WO1998003201A1 - Nouvelles compositions medicinales a usage therapeutique - Google Patents

Nouvelles compositions medicinales a usage therapeutique Download PDF

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Publication number
WO1998003201A1
WO1998003201A1 PCT/JP1997/002524 JP9702524W WO9803201A1 WO 1998003201 A1 WO1998003201 A1 WO 1998003201A1 JP 9702524 W JP9702524 W JP 9702524W WO 9803201 A1 WO9803201 A1 WO 9803201A1
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WO
WIPO (PCT)
Prior art keywords
group
ring
thiazole
indeno
atom
Prior art date
Application number
PCT/JP1997/002524
Other languages
English (en)
Japanese (ja)
Inventor
Hiroyuki Ito
Hidenobu Yuki
Yukinori Nagakura
Kiyoshi Iwaoka
Mitsuaki Ohta
Keiji Miyata
Original Assignee
Yamanouchi Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yamanouchi Pharmaceutical Co., Ltd. filed Critical Yamanouchi Pharmaceutical Co., Ltd.
Priority to AU34634/97A priority Critical patent/AU3463497A/en
Publication of WO1998003201A1 publication Critical patent/WO1998003201A1/fr

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Classifications

    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles

Definitions

  • the present invention relates to a novel therapeutic pharmaceutical composition, particularly a pharmaceutical composition for treating morphine-induced constipation.
  • 5 HT3 receptor agonists can be used in the treatment of intestinal peristaltic disorders, particularly in the treatment of constipation or irritable bowel syndrome (IBS), based on experiments on enhanced fecal excretion of rats (particularly). Kaihei 7-165754) or is useful for the treatment of senile, flaccid, rectal and other constipation (WO 95/24399, etc.).
  • Constipation is a condition in which the content of the small intestine sent to the large intestine is impaired in any of the activities, from defecation movements, and the number of bowel movements and bowel movements are reduced.
  • Flaccid constipation is the most frequent, and occurs when the entire intestinal tract becomes flaccid due to weakness of the colonic wall muscles, decreased tone of the large intestine, and decreased movement, which is common in women and the elderly and also in long-term bedridden patients. It is often seen.
  • spastic constipation is caused by abnormal secretion of the large intestine due to hypersympathetic nervous system or convulsive exercise, which delays the intestinal excretion.
  • Constipation induced by morphine administered for the purpose of pain relief to cancer patients, etc. is a functional stool Within the secret, it is classified as convulsive constipation. Although the mechanism of its onset is not clear, it is thought that morphine administration suppresses the secretion of inhibitory neurotransmitters and consequently induces spastic movements in the large intestine. Therefore, constipation such as senility and flaccidity due to decreased intestinal peristalsis is distinguished in terms of its causes and symptoms, and among convulsive constipation, irritable bowel syndrome (IBS) caused by stress etc. Causes differ. There is no remedy for such morphine-induced constipation, and salt laxatives used for normal constipation and anticholinergic drugs are used in combination to relieve tension in the large intestine, but if the symptoms can be sufficiently resolved, Is hard to say.
  • IBS irritable bowel syndrome
  • the present inventor has proposed a group of compounds that are 5 HT3 receptor agonists, especially International Publication No. 94-06791, for the treatment and improvement of morphine-induced constipation, for which there was no appropriate therapeutic agent.
  • the thiazol derivatives disclosed in WO 95/24399 and WO 95/24406 or a pharmaceutically acceptable salt thereof have been found to be surprisingly effective.
  • the present invention relates to a pharmaceutical composition for treating morphine-induced constipation, which contains a compound that is a 5HT3 receptor agonist as an active ingredient.
  • the present invention relates to a morphine-inducing compound containing a thiazole derivative or a pharmaceutically acceptable salt thereof disclosed in WO94Z06791, WO95 / 24399, or WO95 / 24406 as an active ingredient.
  • the present invention relates to a pharmaceutical composition for treating constipation.
  • the present invention also relates to a group of compounds that are 5HT3 receptor agonists, in particular, the thiazole derivatives disclosed in WO94 / 06791, WO95 / 24399, and WO95 / 24406 or pharmaceuticals thereof. Or a salt acceptable for the treatment of morphine-induced constipation.
  • morphine-induced constipation refers to a constipation disease induced by morphine administered to a patient such as a cancer patient for pain relief.
  • the compound that is a 5HT3 agonist used in the pharmaceutical composition of the present invention is not particularly limited as long as it is a compound having an agonistic action on the intestinal 5HT3 receptor.
  • Preferred are WO 94/06791, JP-A-7-70136, WO 95/24399, WO 95/24406, JP-A-81 31 1066, JP-A 6-65203.
