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WO2017146129A1 - Agent thérapeutique pour le traitement du syndrome du côlon irritable - Google Patents

Agent thérapeutique pour le traitement du syndrome du côlon irritable Download PDF

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Publication number
WO2017146129A1
WO2017146129A1 PCT/JP2017/006749 JP2017006749W WO2017146129A1 WO 2017146129 A1 WO2017146129 A1 WO 2017146129A1 JP 2017006749 W JP2017006749 W JP 2017006749W WO 2017146129 A1 WO2017146129 A1 WO 2017146129A1
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Prior art keywords
bowel syndrome
irritable bowel
substance
receptor
aminophylline
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PCT/JP2017/006749
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English (en)
Japanese (ja)
Inventor
水島　徹
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LTT Bio Pharma Co Ltd
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LTT Bio Pharma Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a therapeutic agent for irritable bowel syndrome.
  • Irritable bowel syndrome is an abdominal symptom centered on the lower abdomen such as abdominal pain and abdominal discomfort, and abnormal bowel movements such as constipation or diarrhea, and there is no functional disorder that causes the symptoms. Is a disease. Symptoms are classified into constipation type, diarrhea type, and alternating type that repeats both alternately. The causes are considered to be abnormalities of gastrointestinal motility centering on the large intestine, a decrease in the threshold for perception of the gastrointestinal tract, psychological factors such as stress, lifestyle distortion, and the like (Non-Patent Document 1).
  • antidiarrheal drugs peripheral movement suppression
  • loperamide and anticholinergic drugs antidepressant drugs and the like
  • antidepressant drugs antidepressant drugs and the like
  • mu opioid receptor agonist and delta opioid receptor antagonist erxadrine antagonists (alosetron, ramosetron) for serotonin 3 (5-HT3) receptor have been used.
  • ramosetron which is a serotonin 3 receptor antagonist
  • ramosetron is effective only for diarrhea-type irritable bowel syndrome and has not been effective for other symptoms of irritable bowel syndrome.
  • an object of the present invention is to provide a new therapeutic agent for irritable bowel syndrome.
  • the present inventor has found that a substance having a specific adenosine receptor inhibitory action, particularly theophylline or a salt thereof, is not only diarrhea.
  • the present invention was completed by finding it useful as a therapeutic agent for irritable bowel syndrome that improves symptoms of visceral hypersensitivity.
  • the present invention provides the following [1] to [16].
  • a therapeutic agent for irritable bowel syndrome comprising as an active ingredient a substance that inhibits one or two selected from A 2A adenosine receptor and A 2B adenosine receptor.
  • the therapeutic agent for irritable bowel syndrome according to any one of [1] to [3], wherein the irritable bowel syndrome is stool improvement and / or improvement of visceral hypersensitivity symptoms.
  • [5] Use of a substance that inhibits one or two selected from A 2A adenosine receptor and A 2B adenosine receptor for the preparation of a therapeutic agent for irritable bowel syndrome.
  • [6] The use according to [5], wherein the substance that inhibits the receptor is theophylline or a salt thereof.
  • [7] The use according to [5] or [6], wherein the substance that inhibits the receptor is aminophylline.
  • [8] The use according to any one of [5] to [7], wherein the irritable bowel syndrome is stool improvement and / or improvement of visceral hypersensitivity symptoms.
  • a substance that inhibits one or two receptors selected from A 2A and A 2B adenosine receptors for treating irritable bowel syndrome [10] The substance according to [9], wherein the substance that inhibits the receptor is theophylline or a salt thereof. [11] The substance according to [9] or [10], wherein the substance that inhibits the receptor is aminophylline. [12] The substance according to any one of [9] to [11], wherein the irritable bowel syndrome is stool improvement and / or improvement of visceral hypersensitivity symptoms. [13] A method for treating irritable bowel syndrome, comprising administering a substance that inhibits one or two receptors selected from an A 2A adenosine receptor and an A 2B receptor.
