WO2015190568A1 - ストレス性疾患の予防および/または治療用医薬 - Google Patents
ストレス性疾患の予防および/または治療用医薬 Download PDFInfo
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- WO2015190568A1 WO2015190568A1 PCT/JP2015/066922 JP2015066922W WO2015190568A1 WO 2015190568 A1 WO2015190568 A1 WO 2015190568A1 JP 2015066922 W JP2015066922 W JP 2015066922W WO 2015190568 A1 WO2015190568 A1 WO 2015190568A1
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- ZBQMTQGDBFZUBG-NRFANRHFSA-N CC(N(CC1(CC1)c1c2[nH]c3cccc(F)c13)[C@H]2c(ccc(Cl)c1)c1OC)=O Chemical compound CC(N(CC1(CC1)c1c2[nH]c3cccc(F)c13)[C@H]2c(ccc(Cl)c1)c1OC)=O ZBQMTQGDBFZUBG-NRFANRHFSA-N 0.000 description 2
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
Definitions
- the present invention provides (1S) -2-acetyl-1- (4-chloro-2-methoxyphenyl) -5-fluoro-1, at a specific dose that can achieve the cerebral TSPO occupancy necessary for the development of drug efficacy.
- 2,3,9-tetrahydrospiro [ ⁇ -carboline-4,1′-cyclopropane] (hereinafter sometimes abbreviated as the compound of the present invention) And / or therapeutic drugs.
- Stress-related diseases that is, diseases caused by stress
- stressors that cause distortion (stress response) in the body that receives the stimuli, and cause some kind of disorder at various sites throughout the body. Etc. are expressed.
- stressors affect the activities of the nervous system, endocrine system, and immune system, causing them to malfunction, leading to organic lesions in the brain itself or peripheral organs, resulting in excessive stress. If received, it may cause a disease that causes a significant deterioration in the quality of life, so-called QOL (Quality of Life).
- stress-related diseases include central diseases such as depression, gastrointestinal diseases such as irritable bowel syndrome (hereinafter sometimes abbreviated as IBS) and gastric ulcers, and cardiovascular diseases such as essential hypertension.
- Drugs that treat these stress-related diseases include antidepressants, anxiolytics, and symptomatic drugs for organ lesions in peripheral organs (for example, to relieve psychological stressors) Development of antacids, gastric mucosa protective agents, etc.) has been made. However, although these drugs exhibit a certain degree of effect, there are many occurrences of dependence, side effects, etc., and the current situation is that they have not been completely cured.
- TSPO Translocator protein 18 kDa
- MBR mitochondrial benzodiazepine receptor
- dopamine D2 receptor see Non-Patent Document 2
- ORL1 opioid-receptor-like 1 receptor
- cannabinoid-1 receptor see Non-Patent Document 4
- neurokinin NK
- the receptor occupancy and the optimal radiotracer also referred to as a radioligand or radioprobe
- the optimal radiotracer also referred to as a radioligand or radioprobe
- Non-Patent Document 5 in order for aprepitant, which is an NK1 receptor antagonist, to exhibit a drug effect, it is necessary to occupy 90% or more of the brain NK1 receptor, and the plasma concentration at that time is about It is noted that it is 100 ng / mL or more.
- Non-Patent Document 7 there are many reports on radioactive tracers that target TSPO (see Non-Patent Document 7). Many of these are used as biomarkers for detecting in which tissue TSPO is expressed and the expression level thereof at the onset of diseases involving TSPO, such as Alzheimer's disease and nerve damage ( Non-Patent Document 8 and Patent Document 1).
- the compound of the present invention is described in Patent Document 2 as Example 38 as a compound having affinity for MBR (TSPO), and prevents and / or prevents diseases caused by stress, such as IBS, ulcerative colitis, Crohn's disease and the like. Or known to be useful in therapy.
- TSPO MBR
- the present inventors have also reported that 41st annual meeting of the Society for Neuroscience (November 12, 2011), 42st annual meeting of the Societyciefor Neuroscience (October 17, 2012) and the 7th Annual Meeting of the Molecular Imaging Society of Japan At the meeting (May 25, 2012), the results of basic experiments on the compounds of the present invention were announced.
- An object of the present invention is to set an optimal dosage for use of the compound of the present invention as a preventive and / or therapeutic agent for stress diseases.
- the present inventors paid attention to the relationship between the TSPO occupancy rate based on the efficacy test using an experimental animal, the Ex vivo test and the PET test, and the blood dynamics, and also considered the species difference. As a result, the present inventors have found the optimal specific dosage for achieving a therapeutic effect on patients with stress diseases, which has excellent efficacy and safety, and completed the present invention.
- the present invention [1] Formula (1S) -2-acetyl-1- (4-chloro-2-methoxyphenyl) -5-fluoro-1,2,3,9-tetrahydrospiro [ ⁇ -carboline-4,1′-cyclopropane ]
- a dose that allows TSPO occupancy in a patient with stress disorder to reach about 50 to about 85% at a time
- the agent according to the above [1] wherein the dose that reaches about 50 to about 85% of the TSPO occupancy is a dose that reaches about 15 to about 150 ng / mL as a blood concentration
- the agent according to [1] or [2], wherein the administration method is oral administration
- the administration method is oral administration
- the agent according to the above [3] wherein the dose that allows the TSPO occupancy to reach about 50 to about 85% when administered orally is about 5 to about 60 mg
- the stress-related disease is irritable
- a formula used for the prevention and / or treatment of stress-related diseases, administered once at a dose that achieves about 50 to about 85% TSPO occupancy in patients with stress-related diseases (1S) -2-acetyl-1- (4-chloro-2-methoxyphenyl) -5-fluoro-1,2,3,9-tetrahydrospiro [ ⁇ -carboline-4,1′-cyclopropane ], [12] Formula (1S) -2-acetyl-1- (4-chloro-2-methoxyphenyl) -5-fluoro-1,2,3,9-tetrahydrospiro [ ⁇ -carboline-4,1′-cyclopropane ] At a dose that achieves a TSPO occupancy rate of about 50 to about 95% in a patient with stress disorder at a time, and a prophylactic and / or therapeutic agent for stress disorder, [13] The agent according to the above [12], wherein the dose that reaches about 50 to about 95% of
- the optimal dosage of the compound of the present invention in the treatment of stress-related diseases found in the present invention is excellent in efficacy and safety. Therefore, when the compound of the present invention is used as a medicament for the treatment of stress-related diseases, Can have a therapeutic effect.
- 1 represents the anxiolytic effect of a compound of the present invention in fear-conditioned stress-loaded rats. It represents an anxiolytic effect of the compound of the present invention in a CCK-4 induced stress model.
- the relationship between the plasma concentration of the compound of the present invention and the brain TSPO occupancy rate in the monkey PET test is shown.
