
＜試験結果＞
　図３に示す通り、対照群と比較し、エテンザミド群の排便数が有意に少なかった。従ってエテンザミドがＩＢＳ症状改善作用を示すことが明らかとなった。 <Test results>
As shown in FIG. 3, the number of defecations in the ethenamide group was significantly smaller than that in the control group. Therefore, it became clear that etenzamide has an effect of improving IBS symptoms.
　本発明によりエテンザミドを有効成分として含有する５－ＨＴ２Ｂ受容体拮抗剤を提供することが可能となった。この５－ＨＴ２Ｂ受容体拮抗剤は、５－ＨＴ２Ｂ受容体の情報伝達異常と関連した様々な疾患及びそれに伴う症状の予防又は治療に利用可能である。 According to the present invention, it has become possible to provide a 5-HT2B receptor antagonist containing ethenzamide as an active ingredient. This 5-HT2B receptor antagonist can be used for the prevention or treatment of various diseases associated with abnormal transmission of 5-HT2B receptor signals and associated symptoms.
　具体的には、本発明の５－ＨＴ２Ｂ受容体拮抗剤は、片頭痛、筋緊張型頭痛、混合型頭痛、炎症性疼痛、侵害受容性疼痛、線維筋痛症、慢性腰痛、内臓痛、胃食道逆流性疾患（ＧＥＲＤ）、便秘、下痢、機能性胃腸疾患、過敏性腸症候群（ＩＢＳ）、喘息、変形性関節炎、リウマチ性関節炎、クローン病、潰瘍性大腸炎、糸球体腎炎、腎炎、皮膚炎、肝炎、血管炎、腎虚血、脳卒中、心筋梗塞、脳虚血、アルツハイマー症、可逆的気道閉塞、成人呼吸器系統症候群、慢性閉塞性肺疾患（ＣＯＰＤ）、肺高血圧、突発性間質性肺炎、気管支炎、肝線維症、多肺線維症、抑うつ症、不安神経症、悪性腫瘍又は肥満などの予防又は治療に利用可能であり、医薬品として有用なものである。

  Specifically, the 5-HT2B receptor antagonist of the present invention includes migraine, myotonic headache, mixed headache, inflammatory pain, nociceptive pain, fibromyalgia, chronic low back pain, visceral pain, stomach Esophageal reflux disease (GERD), constipation, diarrhea, functional gastrointestinal disease, irritable bowel syndrome (IBS), asthma, osteoarthritis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, glomerulonephritis, nephritis, skin Inflammation, hepatitis, vasculitis, renal ischemia, stroke, myocardial infarction, cerebral ischemia, Alzheimer's disease, reversible airway obstruction, adult respiratory system syndrome, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, idiopathic interstitial It can be used for the prevention or treatment of pneumonia, bronchitis, liver fibrosis, polypulmonary fibrosis, depression, anxiety, malignant tumor, obesity, etc., and is useful as a pharmaceutical.

Claims (9)