  • theophylline or a salt thereof is a drug that has already been widely used as a bronchodilator, so its safety has been confirmed, and it is useful as a new therapeutic agent for irritable bowel syndrome.
  • the effect of aminophylline on the number and amount of stool in the restraint stress model (WRS) is shown.
  • the effect of theophylline on the number of feces in a restraint stress model (WRS) is shown.
  • action with respect to the quantity of feces of aminophylline when there is no restraint stress is shown.
  • action of aminophylline with respect to the number of feces by new stress in each condition of the presence or absence of mother-child separation stress (MS) is shown.
  • the effect of aminophylline on serum corticosterone concentration after restraint stress model (WRS) is shown.
  • the effect of aminophylline on the increase in bronchial resistance caused by methacholine is shown.
  • Figure 3 shows the effect of aminophylline on the number of feces in a mouse restraint stress (RS) model.
  • the effects of A2A antagonist, A2B antagonist and A1 antagonist on the number of feces increased by restraint stress are shown.
  • 2 shows the effect of aminophylline on visceral hypersensitivity (colorectal distension). Shows theophylline effects on visceral hypersensitivity (colorectal distension) The effect of aminophylline on visceral hypersensitivity (acetic acid administration) is shown.
  • the effects of A2A antagonist, A2B antagonist and A1 antagonist on visceral hypersensitivity (colorectal distension) are shown.
  • action of the A2A antagonist and A2B antagonist with respect to visceral hypersensitivity (MS) is shown.
  • action of the A2A agonist and A2B agonist with respect to visceral hypersensitivity (no MS) is shown.
  • the active ingredient of the therapeutic agent for irritable bowel syndrome of the present invention is a substance that inhibits one or two receptors selected from A 2A adenosine receptor (A 2A AR) and A 2B adenosine receptor (A 2B AR). It is a component chosen from.
  • Substances that inhibit A 2A AR include theophylline or a salt thereof, 8- (3-chlorostyryl) caffeine, ANR94, Istradefylline, SCH442416, SCH58261, TC-G1004, ZM241385, LuAA47070, MSX-3 Hydrate, CAY10680, CSC, Preladenant (SCH420814), STW5 (Iverogast, BAY98-7411), Tozadenant (SYN115), VER6947, VER7835, Bipadenant (BIIB014), 3,7-dimethyl-1-propargylxanthine (DMPX), (E ) -KF17837, MSX-2, MSX-4, BS-DMPX, CS-DMPX, DPMTX, CP-66713, SCH-63390, 5-amino-7 [4- (4-Hydroxyphenyl) ethyl] -2- (2-furyl) pyrazolo [
  • substances that inhibit A 2B AR include theophylline or a salt thereof, GS6201, MRS1706, MRS1754, PSB0788, PSB1115, PSB603, MRE2029-F20, ATL-801, OSIP-339361, CVT-6883, MRE2028-F20, MRE-2030.
  • receptor inhibitors substances that inhibit A 2A AR and A 2B AR are preferred, and theophylline or a salt thereof is more preferred.
  • theophylline salts include alkali metal salts such as sodium salt and potassium salt, and amine salts such as ethylenediamine salt. Of these theophylline salts, aminophylline which is theophylline / ethylenediamine salt is particularly preferred.
  • theophylline and aminophylline are widely known as bronchodilators and are used as therapeutic agents for bronchial asthma, asthmatic bronchitis, chronic bronchitis and the like.
  • the molecular mechanism of bronchodilator action of theophylline and aminophylline has not been fully clarified, but it has been reported that both phosphodiesterase inhibition and adenosine receptor antagonism are involved (Biochem. Pharmacol. 45 (4): 847). -851, Life Sci. 43 (5): 387-398).
  • theophylline or a salt thereof which is a representative example of a substance that inhibits A 2A AR and / or A 2B AR, improves various symptoms of irritable bowel syndrome, and a wide range of irritable bowel syndrome. It is useful as a therapeutic agent.