  • thiazole derivatives disclosed in WO 94 06791, WO 95/24399 and WO 95/24406. Specifically, they are thiazole derivatives represented by the following general formulas (I), ( ⁇ ) and ( ⁇ ) and pharmaceutically acceptable salts thereof. I)
  • R a hydrogen atom, halogen atom, hydroxyl group, lower alkoxy group, carboxy group, lower alkoxycarbonyl group, nitro group, amino group, cyano group or protected hydroxyl group,
  • a 1 ring phenyl ring or naphthalene ring
  • Li and L 2 is just a bond, the other is
  • L a mere bond, or a linear or branched lower alkylene group
  • I m a group represented by the formula-or
  • Ri, R 2 and R 3 the same or different, a hydrogen atom or a lower alkyl group
  • a 2 ring L or the following rings, each of which may be substituted with one or more substituents selected from the group consisting of halogen atoms, lower alkyl groups and lower alkoxy groups.
  • L 5 lower alkylene group.
  • L e a single bond or a lower alkylene group.
  • Shaku 7 and 18 same or different, hydrogen atom, lower alkyl group, or
  • R 9 a hydrogen atom, a lower alkyl group, an oxo group, or may be protected
  • R 10 absent, or a hydrogen atom, a lower alkyl group, an aralkyl group or
  • Ring B a monocyclic or bicyclic ring which may have an oxygen atom.
  • Ring D a saturated carbocyclic ring of 4 to 8 ring atoms.
  • the nitrogen atom in R can be a quaternary ammonium salt with a substituent
  • H e t a) at least an atom selected from a nitrogen atom, an oxygen atom and a sulfur atom
  • a 5-membered unsaturated heterocyclic group which may be substituted, containing 1 b) a benzofuran ring group or a benzothiphene ring group
  • R c hydrogen atom, lower alkyl group, lower alkenyl group, cycloalkyl group,
  • Compounds preferable as the active ingredient of the medicament of the present invention include all of the compounds embraced by the general formula described in the above-mentioned known literature.
  • the definition of the option can be the definition of the general concept or option of the present invention as it is. That is, to put it simply, "lower” means a linear or branched carbon chain having 1 to 6 carbon atoms. Therefore, a lower alkyl group is a methyl group or an ethyl group.
  • a lower-alkenyl group is a straight-chain or branched C 2-6 alkenyl group such as an ethenyl group or an aryl group;
  • An alkylene group is a linear or branched C 16 alkylene group such as a methylene group or an ethylene group, and a lower alkenylene group is a linear or branched C 16 alkylene group such as a vinylene group or a propenylene group.
  • 2-6 alkenylene groups; lower alkoxy groups are straight-chain or branched C 16 alkoxy groups such as methoxy groups and ethoxy groups; lower alkoxycarbonyl groups are methoxycarbonyl groups and ethoxy groups.
  • Straight-chain or branched C such as carbonyl group It is a 2-6 alkoxycarbonyl group.
  • Examples of the linear or branched lower alkylene group which may be interrupted by an oxygen atom or a sulfur atom include the above-mentioned lower alkylene group and oxymethylene group, methyleneoxy group, thiomethylene group, methylenethio group, 2-year-old oxatrimethylene group, 2- or straight-chain or branched C 1-6 alkyl interrupted by oxygen or sulfur atoms such as 2-triatrimethylene group It is a len group.
  • halogen atom examples include a fluorine atom, a chlorine atom, and a bromine atom.
  • the halogeno lower alkyl group means a group in which the lower alkyl group is substituted with one or two or more halogen atoms, specifically, a trifluoromethyl group, a chloromethyl group and the like.
  • the cycloalkyl group means a saturated carbocyclic group having 4 to 8 ring atoms.
  • the ring is a cyclopentane ring, a cyclohexane ring, a cycloheptane ring or the like, and the ring group is a cyclopentyl group, a cyclohexyl group. And a cycloheptyl group.
  • the aryl group includes a phenyl group, a naphthyl group and the like, and the aralkyl group means a group in which any hydrogen of a lower alkyl group is substituted with the aryl group (for example, a benzyl group, a phenyl group). Group).
  • examples of the substituent of the aryl group and the aralkyl group in the general formula (m) include a lower alkyl group, a halogen atom, a nitro group, an amino group, and a hydroxyl group.
  • the 5- or 6-membered unsaturated heterocycle having one or more heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom include a pyrrole ring, a pyrazonole ring, a pyridine ring, an imidazole Ring, pyrimidine ring, pyrazine ring, pyridazine ring, furan ring, pyran ring, thiophene ring, thiopyran ring, oxazolyl ring, thiazole ring and the like.
  • a 5-membered unsaturated heterocyclic ring containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom include a pyrroyl ring, a furan ring, a thiophene ring, an imidazole ring, and an oxazozo ring.
  • a monocyclic ring, a thiazole ring, a triazoyl ring and the like can be mentioned.