  1. 　エテンザミドを含有することを特徴とするセロトニン２Ｂ受容体拮抗剤。 Serotonin 2B receptor antagonist characterized by containing etenzamid.
  2. 　エテンザミドを含有することを特徴とするセロトニン２Ｂ受容体の情報伝達異常と関連した疾患の予防又は治療剤。 An agent for preventing or treating a disease associated with abnormal signal transmission of serotonin 2B receptor, characterized by containing etenzamid.
  3. 　セロトニン２Ｂ受容体の情報伝達異常と関連した疾患が、片頭痛、筋緊張型頭痛、混合型頭痛、炎症性疼痛、侵害受容性疼痛、線維筋痛症、慢性腰痛、内臓痛、胃食道逆流性疾患（ＧＥＲＤ）、便秘、下痢、機能性胃腸疾患、過敏性腸症候群（ＩＢＳ）、喘息、変形性関節炎、リウマチ性関節炎、クローン病、潰瘍性大腸炎、糸球体腎炎、腎炎、皮膚炎、肝炎、血管炎、腎虚血、脳卒中、心筋梗塞、脳虚血、アルツハイマー症、可逆的気道閉塞、成人呼吸器系統症候群、慢性閉塞性肺疾患（ＣＯＰＤ）、肺高血圧、突発性間質性肺炎、気管支炎、肝線維症、多肺線維症、抑うつ症、不安神経症、悪性腫瘍又は肥満から選ばれた疾患の１種又は２種以上である、請求項２に記載の予防又は治療剤。 Diseases associated with abnormal communication of serotonin 2B receptor are migraine, myotonic headache, mixed headache, inflammatory pain, nociceptive pain, fibromyalgia, chronic low back pain, visceral pain, gastroesophageal reflux Disease (GERD), constipation, diarrhea, functional gastrointestinal disease, irritable bowel syndrome (IBS), asthma, osteoarthritis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, glomerulonephritis, nephritis, dermatitis, hepatitis Vasculitis, renal ischemia, stroke, myocardial infarction, cerebral ischemia, Alzheimer's disease, reversible airway obstruction, adult respiratory system syndrome, chronic obstructive pulmonary disease (COPD), pulmonary hypertension, idiopathic interstitial pneumonia, bronchi The prophylactic or therapeutic agent according to claim 2, which is one or more of diseases selected from inflammation, liver fibrosis, polypulmonary fibrosis, depression, anxiety, malignant tumor or obesity.
  4. 　セロトニン２Ｂ受容体の情報伝達異常と関連した疾患が、片頭痛である請求項２または３に記載の予防または治療剤。 The preventive or therapeutic agent according to claim 2 or 3, wherein the disease associated with abnormal transmission of serotonin 2B receptor information is migraine.
  5. 　セロトニン２Ｂ受容体の情報伝達異常と関連した疾患が、過敏性腸症候群である請求項２または３に記載の予防または治療剤。 The preventive or therapeutic agent according to claim 2 or 3, wherein the disease associated with abnormal transmission of serotonin 2B receptor information is irritable bowel syndrome.
  6. 　エテンザミドと、トリプタン系薬剤、麦角剤、カルシウム拮抗剤、β遮断薬、抗うつ薬、抗てんかん薬およびα遮断薬よりなる群から選ばれる薬剤とを組み合わせてなる偏頭痛の予防または治療用組成物。 A composition for preventing or treating migraine comprising a combination of etenzamide and a drug selected from the group consisting of triptans, ergot agents, calcium antagonists, β-blockers, antidepressants, antiepileptics and α-blockers. .
  7. 　エテンザミドと、抗コリン剤、オピオイド系薬剤、５－ＨＴ３受容体拮抗剤、５－ＨＴ４受容体作動薬および筋弛緩剤よりなる群から選ばれる薬剤とを組み合わせてなる過敏性腸症候群の予防又は治療用組成物。 Prevention or treatment of irritable bowel syndrome comprising a combination of etenzamide and an agent selected from the group consisting of an anticholinergic agent, an opioid agent, a 5-HT3 receptor antagonist, a 5-HT4 receptor agonist and a muscle relaxant. Composition.
  8. 　セロトニン２Ｂ受容体の情報伝達異常と関連した疾患の患者に対し、有効量のエテンザミドを投与する、セロトニン２Ｂ受容体の情報伝達異常と関連した疾患の予防又は治療方法。 A method for preventing or treating a disease associated with abnormal serotonin 2B receptor signaling, comprising administering an effective amount of etenzamide to a patient with a disease associated with abnormal serotonin 2B receptor signaling.
  9. 　エテンザミドのセロトニン２Ｂ受容体の情報伝達異常と関連した疾患の治療のための使用。

          Use of etenzamid for the treatment of diseases associated with abnormal signaling of the serotonin 2B receptor.

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