  • irritable bowel syndrome is characterized by abdominal symptoms such as abdominal pain and abdominal discomfort, mainly in the lower abdomen, and abnormal bowel movements such as constipation or diarrhea. There is no functional disease of the intestinal tract. Symptoms are classified into constipation type, diarrhea type, and alternating type that repeats both alternately.
  • the therapeutic agent for irritable bowel syndrome of the present invention is effective not only for diarrhea but also for visceral hypersensitivity, and is therefore effective for constipation type, diarrhea type, and alternation type (particularly effective for diarrhea type).
  • Examples of the administration form of the therapeutic agent for irritable bowel syndrome of the present invention include injections, oral preparations (tablets, granules, powders, capsules), ointments, creams, patches, suppositories and the like. Of these, oral preparations are particularly preferred.
  • These pharmaceutical compositions can be formulated with a pharmaceutically acceptable carrier. Examples of such carriers include lactose, glucose, D-mannitol, starch, crystalline cellulose, calcium carbonate, kaolin, starch, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, ethanol, carboxymethylcellulose, carboxymethylcellulose calcium.
  • Salt magnesium stearate, talc, acetylcellulose, saccharose, titanium oxide, benzoic acid, p-hydroxybenzoate, sodium dehydroacetate, gum arabic, tragacanth, methylcellulose, egg yolk, surfactant, sucrose, simple syrup, citric acid, distillation Water, ethanol, glycerin, propylene glycol, macrogol, sodium phosphate-sodium hydrogen, sodium dihydrogen phosphate, sodium phosphate, grape , Sodium chloride, phenol, thimerosal, p-hydroxybenzoic acid ester, there are sodium hydrogen sulfite, depending on the form of the preparation, are used in admixture with dextran sulfate or a salt thereof.
  • the content of the active ingredient of the present invention in the pharmaceutical composition preparation of the present invention varies greatly depending on the form of the preparation and is not particularly limited, but is usually 0.01% with respect to the total amount of the composition. To 100% by mass, preferably 1 to 100% by mass.
  • the dose of the therapeutic agent for irritable bowel syndrome of the present invention varies depending on the symptoms, age, and administration method of the patient to be administered, but as a substance that inhibits A 2A AR and / or A 2B AR, per day for adults 50 to 1000 mg is preferred.
  • the dose can be divided into 2 to 4 times a day.
  • VMR visceral motor response
  • CRD colorectal dilatation
  • Rats were restrained with a plastic conical tube (height 15 cm, diameter 6 cm) for 15 minutes before electromyogram recording.
  • a polyethylene bag (2 cm in length) was inserted into the distal colon and placed 1 cm proximal from the rectum and a balloon catheter was connected. Balloon pressure and volume were controlled and monitored with a pressure controller timing device (G & J Electronics, Toronto, Canada, Diender Series II) connected to the balloon.
  • Rats were repeated CRD (12 times at 80 mmHg, duration 30 seconds, stimulation interval 300 seconds) or transient CRD (10, 20, 40, 60, 80 mmHg, duration 20 seconds, stimulation interval for drug screening 150 seconds).
  • Aminophylline or theophylline was dissolved in physiological saline and orally administered 2 hours before CRD.
  • Other drugs AR antagonist and AR agonist
  • EMG Electromyogram
  • 8STAR software Windows 6.0 version 6.0 to 19.2; Star Medical, Tokyo, Japan.
  • the response elicited by contraction of the external oblique muscle was quantified by calculating the area under the curve (AUC) of the EMG amplitude of the voltage change graph.
  • Baseline was determined by data collected for 20 seconds before CRD.
  • Neonatal mother-child separation was performed with some modifications to the method described in Biol. Psychiary 65 (3): 263-267.