- the relationship between the plasma concentration of the compound of the present invention and the brain TSPO occupancy rate in the human PET test is shown.
- Based on Biological Example 8 the prediction result of the relationship between the dose and brain TSPO occupancy in the steady state when the compound of the present invention is administered once a day to humans is shown.
- the vertical axis represents TSPO occupancy (Receptor Occupancy (%)), and the horizontal axis represents the dose (Dose (mg)) of the compound of the present invention.
- the vertical axis represents TSPO occupancy (Receptor Occupancy (%)), and the horizontal axis represents the dose (Dose (mg)) of the compound of the present invention.
- mold female IBS patient is represented.
- the vertical axis represents the amount of change from the baseline, and the horizontal axis represents the week from the start of medication.
- mold female IBS patient is represented.
- the vertical axis represents the amount of change from the baseline, and the horizontal axis represents the week from the start of medication.
- mold female IBS patient is represented.
- the vertical axis represents the daily responder rate.
- the weekly responder rate in each administration group of diarrhea type female IBS patients is shown.
- the vertical axis represents the weekly responder rate.
- the compound of the present invention that is, (1S) -2-acetyl-1- (4-chloro-2-methoxyphenyl) -5-fluoro-1,2,3,9-tetrahydrospiro [ ⁇ -carboline- 4,1′-cyclopropane] is represented by the following structural formula.
- the compound of the present invention can be produced according to Example 36 (2) ⁇ Example 38 described in Patent Document 2.
- TSPO means Translocator protein 18 kDa, and also means a receptor protein called MBR (Mitochondrial benzodiazepine receptor).
- MBR Mitochondrial benzodiazepine receptor
- human TSPO is preferred in the present invention.
- the radioactive tracer is also referred to as a radioactive ligand or a radioactive probe, and means a radioactive tracer that can bind to TSPO.
- the radioactive tracer used in the present invention include [ 3 H] PK11195, [ 11 C] PBR28, and [ 11 C] DPA713.
- PK11195 is 1- (2-chlorophenyl) -N-methyl-N- (1-methylpropyl) isoquinoline-3-carboxamide (CAS registration number: 85532-).
- PBR28 means N- (2-methoxybenzyl) -N- [4- (phenoxy) pyridin-3-yl] acetamide (CAS Registry Number: 253307-65-2)
- DPA713 is N, N-diethyl-2- [2- (4-methoxyphenyl) -5,7-dimethylpyrazolo [1,5-a] pyrimidin-3-yl] acetamide (CAS Registry Number: 386297-97). -8).
- [ 11 C] PBR28 is preferable as the radioactive tracer in the present invention.
- the TSPO occupancy is the amount of radioactive tracer bound to TSPO in the brain measured when the radiotracer was administered before administration of the compound of the present invention, and the radiotracer administered after administration of the compound of the present invention. It means the occupancy rate of TSPO in the brain of the compound of the present invention calculated using the amount of binding of radioactive tracer to brain TSPO measured at the time.
- the dose of the compound of the present invention to be administered to a patient for the prevention and / or treatment of a stress disorder is as follows: Examples include doses that reach a blood (serum) concentration that can achieve a TSPO occupancy of about 50 to about 85%, ie, about 15 to about 150 ng / mL.
- the dose of the compound of the present invention to be administered to a patient for the prevention and / or treatment of stress-related diseases is as follows. Examples include doses that reach a blood (serum) concentration that can achieve a TSPO occupancy of about 50 to about 95%, ie, about 15 to about 250 ng / mL.
- the method of administering the compound of the present invention for achieving the above-mentioned blood (serum) concentration is not particularly limited, and examples thereof include oral administration, subcutaneous administration, intravenous administration, intramuscular administration, and intraperitoneal administration. , Transdermal administration, nasal administration, pulmonary administration, and the like.
- the dose of the compound of the present invention for achieving the above blood concentration varies depending on the administration method.
- the blood concentration reaches about 15 to about 250 ng / mL.
- the dose includes a dose of about 5 mg to about 100 mg per day.
- a dose of about 20 mg to about 100 mg, more preferably about 50 mg to about 100 mg, particularly preferably about 60 mg is mentioned.
- Specific doses include about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg about 65 mg, about 70 mg, about 75 mg.
- the dose may be used by appropriately increasing or decreasing within the range of about 100 mg as the maximum daily dose. Further, the dose may be a dose at a single administration or a dose at a plurality of administrations, for example, a dose when administered in 1 to 4 divided doses per day. When administered multiple times, each dose may be the same or different.
- the administration period for maintaining the above-mentioned blood concentration of the compound of the present invention and exerting the preventive and / or therapeutic effect of stress diseases is not particularly limited, but for example, 1 day to 1 year, Day to 6 months, 1 day to 3 months, 1 day to 2 months, 1 day to 1 month, 1 day to 3 weeks, 1 day to 2 weeks, 1 day to 1 week.
- stress diseases include, for example, irritable bowel syndrome, functional gastrointestinal dysfunction, peptic ulcer, gastric / duodenal ulcer, biliary dyskinesia, esophageal spasm, gastric atony, dysphagia, chronic gastritis, chronic hepatitis Chronic pancreatitis, eating disorders (eg anorexia nervosa, anorexia nervosa, bulimia etc.), neurogenic (psychogenic) vomiting, neurogenic (psychogenic) nausea, inflammatory Bowel disease (eg, ulcerative colitis, Crohn's disease), abdominal constriction, gastrointestinal neurosis (eg, fear of belly), anxiety related disease, neurosis, panic disorder, sleep disorder, depression, reactive depression , Epilepsy, Parkinson's disease, Parkinson's syndrome, schizophrenia, autonomic dysfunction, Huntington's disease, Alzheimer's disease, affective disorder, cognitive impairment, migraine, tension headache, cluster headache, post-traumatic stress disorder (Post Traumatic Stress Disorder (PTSD
- functional gastrointestinal disorders include, for example, functional gastroenteropathy (functional dyspepsia), functional abdominal pain syndrome, and functional heartburn.
- anxiety-related diseases include neurosis, generalized anxiety disorder (GAD), social anxiety disorder (Social Anxiety Disorder; SAD), panic disorder, hyperactivity disorder, attention deficit, personality. Disorders, bipolar disorder, autism and the like.
- GAD generalized anxiety disorder
- SAD Social anxiety disorder
- panic disorder is used.
- the toxicity of the compound of the present invention is sufficiently low and can be used safely as a pharmaceutical product.
- the compound of the present invention Since the compound of the present invention has a TSPO antagonistic action, it is useful as a preventive and / or therapeutic agent for the aforementioned stress-related diseases.
