WO2005004875A1 - Composition medicinale a administration pulmonaire - Google Patents

Composition medicinale a administration pulmonaire Download PDF

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Publication number
WO2005004875A1
WO2005004875A1 PCT/JP2004/010237 JP2004010237W WO2005004875A1 WO 2005004875 A1 WO2005004875 A1 WO 2005004875A1 JP 2004010237 W JP2004010237 W JP 2004010237W WO 2005004875 A1 WO2005004875 A1 WO 2005004875A1
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WO
WIPO (PCT)
Prior art keywords
group
inhalant
compound
dichlorophenyl
morpholine
Prior art date
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PCT/JP2004/010237
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English (en)
Japanese (ja)
Inventor
Kiyoshi Morimoto
Yumiko Satoh
Original Assignee
Sankyo Company, Limited
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Application filed by Sankyo Company, Limited filed Critical Sankyo Company, Limited
Publication of WO2005004875A1 publication Critical patent/WO2005004875A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/10—Expectorants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents

Definitions

  • the present invention relates to an inhalant containing a neurokinin receptor antagonist as an active ingredient.
  • the compounds of the present invention having the general formula (1) are known, and are known to have neurokinin receptor antagonistic activity (US Pat. No. 6,159,967, US Pat. No. 6,336,262). No. 179, U.S. Pat. No. 6,511,975 and Japanese Patent Laid-Open Publication No. 2000-33428). However, the effect of using these compounds as an active ingredient of an inhalant is not known.
  • the present inventors have conducted intensive studies on the pharmacological effects of morpholine derivatives, and as a result, have found that the use of the morpholine derivative as an inhalant has a stronger effect on the respiratory organs than in the case of oral administration. Completed the invention.
  • the present invention
  • a r 1 is substituted with 1 to 3 groups selected from Substituent group ⁇ Hue indicates the Le group
  • a r 2 is substituted with one or two halogen atoms
  • X is, CH (OH)
  • n represents 1 or 2
  • Ar 1 is 3,5-bis (trifluoromethyl) phenyl, 3,4,5-trimethoxyphenyl, 3-hydroxy-1,4,5-dimethoxyphenyl, 4-hydroxy-3
  • An inhalant that is, 5-dimethoxyphenyl or 2-methoxy-5- (1-tetrazolyl) phenyl,
  • Ar 1 is 3,5-bis (trifluoromethyl) phenyl, 3,4,5-trimethoxyphenyl or 2-methoxy-5- (1-tetrazolyl) phenyl,
  • a r 1 is 3,5-bis (trifluoromethyl) phenyl or 3,4,5-trimethoxyphenyl;
  • a r 2 is 1 or 2 fluorine atoms or a phenyl group substituted with a chlorine atom inhalants
  • Ar 2 is 3,4-difluorophenyl or 3,4-dichlorophenyl
  • the inhalant described in the above (1) to (12) includes a medicine, an antitussive, an expectorant, and a medicine for preventing or treating a respiratory disease (for example, chronic obstructive pulmonary disease, bronchitis, and asthma). And can be used as a medicament for preventing or treating rhinitis. Further, the present invention
  • Ar 1 represents a phenylene Le group substituted with 1 to 3 groups selected from Substituent group alpha
  • a r 2 is Hue substituted by one or two halogen atoms indicates a nil group
  • X is, CH (OH)
  • n represents 1 or 2
  • the ⁇ substituent group hydroxyl group
  • Ci one C 4 alkoxy groups
  • Ci one C 4 halogen A group consisting of an alkylated group and tetrazolyl.
  • Respiratory diseases comprising administering to a mammal (preferably a human) an inhalant containing a compound having the following or a pharmacologically acceptable salt thereof.
  • a mammal preferably a human
  • an inhalant containing a compound having the following or a pharmacologically acceptable salt thereof.
  • a method for the prevention or treatment of rhinitis comprising administering to a mammal (preferably a human) an inhalant containing a compound having the following or a pharmacologically acceptable salt thereof.
  • a agonist or a steroid is administered simultaneously, separately or sequentially with the chemical having the general formula (1) or a pharmaceutically acceptable salt thereof. You may. Further, the present invention
  • the inhalant is an inhalant comprising a compound having the general formula (1) or a pharmacologically acceptable salt thereof, and a / 32 agonist or a steroid as an active ingredient.
  • Halogen atom "one or two phenyl group substituted with a halogen atom" in the definition of A r 2 is a fluorine atom, a chlorine atom may be a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom And particularly preferably a chlorine atom.