  • Late-term pregnant Wistar female rats were individually housed for about a week to give birth to children (10-15 / rat). The pups were separated from the mother for 180 minutes every day for 10 days (from day 2 to 12 after birth). Separation was performed between 9 am and 12 am in a plastic cage with a heater pad (30 ° C. to 33 ° C.) and placed in a room separated from the mother. Control rats were bred with their mothers. From day 12 onwards, both groups of rats were raised undisturbed every two days except for regular cage cleaning.
  • CRD VMR was tested in both groups of rats at 5-6 weeks of age.
  • An acetic acid-induced colorectal hypersensitivity test was performed with some modifications to the method described in Nat. Commun. 4: 2686 (2013).
  • the pups were given 0.2 mL of 0.5% acetic acid (in saline) intracolonically at a position 2 cm from the anus.
  • Control rats received an equal volume of saline.
  • CRD VMR was tested in both groups of rats at 5-6 weeks of age.
  • Rats were subjected to WRS for 1 hour and the number of excreted feces or wet weight during this WRS period (1 hour) was measured.
  • WRS was performed as described in Neurogastroenterol. Motil 20 (10): 1147-1156. Rats were lightly anesthetized with isoflurane and wrapped with paper tape to limit movement of the upper shoulders, forelimbs, and upper torso of the chest to prevent movement. Animals recovered from isoflurane within 2-5 minutes and immediately moved through the cage. Control animals were anesthetized with isoflurane but not restrained by paper tape.
  • mice were placed individually in 50 mL Falcon tubes (Becton Dickinson, Franklin Lakes, NJ) for 1 hour. These tubes are small enough to keep the mouse from moving. It is therefore possible to breathe but not to move freely. Control mice were allowed to move freely within the cage. Aminophylline was dissolved in physiological saline and orally administered (10 mL / kg) 2 hours before RS. During this RS period (1 hour), the number of excreted feces or wet weight was measured. The control and the mother-infant separated rat were tested for responsiveness to new stress. As in (2) above, new stress was induced by transferring rats from the home cage to a new cage of wire mesh with a white paper towel. Aminophylline was orally administered to rats 2 hours before subjecting to new stress. The animals were placed in a new cage for 1 hour and the number of feces excreted during this period was counted.
  • the measurement of pulmonary airway resistance was carried out using a computer-controlled small animal ventilator (FlexiVent, SCIREQ, Montreal, Am. J. Physiol. Gastrointest. Liver Physiol. 294 (5): G1268-1280. (Canada). Mice were anesthetized with chloral hydrate (500 mg / kg), a tracheotomy was performed, and an 8 mm metal tube was inserted into the trachea. Mice were mechanically ventilated at a respiratory rate of 150 breaths per minute using a tidal volume of 8.7 mL / kg and a positive end-expiratory pressure of 2-3 cm H 2 O.
  • a computer-controlled small animal ventilator FexiVent, SCIREQ, Montreal, Am. J. Physiol. Gastrointest. Liver Physiol. 294 (5): G1268-1280. (Canada). Mice were anesthetized with chloral hydrate (500 mg / kg), a tracheotomy
  • mice were nebulized with methacholine (1 mg / mL) five times for 20 seconds (at 40 second intervals). Airway resistance was measured after each methacholine exposure by the snapshot technique. Aminophylline was orally administered to mice 1 hour before the test. All data was analyzed using FlexiVent software.
  • Plasma corticosterone concentration in rats was measured using an ELISA kit according to the manufacturer's instructions. After WRS, rats were sacrificed and blood was collected to measure plasma corticosterone levels.
  • the A2B antagonist suppressed the dose of stool increased with WRS in a dose-dependent manner, but the A1 antagonist (DPCPX) and the A2A antagonist (Istradefylline) had no effect (FIG. 3).

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  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
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Abstract

La présente invention concerne un nouvel agent thérapeutique destiné à traiter le syndrome du côlon irritable. Ledit agent thérapeutique destiné à traiter le syndrome du côlon irritable contient, comme principe actif, une substance permettant d'inhiber un ou deux récepteurs choisis parmi un récepteur de l'adénosine A2A et un récepteur de l'adénosine A2B.