- the compound of the present invention is 1) complementation and / or enhancement of the preventive and / or therapeutic effects of the compound of the present invention on the above-mentioned stress-related diseases, 2) improvement of kinetics / absorption of the compound of the present invention, reduction of dosage, and / or 3 )
- it may be administered in combination with other drugs as a concomitant drug.
- the concomitant drug of the compound of the present invention and another drug may be administered in the form of a combination drug containing both components in one preparation, or may be administered in separate preparations.
- simultaneous administration and administration by time difference are included.
- administration by time difference may be such that the compound of the present invention is administered first and the other drug may be administered later, or the other drug may be administered first and the compound of the present invention may be administered later.
- the administration method may be the same or different.
- examples of the benzodiazepine anxiolytic drugs include alprazolam, oxazepam, oxazolam, cloxazolam, chlorazepate dipotassium, chlordiazepoxide, diazepam, tofisopam, triazolam, prazepam, fludiazepam, flutazolam, fltopazepam, xazopam, Examples include ethyl loflazepate and lorazepam.
- examples of the thienodiazepine anxiolytic include etizolam and clothiazepam.
- non-benzodiazepine anxiolytics examples include tandospirone citrate and hydroxylidine hydrochloride.
- examples of the neurokinin-1 antagonist include aprepitant and fosaprepitant meglumine.
- examples of the tricyclic antidepressant include amitriptyline hydrochloride, imipramine hydrochloride, clomipramine hydrochloride, dosrepin hydrochloride, nortriptyline hydrochloride, lofepramine hydrochloride, trimipramine maleate, and amoxapine.
- examples of the tetracyclic antidepressant include maprotiline hydrochloride, mianserin hydrochloride, and cetiptyline maleate.
- examples of the monoamine oxidase (MAO) inhibitor include safrazine hydrochloride.
- examples of serotonin and noradrenaline reuptake inhibitor include milnacipran hydrochloride, venlafaxine hydrochloride, and duloxetine hydrochloride.
- examples of the selective serotonin reuptake inhibitor include fluvoxamine maleate, paroxetine hydrochloride, fluoxetine hydrochloride, citalopram hydrochloride, sertraline hydrochloride, and escitalopram oxalate.
- examples of the serotonin reuptake inhibitor include trazodone hydrochloride.
- examples of noradrenergic and selective serotonergic antidepressants include mirtazapine.
- examples of the noradonaline and dopamine desuppression agent include agomelatine.
- examples of the serotonin reuptake promoter include tianeptine.
- examples of the N-methyl-D-aspartate receptor inhibitor include memantine.
- an example of the dopamine precursor is levodopa.
- an example of a dopamine receptor agonist is bromogliptin.
- examples of the COMT inhibitor include entacapone.
- examples of the cholinesterase inhibitor include donepezil and rivastigmine.
- examples of the anticholinergic agent include trihexyphenidyl, biperidene, ipratropium bromide, and mepenzolate bromide.
- examples of serotonin / dopamine antagonists include risperidone, perospirone hydrochloride hydrate, quetiapine fumarate, and olanzapine.
- examples of the antiepileptic drug include phenobarbital, phenytoin, carbamazepine, valproic acid, clonazepam, levetiracetam, topiramate, and lamotrigine.
- examples of the anti-vertigo drug include diphenidol and betahistine.
- examples of the gastrointestinal function regulator include trimebutine maleate and polycarbophil calcium.
- examples of the histamine H 2 receptor antagonist include cimetidine, ranitidine, famotidine, nizatidine, and lafutidine.
- examples of the proton pump inhibitor include omeprazole, lansoprazole, and rabeprazole.
- examples of the muscarinic receptor antagonist include pirenzepine.
- examples of the protective factor enhancer include gefarnate, teprenone, sucralfate, aldioxa, cetraxate hydrochloride, and ornoprostil.
- examples of the prostaglandin derivative include ornoprostil and misoprostol.
- examples of the opioid agonist include asimadoline and nalflavine.
- examples of the 5-HT 4 agonist include tegaserod, cisapride, and mosapride citrate.
- examples of the 5-HT 3 antagonist include ramosetron, alosetron, and silane setron.
- examples of the chloride channel activator include rubiprostone.
- examples of the guanylate cyclase agonist include linaclotide.
- examples of the expansive laxative include methyl cellulose, carmellose, and lactulose.
- examples of the salt laxative include magnesium sulfate and magnesium oxide.
- examples of the stimulant laxative include picosulfate, lactulose, castor oil, senna, and large yellow.
- examples of the affinity polyacrylic resin include polycarbophil calcium.
- opioid ⁇ receptor agonists and opioid ⁇ receptor antagonists examples include erxadrine.
- examples of the tryptophan hydroxylase inhibitor include LX1033.
- examples of the antibiotic include rifaximin.
- Biological Example 1 Examination of anti-stress action and ex vivo brain occupancy in rats Male Slc: Wistar rats (Japan SLC, 11 weeks old when used) were loaded with physical and mental stressors ( Journal of Pharmacological Science, 104, 263-273, 2007). Two hours after oral administration of a vehicle (0.5 w / v% methylcellulose 400 cP solution) or a compound of the present invention at doses of 0.1, 0.3, 1 and 3 mg / kg, rats were restrained in a restraint stress cage (Natsume Manufacturing Co., Ltd.). ) To start the stressor load. The anti-stress effect was evaluated by measuring the weight of feces excreted during one hour of stressor loading (12 mice in each group).
- PK11195 was dissolved to 4 mmol / L using dimethyl sulfoxide (DMSO), and [ 3 H] PK11195 (PerkinElmer, Inc.) was prepared after preparing a 100 nmol / L ethanol solution and then adding 50 mmol / L HEPES. The sample was diluted 50 times with a buffer (Sigma Aldrich Co., Ltd.).
- ACS-II scintillation cocktail (7 mL) was added to a liquid scintillation vial and stirred, and radioactivity was measured with a liquid scintillation counter (TRI-CARB2900TR, PerkinElmer Life and Analytical Sciences Inc.).
- the specific binding amount (dpm) of [ 3 H] PK11195 in each brain homogenate was a value obtained by subtracting the nonspecific binding amount (dpm) from the total binding amount (dpm).
- the intracerebral TSPO occupancy rate (%) in the cerebral cortex and hippocampus of the compound-administered group was calculated according to the following formula.
- TSPO occupancy rates in the cerebral cortex of the 0.1, 0.3, 1 and 3 mg / kg groups of the compound of the present invention were 11.8, 47.7, 83.8 and 94.5% on average, and the hippocampus
- the average TSPO occupancy ratios were 25.7, 50.7, 86.3 and 95.1%.
- the head of a rat anesthetized with sodium pentobarbital was fixed to a stereotaxic device (ASI Instruments Inc., NARISHIGE), and after incision of the scalp, the left and right olfactory bulb sites (7 mm forward from bregma, 1.8 mm laterally) ) was drilled using a dental drill, the left and right olfactory bulbs were aspirated and removed with an aspirator connected to an oral sonde excluding the tip, and then the scalp was sutured.