  • the “C i -C 4 alkoxy group” in the definition of the substituent group may be a linear or branched alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy or butoxy. Methoxy, ethoxy or propoxy, more preferably methoxy or ethoxy, and particularly preferably methoxy.
  • the ⁇ Ci-C 4 halogenated alkyl group '' in the definition of the substituent group ⁇ is a group in which one or two or more hydrogen atoms of a C 4 alkyl group have been substituted with the above-mentioned ⁇ halogen atom ''. Include trifluoromethyl, trichloromethyl, difluoromethyl, Dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 2-promoethyl, 2-chloroethyl, 2-fluoroethyl or 2,2-dibromoethyl, and more preferred. Is trifluoromethyl, trichloromethyl, difluoromethyl or fluoromethyl, and particularly preferably trifluoromethyl.
  • Substituted with 1 to 3 groups selected from Substituent group a phenyl group in the definition of A r 1 is preferably hydroxyl, methoxy, ethoxy, 'bird, Furuoromechiru, trichloromethyl, Jifuruoromechiru, Furuoromechiru And phenyl substituted with 1 to 3 groups selected from the group consisting of tetrazolyl, and more preferably 1 to 3 selected from the group consisting of hydroxyl, methoxy, trifluoromethyl, and tetrazolyl Phenyl groups substituted by three groups (eg, 3,5-bis (trifluoromethyl) phenyl, 3,4,5-trimethoxyphenyl, 3-hydroxy-4,5-dimethoxyphenyl, 4-hydroxy-13 , 5-dimethoxyphenyl or 2-methoxy-1- (1-tetrazolyl) phenyl), and more preferably methoxy.
  • Ru us to the definition of A r 2 "one or two phenyl group substituted with a halogen atom" is preferably 1 or 2 fluorine atoms or a phenyl group substituted by a chlorine atom, more preferably Is a phenyl group substituted with two fluorine atoms or chlorine atoms, more preferably 3,4-difluorophenyl or 3,4-dichlorophenyl, and particularly preferably 4-Dichlorophenyl.
  • the "pharmacologically acceptable salt” means that the compound represented by the general formula (1) has an amine structure in its molecule and can be converted to an acid addition salt by reacting with an acid. Shows such salts.
  • hydrochloride, hydrobromide or hydroiodide Inorganic salts such as hydrohalides, nitrates, perchlorates, sulfates or phosphates; lower alkanesulfonic acids such as methanesulfonate, trifluoromethanesulfonate or ethanesulfonate; Salts, arylsulfonates such as benzenesulfonate or P-toluenesulfonate or acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate Organic salts such as carboxylate such as oxalate or maleate; or amino acid salts such as glycine, lysine, arginine, ordinine, glutamate or aspartate.
  • the compound having the general formula (1) or a pharmacologically acceptable salt thereof is allowed to stand in the air or recrystallize to absorb moisture, adhere to adsorbed water, or form a hydrate. And such hydrates are also encompassed by the present invention.
  • the JS 2 agonist is not particularly limited as long as it is usually used as a bronchodilator, and is preferably salmeterol xinafoate, salvuvol sulphate, levarobuterol hydrochloride, folmote fumarate, roll, hydrobromic acid. It can be phenoterol or allobuterol hydrochloride, particularly preferably salmeterol xinafoate, salbu sulfate, levalobuterol hydrochloride or formoterol fumarate.
  • the steroid is not particularly limited as long as it is used clinically for the prevention of asthma attack, used for asthma attack, or used for the prevention or treatment of chronic obstructive pulmonary disease.
  • the compound having the general formula (1) and a pharmacologically acceptable salt thereof include, for example, US Pat. No. 6,159,967, US Pat. No. 6,362,179, US Pat. Produced according to the method described in 1 197 75 and JP 2000-34 288 be able to.
  • the inhalant of the present invention means a pharmaceutical composition for allowing a compound having the general formula (1) or a pharmaceutically acceptable salt thereof to reach the trachea, bronchi, lungs, etc. of a recipient, It can be a nasal drop or a composition suitable for nasal or pulmonary administration, more preferably a composition suitable for pulmonary administration.
  • the inhalant of the present invention can be produced in the form of a powder, a solution or a suspension using the compound having the general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound having the general formula (1) or a pharmaceutically acceptable salt thereof may be used as it is or as an excipient, a lubricant, a binder, a disintegrant, a stabilizer, It can be manufactured by adding additives such as a flavoring agent to make finer.
  • Excipients may include, for example, lactose, sucrose, glucose, sugar derivatives such as mannitol or sorbitol, corn starch, potato starch, ⁇ -starch, starch derivatives such as dextrin or carboxymethyl starch, crystalline cell mouth.