  • the substituents that may be substituted on these rings include a carbon substituent bonded to a ring carbon atom such as a lower alkyl group, a halogen atom and a nitro group, and a nitrogen atom bonded to a ring nitrogen atom such as a benzenesulfonyl group and a benzoyl group. Nitrogen substituents.
  • Examples of the nitrogen-containing saturated heterocyclic ring having 4 to 16 ring atoms, which may be an oxygen atom, which may be an L, a monocyclic or bicyclic ring, include a pyrrolidine ring, an imidazolidine ring, an oxazolidine ring, Peridine ring, piperazine ring, morpholine ring, pyrrolidine ring (1 -azavinclo [3.3.0] octane ring), quinuclidine ring (1-aza Bicyclo [2.2.2] octane ring), 1-azabicyclo [2.2.1] heptane ring, 1-azabicyclo [3.3.1] nonane ring, 8-azabicyclo [3.2.1] octane Ring, 1-azabicyclo [4.4.0] decane ring, etc., which may have an oxygen atom, and is a ring atom having one unsaturated bond, which is mentioned as the following monocyclic or bicyclic ring
  • Protecting groups such as a hydroxyl protecting group, a protected amino group, and an amino protecting group are commonly used as protecting groups for a hydroxyl group or an amino group in pharmaceuticals in the art, and a protecting group for a hydroxyl group is a methyl group.
  • a protecting group for a hydroxyl group is a methyl group.
  • T-butyl group, benzyl group, benzoyl group, etc. and the protecting group for the amino group is acetyl, t-butyl, ethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, benzyl, A benzyl group or a phthalimid group formed integrally with the nitrogen atom of the amino group.
  • the active ingredient of the present invention forms a salt with an inorganic acid such as hydrochloric acid, an organic acid such as fumaric acid, an inorganic base such as sodium, or an organic base such as diethanolamine, a quaternary ammonium salt is used.
  • the active ingredient of the present invention includes pharmaceutically acceptable salts of the above compounds. Further, the active ingredient of the present invention includes a mixture of various isomers and all of its isolated, hydrated, solvated and various crystalline forms.
  • compositions of the present invention can be prepared in a solid, semi-solid, It can be prepared as a liquid formulation.
  • tablets, powders, granules, capsules, pills, and the like are used as the solid composition for oral administration according to the present invention.
  • one or more active substance (s) and at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicate It is mixed with magnesium aluminate.
  • the composition may be formulated in accordance with conventional practice with additives other than inert diluents, e.g., lubricating agents such as magnesium stearate, starch, talc, disintegrating agents such as calcium cellulose glycolate, and lactose.
  • Tablets or pills may be sugar-coated such as sucrose, gelatin, agar, pectin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or gastric or enteric substances, if necessary. Film.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert diluents, for example, Contains purified water and ethanol.
  • the composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.
  • adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.
  • injections such as intravenous and intramuscular injections, or solid, solid to semi-solid, semi-solid or liquid external preparations for transmucosal or transdermal administration such as suppositories Is included.
  • Injectables include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Diluents for aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline.
  • examples of diluents for water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80.
  • Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing (eg, lactose) and solubilizing agents (eg, glutamic acid, aspartic acid).
  • Solid preparations for external use include suppositories.
  • Suppositories include commonly used inert carriers such as water, bases, oils, and surfactants.
  • inert diluent in addition to the inert diluent, other additives such as a transmucosal absorption enhancer, a stabilizer, a solubilizer, an aromatic agent, a preservative, and the like may be contained.
  • oleaginous bases such as cocoa butter, laurin fat, and witepsol, or (/ means 47% cocoa butter, 3% cholesterol and 50% glycerin, and 0-type emulsion base of surfactant, 0-ZW-type emulsion base of cocoa butter 79%, lecithin 1% and water 20%, or gel base such as macrogol, glycerose gelatin, carmellose sodium And a water-soluble base such as an agent.
  • oleaginous bases such as cocoa butter, laurin fat, and witepsol, or (/ means 47% cocoa butter, 3% cholesterol and 50% glycerin, and 0-type emulsion base of surfactant, 0-ZW-type emulsion base of cocoa butter 79%, lecithin 1% and water 20%, or gel base such as macrogol, glycerose gelatin, carmellose sodium And a water-soluble base such as an agent.
  • Surfactants enamine derivatives of amino acids, Micelle mixed with a salicylic acid derivative, a medium-chain fatty acid, and a surfactant of a lipid.
  • semi-solid to solid preparations for external use include patches for transdermal or transmucosal administration of ointments (rubber plaster, plaster), films, tapes, and cataplasms.