- Rats after surgery were placed in a stainless steel five-lined cage in which each breeding space was divided in half by a black acrylic plate, and were kept in isolation so that the next door could not be seen.
- the entire breeding shelf on which the stainless steel five-cage cage was placed was covered with a black vinyl sheet, and the breeding shelf was kept dark.
- the head was fixed under anesthesia, the scalp was incised, holes were made in the left and right olfactory bulbs of the skull, and the scalp was sutured without aspiration / removal of the olfactory bulb.
- no isolation and isolation were conducted. 14 days after the operation, animals were evaluated for affective hyperreactivity with reference to the method of Gomida et al. (Japanese Journal of Pharmacology, Vol. 82, pp. 267-292, 1983). Was used in the experiment.
- ⁇ Evaluation criteria for emotional hyperreactivity> A. Response to a stick placed at the tip of the nose 0: No response 1: Interest in the subject 2: Defensive or escape behavior to the subject 3: Aggressive behavior such as biting 4: Intense aggressive behavior Response when air is blown 0: No response 1: Slight body movement 2: Startle response 3: Shows startle response but does not jump 4: Shows startle response and jumps Resistance to capture and handling 0: No resistance, significant muscle relaxation 1: Easy to capture and handle 2: Easy to capture and handle, but mild muscle tension 3: With muscle tension, difficult to capture and handle 4: Capture Is extremely difficult and marked muscle tone.
- the current load was not applied during the fear conditioning, and a warning sound and light irradiation were given to the rats.
- rats were orally administered vehicle (0.5 w / v% methylcellulose 400 cP solution) or compounds of the present invention (0.3, 1 and 3 mg / kg).
- the rats were placed in an electric shock device. Only 5 seconds of light irradiation followed by 3 seconds of warning sound was given to the rats for 30 minutes in total at 1 minute intervals, and stress was applied. The behavior of the rats under stress for 30 minutes was photographed with a video camera, and the freezing time was measured.
- FIG. 2 (#### indicates that p ⁇ 0.001 for the non-stressed group in the t test, and * indicates p ⁇ 0 for the vehicle control group in the Dunnett test. .05), the freezing time of the group in which the vehicle was administered to the stressed rats was longer than that of the non-stressed group. This increase in freezing time was significantly shortened by the compounds of the present invention at doses of 1 and 3 mg / kg. From this result, it was revealed that the compound of the present invention has an anxiolytic action.
- Biological Example 4 Examination of anti-anxiety action (2) Male LEW / CrlCrlj rats (Nippon Charles River, Inc., age at evaluation: 6 weeks old) were used. Induction of freezing behavior by subcutaneous administration of cholecystokinin tetrapeptide (CCK-4) (3 mg / kg) to rats according to the method of Rupprecht et al. (Science, 325, 490-493, 2009) And used as an indicator of anxiety.
- CCK-494 cholecystokinin tetrapeptide
- Rats were subcutaneously administered with 3 mg / kg CCK-4 2 hours after oral administration of vehicle (0.5 w / v% methylcellulose 400 cP solution) or the compound of the present invention (1 and 3 mg / kg), and 2 minutes later
- vehicle 0.5 w / v% methylcellulose 400 cP solution
- the compound of the present invention (1 and 3 mg / kg)
- the forelimb was placed on a 7 cm high wooden block, and the time during which the rat did not move at all other than the movement associated with breathing was defined as the freezing time and measured with a stopwatch.
- 1% dimethylformamide as the vehicle was administered instead of CCK-4.
- the cut-off time was 120 seconds. This trial was performed a total of 5 times at intervals of about 2 minutes, and the total free time was calculated.
- FIG. 3 shows that Wilcoxon rank sum test is p ⁇ 0.001 for the normal group, and * is Steel test for p ⁇ 0. 05, ** means Steel test and p ⁇ 0.01 for the media group, *** means Steel test and p ⁇ 0 for the media group.
- the freezing time of the group in which the vehicle was administered to the stressed rats was longer than that of the normal group. This increase in freezing time was significantly shortened by the compounds of the present invention at doses of 1 and 3 mg / kg. From this result, it was revealed that the compound of the present invention has an anxiolytic action.
- Biological Example 5 Comparison of radiotracer in rat ex vivo brain occupancy
- Male Slc Wistar rats (Japan SLC, 11 weeks old when used) were used as a vehicle (0.5 w / v% methylcellulose 400 cP solution). Or the compound of the present invention was orally administered at doses of 0.03, 0.1, 0.3, 1 and 3 mg / kg.
- Biological Example 6 Examination of ex vivo brain occupancy in monkeys Using male rhesus monkeys (Shin Nihon Kagaku Co., Ltd., 4-6 kg when used), medium (0.5 w / v% methylcellulose 400 cP solution) or the present The compound of the invention was orally administered at a dose of 0.4 and 1 mg / kg twice a day for 3 days, and then once on the 4th day. Using the brain (anterior cingulate cortex, caudate nucleus, amygdala, hippocampus and occipital lobe) homogenate 2 hours after the final administration, the amount of specific binding of [ 3 H] PBR28 was determined in the same manner as in Biological Example 1.
- the occupancy rate of the compound of the present invention in the brain based on the specific binding amount of the vehicle-treated group was measured (medium group: 3 cases, inventive compound-administered group: 5 cases each).
- the average TSPO occupancy rates at 5 brain sites in the 0.4 and 1 mg / kg groups of the compound of the present invention were 37.9 and 56.6% on average.
- the concentration of the compound of the present invention in the plasma of the 0.4 and 1 mg / kg groups was 23.9 and 154 ng / mL on average.
- Biological Example 7 Examination of brain occupancy using PET in monkeys Male rhesus monkeys (Hamley Co., Ltd., 5-8 kg when used) were used. Three rhesus monkeys were orally administered with a vehicle (0.5 w / v% methylcellulose 400 cP solution) or a compound of the present invention at a dose of 0.3 to 30 mg / kg, and 2 hours later, [ 11 C] PBR28 was used. PET measurement was performed as follows.
- Measuring equipment PET camera; SHR-7700 (Hamamatsu Photonics) Image reconstruction: SHR Control II program (Hamamatsu Photonics) Time course of radioactivity concentration in brain and calculation of distribution volume: PMOD program (PMOD Technologies Ltd.) Measurement method: A blank measurement was performed for 120 minutes and a transmission measurement was performed for 30 minutes using a 68 Ge / 68 Ga calibration radiation source. Then, the [11 C] PBR28, were administered the total amount over a period of about 30 seconds intravenously. Simultaneously with the start of administration, emission measurement (total of 121 minutes, 55 frames) was performed while collecting arteries for measuring plasma concentration.