PCT/JP2017/006749 2016-02-24 2017-02-23 Agent thérapeutique pour le traitement du syndrome du côlon irritable Ceased WO2017146129A1 (fr)

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JP2016-032630 2016-02-24
JP2016032630A JP2017149663A (ja) 2016-02-24 2016-02-24 過敏性腸症候群治療剤

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001080893A1 (fr) * 2000-04-26 2001-11-01 Eisai Co., Ltd. Compositions medicinales favorisant les mouvements intestinaux
WO2002014282A1 (fr) * 2000-08-11 2002-02-21 Eisai Co., Ltd. Composes 2-aminopyridine et leur utilisation comme medicaments
WO2003035639A1 (fr) * 2001-10-22 2003-05-01 Eisai Co., Ltd. Compose de pyrimidine et composition medicinale contenant ledit compose
WO2003035640A1 (fr) * 2001-10-22 2003-05-01 Eisai Co., Ltd. Composes de pyrimidone et compositions pharmaceutiques contenant lesdits composes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001080893A1 (fr) * 2000-04-26 2001-11-01 Eisai Co., Ltd. Compositions medicinales favorisant les mouvements intestinaux
WO2002014282A1 (fr) * 2000-08-11 2002-02-21 Eisai Co., Ltd. Composes 2-aminopyridine et leur utilisation comme medicaments
WO2003035639A1 (fr) * 2001-10-22 2003-05-01 Eisai Co., Ltd. Compose de pyrimidine et composition medicinale contenant ledit compose
WO2003035640A1 (fr) * 2001-10-22 2003-05-01 Eisai Co., Ltd. Composes de pyrimidone et compositions pharmaceutiques contenant lesdits composes

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
B. P. CHANDRASEKHARAN ET AL.: "Adenosine 2B receptors (A2B AR ) on enteric neurons regulate murine distal colonic motility", THE FASEB JOURNAL, vol. 23, 2009, pages 2727 - 2734, XP055410438 *
C. CEKIC ET AL.: "Adenosine A2B Receptor Blockade Slows Growth of Bladder and Breast Tumors", THE JOURNAL OF IMMUNOLOGY, vol. 188, 2012, pages 198 - 205, XP055410427 *
C. LEMOS ET AL.: "Adenosine A2B receptor activation stimulates glucose uptake in the mouse forebrain", PURINERGIC SIGNALLING, vol. 11, 2015, pages 561 - 569, XP035936199 *
J. LINDEN ET AL.: "Characterization of Human A2B Adenosine Receptors: Radioligand Binding, Western Blotting, and Coupling to Gq in Human Embryonic Kidney 293 Cells and HMC-1 Mast Cells", MOLECULAR PHARMACOLOGY, vol. 56, 1999, pages 705 - 713, XP000942531 *
S. UCHIDA ET AL.: "The Adenosine A2A-Receptor Antagonist Istradefylline Enhances the Motor Response of L-DOPA Without Worsening Dyskinesia in MPTP-Treated Common Marmosets", JOURNAL OF PHARMACOLOGICAL SCIENCES, vol. 124, 2014, pages 480 - 485, XP055410432 *
T. A. PSARRA ET AL.: "Comparative Study of the Effects of Theophylline on Different Parts of the Rabbit Intestine", REVIEW OF CLINICAL PHARMACOLOGY AND PHARMACOKINETICS, INTERNATIONAL EDITION, vol. 20, 2006, pages 308 - 310 *
T. ASANO ET AL.: "Aminophylline suppresses stress-induced visceral hypersensitivity and defecation in irritable bowel syndrome", SCIENTIFIC REPORTS, vol. 7, no. 40214, 5 January 2017 (2017-01-05), XP055410435 *

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