  • Inert carriers commonly used, for example, rubber-based polymers such as natural rubber, synthetic rubber such as natural rubber, SBR and SIS; mud-forming agents such as gelatin, kaolin and zinc oxide; sodium polyacrylate, methyl Contains hydrophilic polymers such as vinyl ether / maleic anhydride copolymer and carboxylmethyl cellulose sodium; acryl resin; tackifiers such as liquid paraffin and polybutene; and water, other oils and surfactants. Further, these compositions may contain adjuvants such as transdermal absorption enhancers, stabilizers and solubilizers, and other additives such as fragrances and preservatives.
  • rubber-based polymers such as natural rubber, synthetic rubber such as natural rubber, SBR and SIS
  • mud-forming agents such as gelatin, kaolin and zinc oxide
  • sodium polyacrylate methyl Contains hydrophilic polymers such as vinyl ether / maleic anhydride copolymer and carboxylmethyl cellulose sodium; acryl resin; tack
  • Semi-solid preparations for external use include ointments such as oily ointments and hydrophilic ointments, and are generally used inert carriers such as water, petrolatum, polyethylene glycol, carboxyvinyl polymer, and oil. , Including a surfactant.
  • these compositions contain, in addition to the inert diluent, other additives such as transdermal absorption enhancers, stabilizers, solubilizers, fragrances, preservatives, etc. You may.
  • Liquid compositions for external use include liquid preparations such as pharmaceutically acceptable emulsions, emulsions such as lotions, tinctures for external use, and solutions for transmucosal administration. These compositions contain commonly used inert diluents such as water, ethanol, oils, emulsifiers. These compositions may contain, in addition to the inert diluent, other additives such as transdermal absorption enhancers, stabilizers, solubilizers, fragrances, preservatives, and the like.
  • the dose of the disclosed thiazole derivative or a pharmaceutically acceptable salt thereof is appropriately determined according to the individual case in consideration of the administration route, the symptoms of the disease, the age and sex of the administration subject, and the like. However, usually, in the case of oral administration, about 0.001 to 100 mg, preferably 0.01 to 500 mg, more preferably 0.05 to 100 mg of the active ingredient per adult human is preferred.
  • the pharmaceutical composition is a suppository
  • the adult is usually administered with 0.05 to 500 mg, preferably 0.05 to 100 mg of the suppository once or more times a day for the active ingredient.
  • the pharmaceutical composition which can improve and eliminate the constipation symptom induced by morphine administered to a cancer patient etc. for the purpose of pain relief can be provided effectively.
  • the pharmaceutical composition of the present invention can effectively ameliorate and eliminate morphine-induced constipation symptoms at a dose approximately the same as the effective amount for flaccid constipation.
  • Ferrets were fed once daily. Subcutaneous administration of 0.3 mg Zkg of morphine hydrochloride 90 minutes after feeding resulted in decreased defecation, ie, constipation-like symptoms, until about 3.5 hours later. Ninety minutes after the administration of morphine, a 5HT3 receptor agonist was orally administered, and the number of bowel movements and fecal water content for 2 hours were measured thereafter (20 animals per group).
  • compound 1 2- (4-imidazolylmethyl) —8H-indeno [1,2-d] thiazolyl significantly improved the average number of bowel movements after oral administration of 0.03 mgZkg. did.
  • Example 2 Oral tablet 20 mg tablet

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Compositions médicinales permettant de traiter la constipation induite par la morphine, qui contiennent en tant qu'ingrédient actif un agoniste de récepteur de 5HT3, et compositions médicinales permettant de traiter la constipation induite par la morphine, qui contiennent en tant qu'ingrédient actif des dérivés de thiazole de formule générale (I), (II) ou (III), ou des sels pharmaceutiquement acceptables desdits dérivés.
PCT/JP1997/002524 1996-07-23 1997-07-22 Nouvelles compositions medicinales a usage therapeutique WO1998003201A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU34634/97A AU3463497A (en) 1996-07-23 1997-07-22 Novel medicinal compositions for therapeutic use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP19309096 1996-07-23
JP8/193090 1996-07-23

Publications (1)

Publication Number Publication Date
WO1998003201A1 true WO1998003201A1 (fr) 1998-01-29

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WO (1) WO1998003201A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07165754A (ja) * 1993-10-11 1995-06-27 Sanofi Sa ヘテロアリールピペリジン、その製造方法およびそれを含有する医薬組成物

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07165754A (ja) * 1993-10-11 1995-06-27 Sanofi Sa ヘテロアリールピペリジン、その製造方法およびそれを含有する医薬組成物

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