- the compound of the present invention was orally administered to 3 rhesus monkeys at a dose of 0.3 to 10 mg / kg twice a day for 3 days, then once orally on the 4th day, 2 hours or 24 hours after the final administration. It was performed [11 C] PET measurement using the PBR28.
- Each region of interest (cerebellum, hippocampus, striatum, thalamus, occipital lobe, temporal region) from the time course of [ 11 C] PBR28 in the brain and the arterial blood plasma radioactivity corrected by the unmetabolized rate of [ 11 C] PBR28 Leaf, frontal lobe, parietal lobe) was calculated, and the brain TSPO occupancy was calculated based on the distribution volume of the vehicle administration group.
- the relationship between the plasma concentration of the compound of the present invention in each individual and the brain TSPO occupancy was analyzed, and the brain TSPO occupancy in each individual was determined to be the plasma concentration of the compound of the present invention. It turned out to be dependent.
- Biological Example 8 Examination of brain occupancy rate using PET in humans (1) Using male and female healthy adult, prior to administering the present compound, and 24 hours after a single oral dose at a dosage of the present compounds 6 ⁇ 200 mg, below PET measurement using [11 C] PBR28 as radiotracers The procedure was implemented. Measuring instrument: PET; ECAT HR + (Siemens) Measurement method: Blank measurement was performed for 90 minutes and Transmission measurement was performed for 10 to 15 minutes using a 68Ge / 68Ga calibration source. Next, [ 11 C] PBR28 was administered intravenously over the course of about 30 seconds. Emission measurement (total 90 minutes, 26 frames) was performed simultaneously with the start of administration while performing arterial blood collection for measuring plasma concentration.
- the binding potential (BP) of each region of interest is calculated from the time course of [ 11 C] PBR28 radioactivity concentration in the brain, the amount of non-specific binding, and the arterial blood plasma radioactivity corrected by the unmetabolized rate of [ 11 C] PBR28.
- the occupancy rate in the brain was calculated based on BP before medication (3 to 4 people in each group).
- the average brain volume of all regions of interest from the Lassen plot obtained by taking the distribution volume before administration on the horizontal axis and the value obtained by subtracting the distribution volume after administration from the distribution volume before administration on the vertical axis.
- TSPO occupancy was determined.
- Emax Emax
- EC50, ng / mL blood concentration that achieves 50% of Emax
- NONMEM 7.1.2 ICON Development Solutions
- the plasma concentration for reaching the brain TSPO occupancy rate of about 50% is about 15 ng / mL, and the plasma concentration for reaching about 85% is also about 150 ng / mL. I understood it.
- the transition of plasma concentration of the compound of the present invention in the steady state at the time of once-daily administration is predicted, and the brain TSPO occupancy is predicted using the relationship between the plasma concentration and the brain TSPO occupancy shown in FIG.
- the dose of the compound required to achieve a minimum value of TSPO occupancy of about 50 to about 90% in the steady state was about 5 mg to about 100 mg per day.
- the TSPO occupancy rate showing effective anti-stress action, antidepressant action and anxiolytic action in rats is about 50 to about 95%. Based on these results, the relationship between the occupancy rate of TSPO that can exert an anti-stress effect in monkeys and the plasma concentration was found. Furthermore, since [ 11 C] PBR28 functioned in humans as a radioactive tracer in TSPO, the relationship between TSPO occupancy and plasma concentration in humans of the compounds of the present invention became clear for the first time, and the correlation between TSPO occupancy and plasma concentration It was also found that there are species differences between monkeys and humans.
- Biological Example 9 Examination of brain occupancy rate using PET in humans (2) Analysis method different from biological example 8, ie, [ 11 C] PBR28 brain radioactivity concentration time change, non-specific binding amount, and [ 11 C] PBR28 unmetabolized rate corrected for arterial blood plasma radiation
- the binding potential (BP) of each region of interest was calculated from the ability, and the occupancy rate in the brain was calculated based on BP before medication (3 to 4 people in each group).
- the distribution volume before administration (Vt baseline) and the value obtained by subtracting the distribution volume after administration from the distribution volume before administration (Vt baseline-Vt onmed) for each region of interest are plotted on the horizontal and vertical axes, respectively.
- the average cerebral TSPO occupancy rate of the entire region of interest was determined from the obtained Lassen plot.
- the TSPO occupancy rate showing effective anti-stress action, antidepressant action and anxiolytic action in rats is about 50 to about 95%. Based on these results, the relationship between the occupancy rate of TSPO that can exert an anti-stress effect in monkeys and the plasma concentration was found. Furthermore, since [ 11 C] PBR28 functioned in humans as a radioactive tracer in TSPO, the relationship between TSPO occupancy and plasma concentration in humans of the compounds of the present invention became clear for the first time, and the correlation between TSPO occupancy and plasma concentration It was also found that there are species differences between monkeys and humans.
- human efficacy tests can be performed. For example, there are the following three clinical trials.
- Biological Example 10 Efficacy study 1 in humans As a clinical trial, a double-blind parallel group study was conducted on diarrhea-type female IBS patients under the following conditions. Objective: To confirm the effectiveness of IBS for clinical symptoms: This study was conducted at 49 institutions in the United States and met the Rome III diagnostic criteria (Gastroenterology, 2006, 130, 1480-1491) 200 women with diarrhea type IBS (18-65 years old) were accumulated. Subjects were randomly assigned 1: 1: 1 in any of the following three dose groups and were orally dosed once a day for 4 weeks. Subjects recorded IBS symptoms in the electronic diary every day during the 2-week pre-observation period, 4-week medication period, and 4-week post-observation period. Safety observations were made throughout the study.
- the main evaluation items are stool shape (assessment based on Bristol Stool Scale (BSS)), number of bowel movements and abdominal pain (scoring based on Numerical Rating Scale (NRS)) The amount of change from the baseline (pre-observation period).
- the responder was analyzed according to FDA guidance (Guidance for Industry Irritable Bowel Syndrome-Clinical Evaluation of Drugs for Treatment).
- Administration group (1) Placebo group (2) Compound of the present invention (20 mg administration) group (3) Compound of the present invention (60 mg administration) group Evaluation items: IBS symptoms (abdominal pain, fecal shape, number of bowel movements, feeling of urgency, severity ), QOL, psychiatric symptoms, safety, pharmacokinetics, biomarker results: Baseline values of patient group and parameters (stool shape, number of bowel movements and abdominal pain) were similar in each treatment group. In the 60 mg administration group of the compound of the present invention in the weekly average score of abdominal pain felt most intensely throughout the day, and the number of days in which BSS equivalent to 6 or 7 was once in BSS throughout the week for 4 weeks Improvement was observed for the placebo group (FIGS. 8 and 9).
- abdominal pain score when the day when it decreased by 30% or more from the baseline was 50% or more during the 4 weeks of the medication period, the abdominal pain was regarded as a daily responder.
- stool shape when the BSS was less than 5 or the day without stool was 50% or more of the medication period of 4 weeks, a stool-shaped daily responder was used. If the day that meets the criteria for abdominal pain score (more than 30% lower than baseline) and stool shape (less than 5 in BSS or no stool) was 50% or more of 4 weeks of medication, abdominal pain and stool shape Daily responder.
- Biological Example 11 Human efficacy study 2 As a clinical trial, a double-blind parallel group study is conducted under the following conditions for diarrhea-type female IBS patients. Objective: Use barostat method to confirm effectiveness on perception and exercise during intestinal dilatation. Administration group: Oral administration once a day after each meal in each group; (1) Placebo (placebo) group (2) Compound of the present invention (60 mg administration) administration period: 2 weeks Evaluation items: Abdominal pain, urgency, intestinal motility during intestinal dilatation, IBS severity, QOL, psychiatric symptoms, safety , Pharmacokinetics, biomarker
- Biological Example 12 Therapeutic Effect of Stress Diseases (Depression, Anxiety Related Diseases) in Humans
- PSS Perceived Stress Scale
- HAM-A Halton Anxiety Scale
- HAM-D Hamilton Depression Scale
- Table 4 shows the PSS score
- Table 5 shows the HAM-A score
- Table 6 shows the HAM-D score.
- the TSPO occupancy rate of the compound of the present invention can reach about 50 to about 95% in a patient with a stress disorder, the effectiveness of the compound of the present invention is maximized, and the stress property It is useful as a medicament for the prevention and / or treatment of diseases.
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Abstract
Description
[1] 式
[2] TSPO占有率を約50乃至約85%に到達せしめる用量が、血中濃度として約15乃至約150ng/mLに到達する用量である前記[1]記載の剤、
[3] 投与方法が経口投与である前記[1]または[2]記載の剤、
[4] 経口投与時に、TSPO占有率を約50乃至約85%に到達せしめる用量が、約5乃至約60mgである前記[3]記載の剤、
[5] ストレス性疾患が、過敏性腸症候群、機能性消化管障害、うつ病、または不安関連疾患である前記[1]乃至[4]のいずれかに記載の剤、
[6] ストレス性疾患が、過敏性腸症候群である前記[5]記載の剤、
[7] TSPO占有率が、放射性トレーサーとして[11C]PBR28を用いて測定されたTSPO占有率である前記[1]乃至[6]のいずれかに記載の剤、
[8] 式
[9] 放射性トレーサーとして[11C]PBR28を用いることを特徴とする、ストレス性疾患を予防および/または治療するためのTSPO拮抗薬の有効用量を設定する方法、
[10] 式
[11] 1回当たり、ストレス性疾患の患者におけるTSPO占有率を約50乃至約85%に到達せしめる用量で投与して、ストレス性疾患の予防および/または治療のために使用される、式
[12] 式
[13] TSPO占有率を約50乃至約95%に到達せしめる用量が、血中濃度として約15乃至約250ng/mLに到達する用量である前記[12]記載の剤、
[14] 投与方法が経口投与である請求項[12]または[13]記載の剤、
[15] 経口投与時に、TSPO占有率を約50乃至約95%に到達せしめる用量が、約5乃至約100mgである前記[14]記載の剤、
[16] ストレス性疾患が、過敏性腸症候群、機能性消化管障害、うつ病、または不安関連疾患である前記[12]乃至[15]のいずれかに記載の剤、
[17] 不安関連疾患が、神経症、全般性不安障害、社交不安障害、パニック障害、多動性障害、注意欠陥、人格障害、双極性障害、自閉症である前記[16]に記載の剤、
[18] 式
[19] 1回当たり、ストレス性疾患の患者におけるTSPO占有率を約50乃至約95%に到達せしめる用量で投与して、ストレス性疾患の予防および/または治療のために使用される、式
本発明化合物の毒性は十分に低いものであり、医薬品として安全に使用することができる。
本発明化合物は、TSPO拮抗作用を有するため、上記したストレス性疾患の予防および/または治療剤として有用である。
[実験例]
以下に生物学的実験例を示し、これらの実験方法に基づいて、本発明化合物の効果を確認した。
雄性Slc:Wistarラット(日本エスエルシー、使用時11週齢)を用いて、身体・精神的ストレッサーを負荷した(ジャーナル・オブ・ファーマコロジカルサイエンス(Journal of Pharmacological Science)、第104号、263~273ページ、2007年)。媒体(0.5w/v%メチルセルロース400cP溶液)あるいは本発明化合物を0.1、0.3、1および3mg/kgの用量で経口投与した2時間後に、ラットを拘束ストレスケージ(株式会社夏目製作所)に入れることによりストレッサー負荷を開始した。抗ストレス作用の評価は、1時間のストレッサー負荷中に排泄した便重量を計測することにより行った(各群12匹)。ストレッサーを負荷しない正常群の脱糞量(排便湿重量:平均0.04g)と比較して、ストレッサーを負荷した媒体処置群には顕著な脱糞が認められた(排便湿重量:平均1.79g)。本発明化合物の0.1、0.3、1および3mg/kg投与群における排便湿重量は、平均でそれぞれ、1.48、0.96、0.60および0.67gであったことから、0.3、1および3mg/kgの用量で媒体処置群より有意に排便湿重量を抑制することが判明した。
雄性Crlj:WIラット(日本チャールス・リバー株式会社、手術時週齢:11週齢)を用い,Yamaguchiらの方法(日本薬理学雑誌、第130巻、175~183ページ、2007年)に準じて、嗅球摘出ラットを作製した。ペントバルビタールナトリウムで麻酔したラットの頭部を、脳定位固定装置 (ASI Instruments Inc.、NARISHIGE) に固定し、頭皮を切開後、頭蓋骨の左右嗅球部位 (bregmaから前方に7mm、横に1.8mm) に歯科用ドリルを用いて穴を開け、先端を除いた経口ゾンデに連結したアスピレータで左右嗅球を吸引・除去した後、頭皮を縫合した。手術後のラットを、個々の飼育スペースを黒色アクリル板で半分に仕切ったステンレス製五連ケージに入れ、隣が見えないように隔離して飼育した。また、ステンレス製五連ケージを置く飼育棚全体を黒ビニールシートで覆い、飼育棚内を暗い状態にして飼育した。なお、偽手術群のラットは、麻酔下で頭部を固定、頭皮を切開し、頭蓋骨の左右嗅球部位に穴をあけた後、嗅球の吸引・除去を行わず、頭皮を縫合した。また、単離隔離飼育を実施しなかった。手術後14日間経過した後、五味田らの方法(日本薬理学雑誌、第82巻、267~292ページ、1983年)を参考にして情動過多反応性を評価し、合計評点が20点の動物を実験に使用した。
A.鼻先に差し出した棒に対する反応
0:無反応
1:対象への関心
2:対象への防御的または逃避的行動
3:噛みつくなどの攻撃的行動
4:激しい攻撃的行動
B.空気を吹きかけた時の反応
0:無反応
1:わずかに身体が動くだけ
2:驚愕反応
3:著明な驚愕反応を示すが、飛び上がらない
4:著明な驚愕反応を示し、飛び上がる
C.捕獲や取り扱いに対する抵抗性
0:無抵抗、著明な筋弛緩
1:捕獲や取り扱いが容易
2:捕獲や取り扱いは容易だが、軽度の筋緊張
3:筋緊張有り、捕獲や取り扱いが困難
4:捕獲がきわめて困難で著しい筋緊張
D.尾を鉗子で挟んだ時の反応
0:無反応
1:対象への関心
2:対象への防御的または逃避的行動
3:噛みつくなどの攻撃的行動
4:激しい攻撃的行動
E.テスト中 (A~D)の鳴き声
0:全く鳴かない
1:時々鳴く
2:激しく鳴く
雄性Crj:CD(SD)ラット(日本チャールス・リバー株式会社、評価時週齢:8週齢)を用い、Funatsuらの方法(ヨーロピアン・ジャーナル・オブ・ファーマコロジー(Eur. J. Pharmacol.)、第573巻、190~195ページ、2007年)に準じて、恐怖条件付けストレスを負荷した。恐怖条件付け前日に、防音箱内に設置した電気ショック装置内にラットを入れ、評価環境に馴化させた。恐怖条件付け当日に、電気ショック装置内にラットを入れた。3秒間の警告音(60~70デシベル)に続き5秒間の電流負荷(2.0mA)及び光照射(40W型蛍光灯電球3個)をラットに与える条件付けを、1分間隔で計15回行った。なお、非ストレス負荷群には、恐怖条件付けの間に電流負荷を実施せず、警告音と光照射をラットに与えた。恐怖条件付け翌日、媒体(0.5w/v% メチルセルロース400cP溶液)あるいは本発明化合物(0.3、1および3mg/kg)をラットに経口投与した。投与後2時間に、ラットを電気ショック装置内に入れた。3秒間の警告音に続く5秒間の光照射のみを1分間隔で計30分間、ラットに与え、ストレスを負荷した。ストレスが負荷されている30分間のラットの行動をビデオカメラで撮影し、すくみ時間を計測した。
雄性LEW/CrlCrljラット(日本チャールス・リバー株式会社,評価時週齢:6週齢)を使用した。Rupprechtらの方法(サイエンス(Science)、325、490-493、2009年)に準じて、ラットにコレシストキニンテトラペプチド(CCK―4)(3mg/kg)を皮下投与することによりすくみ行動を誘発し、不安の指標とした。
雄性Slc:Wistarラット(日本エスエルシー、使用時11週齢)を用いて、媒体(0.5w/v%メチルセルロース400cP溶液)あるいは本発明化合物を0.03、0.1、0.3、1および3mg/kgの用量で経口投与した。生物学的実施例1と同様の方法で、投与3時間後の脳(大脳皮質)ホモジネートを用いて、[3H]PK11195あるいは[3H]PBR28(積水メディカル株式会社)の特異的結合量を計測し、媒体処置群の特異的結合量を基準とした本発明化合物の脳内TSPO占有率を測定した(各群8匹)。その結果、[3H]PK11195を放射性トレーサーとして使用した場合、本発明化合物の0.03、0.1、0.3、1および3mg/kg処置群の大脳皮質におけるTSPO占有率は、平均で-1.3、14.9、48.1、80.9および91.3%であった。一方、[3H]PBR28を放射性トレーサーとして使用した場合では、平均で6.5、11.5、40.4、77.7および90.2%であった。以上のことから、[3H]PK11195と[3H]PBR28のいずれの放射性トレーサーを用いた場合でも、本発明化合物のTSPO占有率は同程度であることが判明した。
雄性アカゲザル(株式会社新日本科学、使用時4-6kg)を用いて、媒体(0.5w/v%メチルセルロース400cP溶液)あるいは本発明化合物を0.4および1mg/kgの用量で1日2回3日間経口投与後、4日目に1回経口投与した。最終投与2時間後の脳(前帯状皮質、尾状核、扁桃体、海馬および後頭葉)ホモジネートを用いて、生物学的実施例1と同様の方法で、[3H]PBR28の特異的結合量を計測し、媒体処置群の特異的結合量を基準とした本発明化合物の脳内占有率を測定した(媒体群3例、本発明化合物投与群各5例)。その結果、本発明化合物の0.4および1mg/kg群における脳5部位の平均TSPO占有率は平均で37.9および56.6%であった。また、0.4及び1mg/kg群の血漿中の本発明化合物濃度は平均で23.9および154ng/mLであった。
雄性アカゲザル(ハムリー株式会社、使用時5-8kg)を用いた。3頭のアカゲザルに媒体(0.5w/v%メチルセルロース400cP溶液)あるいは本発明化合物を0.3~30mg/kgの用量で単回経口投与し、その2時間後に[11C]PBR28を用いたPET計測を以下の要領で実施した。
測定機器:PETカメラ;SHR-7700(浜松ホトニクス株式会社)
画像再構成:SHR Control IIプログラム(浜松ホトニクス株式会社)
脳内放射能濃度の経時変化および分布体積の算出:PMODプログラム(PMOD Technologies Ltd.)
測定法:68Ge/68Ga校正線源を用いてブランク計測を120分間、Transmission計測を30分間実施した。次に、[11C]PBR28を、約30秒かけて全量を静脈内に投与した。投与開始と同時にEmission 計測(計121分間、55フレーム)を、血漿中濃度測定用に動脈採血を行いながら実施した。
男女健康成人を用い、本発明化合物を投与する前、および本発明化合物を6~200mgの用量で単回経口投与した24時間後に、放射性トレーサーとして[11C]PBR28を用いたPET計測を以下の要領で実施した。
測定機器:PET;ECAT HR+(Siemens)
測定法:68Ge/68Ga校正線源を用いてブランク計測を90分間、Transmission計測を10~15分間実施した。次に、[11C]PBR28を、約30秒かけて全量を静脈内に投与した。投与開始と同時にEmission計測(計90分間、26フレーム)を、血漿中濃度測定用に動脈採血を行いながら実施した。
生物学的実施例8とは別の解析方法、すなわち[11C]PBR28の脳内放射能濃度時間変化、非特異的結合量、および[11C]PBR28の未代謝率で補正した動脈血血漿放射能から各関心領域のバインディングポテンシャル(BP)を算出し、投薬前のBPを基準とした脳内占有率を算出した(各群3~4名)。また、各関心領域の投与前の分布体積(Vt baseline)及び投与前の分布体積から投与後の分布体積を差し引いた値(Vt baseline - Vt onmed)をそれぞれ横軸および縦軸にプロットして得られるラッセンプロットから全関心領域の平均脳内TSPO占有率を求めた。また、図7で示すように、各個体における本発明化合物の血漿中濃度と、脳内TSPO占有率の関係を解析するために、Emaxモデルを用いた本モデルにおけるパラメータとして、最大結合数(Bmax)およびBmaxの50%を達成する血中濃度(Ki、ng/mL)を用いた。本解析ではBmaxを1に固定し、解析ソフトにはSAS Version 9.2(SAS Institute)を用いた。パラメータおよびEmaxモデルの計算式は以下に示した。
臨床試験として、下痢型女性IBS患者を対象に、以下の条件で二重盲検並行群間試験を行った。
目的:IBSの臨床症状に対する有効性の確認
方法:本試験は、米国49施設で実施され、RomeIII(ローマ・スリー)診断基準(Gastroenterology、2006年、第130巻、1480-1491ページ)に合致する下痢型女性IBS患者200名(18~65歳)が集積された。被験者は、下記3つの投与群のいずれかに1:1:1の割合で無作為に割り付けられ、4週間、1日1回経口服薬した。被験者は、2週間の前観察期間、4週間の服薬期間および4週間の後観察期間中の毎日、電子日記にIBS症状を記録した。安全性の観察は、試験期間中を通じて行った。下記評価項目のうち、主評価項目は、4週間の服薬期間の便形状(ブリストル便形状スケール(Bristol Stool Scale;BSS)による評価)、排便回数および腹痛(Numerical Rating Scale (NRS)によるスコア化)のベースライン(前観察期間)からの変化量とした。また、副次的評価項目として、FDAガイダンス(Guidance for Industry Irritable Bowel Syndrome - Clinical Evaluation of Drugs for Treatment)に準じたレスポンダーの解析を行った。
投与群:
(1)偽薬(プラセボ)群
(2)本発明化合物(20mg投与)群
(3)本発明化合物(60mg投与)群
評価項目:IBS症状(腹痛、便形状、排便回数、便意切迫感、重症度)、QOL、精神症状、安全性、薬物動態、バイオマーカー
結果:患者層および各パラメータ(便形状、排便回数および腹痛)のベースライン値は、各投与群で同等であった。4週間の服薬期間を通じて、1週間におけるBSSで6または7に相当する便が1回でもあった日数、および1日を通じて最も強く感じた腹痛の週平均スコアにおいて、本発明化合物の60mg投与群において、プラセボ群に対する改善が認められた(図8および図9)。また、本発明化合物の60mg投与群において、プラセボ群と比べてより多くの被験者がレスポンダー基準を満たした(表3、図10および図11)。一方、投与4週目における週当たりの腹痛のない日について評価したところ、プラセボ群では0.61日の増加に対して、20mg投与群では1.16日の増加、60mg投与群では1.51日の増加であった。また、本発明化合物は忍容であり、良好な安全性プロファイルを示した。
臨床試験として、下痢型女性IBS患者を対象に、以下の条件で二重盲検並行群間試験を行う。
目的:バロスタット法を用い、腸管拡張時の知覚および運動に対する有効性を確認
投与群:各群1日1回食後に経口投与;
(1)偽薬(プラセボ)群
(2)本発明化合物(60mg投与)群
投与期間:2週間
評価項目:腸管拡張時の腹痛・切迫感・腸管運動、IBS重症度、QOL、精神症状、安全性、薬物動態、バイオマーカー
生物学的実施例10の臨床試験において、PSS(Perceived Stress Scale)(Journal of Health and Social Behavior, 24, 386-396, 1983年参照)、HAM-A(Hamilton Anxiety Scale)(The British journal of medical psychology, 32, 50-55, 1959年参照)およびHAM-D(Hamilton Depression Scale)(Journal of Neurology, Neurosurgery and Psychiatry, 23, 56-62, 1960年参照)の評価尺度を用いて、本発明化合物60mg投与時のうつ病、不安関連疾患の治療効果を評価した。以下にその結果を示す。表4はPSSスコア、表5はHAM-Aスコア、および表6はHAM-Dスコアの結果をそれぞれ示す。
Claims (17)
- TSPO占有率を約50乃至約85%に到達せしめる用量が、血中濃度として約15乃至約150ng/mLに到達する用量である請求項1記載の剤。
- 投与方法が経口投与である請求項1または2記載の剤。
- 経口投与時に、TSPO占有率を約50乃至約85%に到達せしめる用量が、約5乃至約60mgである請求項3記載の剤。
- ストレス性疾患が、過敏性腸症候群、機能性消化管障害、うつ病、または不安関連疾患である請求項1乃至4のいずれかに記載の剤。
- ストレス性疾患が、過敏性腸症候群である請求項5記載の剤。
- TSPO占有率が、放射性トレーサーとして[11C]PBR28を用いて測定されたTSPO占有率である請求項1乃至6のいずれかに記載の剤。
- 放射性トレーサーとして[11C]PBR28を用いることを特徴とする、ストレス性疾患を予防および/または治療するためのTSPO拮抗薬の有効用量を設定する方法。
- TSPO占有率を約50乃至約95%に到達せしめる用量が、血中濃度として約15乃至約250ng/mLに到達する用量である請求項12記載の剤。
- 投与方法が経口投与である請求項12または13記載の剤。
- 経口投与時に、TSPO占有率を約50乃至約95%に到達せしめる用量が、約5乃至約100mgである請求項14記載の剤。
- ストレス性疾患が、過敏性腸症候群、機能性消化管障害、うつ病、または不安関連疾患である請求項12乃至15のいずれかに記載の剤。
- 不安関連疾患が、神経症、全般性不安障害、社交不安障害、パニック障害、多動性障害、注意欠陥、人格障害、双極性障害、自閉症である請求項16に記載の剤。
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US10647724B2 (en) | 2016-02-05 | 2020-05-12 | Inventisbio Inc. | Selective estrogen receptor degraders and uses thereof |
WO2020121908A1 (ja) * | 2018-12-13 | 2020-06-18 | 株式会社ヤクルト本社 | 便の硬さを測定する方法およびこれを利用した便の状態の評価方法 |
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EP3243514A4 (en) * | 2015-01-09 | 2017-12-06 | ONO Pharmaceutical Co., Ltd. | Prevention and/or therapeutic agent for fibromyalgia |
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JP2020075933A (ja) | 2020-05-21 |
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