  • Lubricants include, for example, stearic acid metal salts such as stearic acid, calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as gum or gay; boric acid; adipic acid; Sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; sodium fatty acid salt; such as sodium lauryl sulfate or magnesium lauryl sulfate Lauryl sulfate; silicic acid such as silicic anhydride or silicic acid hydrate; or the above-mentioned starch derivative.
  • the binder may be, for example, polyvinylpyrrolidone or macrogol, or a compound similar to the excipient.
  • Disintegrants may be, for example, compounds similar to the above-mentioned excipients or chemically modified starch cells such as croscarmellose sodium, sodium carboxymethyl starch or crosslinked polypinylpyrrolidone.
  • Stabilizers include, for example, parabenzoic esters such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenol such as phenol or cresol. Thimerosal; dehydroacetic acid; or sorbic acid.
  • the flavoring agent may be a commonly used sweetener, acidulant or flavor.
  • the inhalant is prepared as a solution or suspension
  • the compound having the general formula (1) or a pharmacologically acceptable salt thereof is prepared by adding water or water and an auxiliary solvent (eg, ethanol, propylene). Glycol, polyethylene glycol, etc.).
  • auxiliary solvent eg, ethanol, propylene
  • Such solutions or suspensions may also contain preservatives (eg, benzoconic chloride), solubilizing agents (eg, polysorbates such as Tween 80 or Span 80, or surfactants such as benzalkonium chloride). Buffers, isotonic agents (eg, sodium chloride), absorption enhancers and Z or thickeners may be included.
  • the suspension may further contain a suspending agent (for example, microcrystalline cellulose, sodium carboxymethylcell or the like).
  • a suspending agent for example, microcrystalline cellulose, sodium carboxymethylcell or the like.
  • the compound having the general formula (1) and a pharmacologically acceptable salt thereof are converted to a suitable propellant (for example, dichlorofluoromethane, trichlorofluoromethane or Fluorocarbon such as dichlorotetrafluoroethane, or a gas such as carbon dioxide) can be sprayed on as an aerosol in the form of a pressurized pack, or administered using a nebulizer.
  • a suitable propellant for example, dichlorofluoromethane, trichlorofluoromethane or Fluorocarbon such as dichlorotetrafluoroethane, or a gas such as carbon dioxide
  • a suitable propellant for example, dichlorofluoromethane, trichlorofluoromethane or Fluorocarbon such as dichlorotetrafluoroethane, or a gas such as carbon dioxide
  • a suitable propellant for example, dichlorofluoromethane, trichlorofluoromethane or
  • the 2agonist or steroid is administered separately or continuously with the compound having the general formula (1) and a pharmacologically acceptable salt thereof, a commercially available inhaler / 32agonist or steroid for inhalation It is also possible to use.
  • the amount of the compound having the general formula (1) of the present invention or a pharmacologically acceptable salt thereof varies depending on symptoms, age, sex and the like. H g / g (preferably 0.05 gZk g), and, as an upper limit, l OOO gZk g (preferably 100 / g / kg, more preferably 20 kg) in one or several divided doses It is desirable to administer according to.
  • salmeterol xinafoate is 10 g to 100 / ig (preferably 25 pg to 75, particularly preferably 50 tg). Is administered twice daily; in the case of Salbu Even Sulphate (inhalation), 50 ⁇ g to 200 g (preferably 1 to 200 g, particularly preferably 180 g) is 1 Given 3 or 4 times a day; in the case of levalobuterol hydrochloride (inhalation), 0.03 lmg to 1.25 mg (preferably 0.63 mg to 1.25 mg) given 3 times a day; fumaric acid For formoterol (inhalation) & gn to 24: fig (preferably 12 g to 24 ⁇ g) is administered twice daily; for phenoterol hydrobromide (inhalation) 0.2 mg to 0 mg 6 mg (preferably 0.2 mg to 0.4 mg) is administered 1 to 4 times a day; for rlobbuterol hydrochloride
  • the usual doses used clinically as bronchodilators are preferably used.
  • 50 / ig to 100 g preferably 100 g to 100 g
  • fluticasone propionate inhaled
  • 50 ⁇ to 500 preferably 100 g to 400 g
  • beromesone propionate preferably 100 g to 200 g
  • 50 g to 200 g / ig is administered four times a day.
  • the usual doses used clinically for the prevention or treatment of asthma attack, asthma attack, or chronic obstructive pulmonary disease are preferably used.
  • test substance is dissolved in 5% aqueous glucose, and 0.5 ml 1 Z kg of the solution is injected into the endotracheal tube under anesthesia with ventalpital (0.2 to 0.25 ml body, p.).
  • 1A-1B manufactured by penn-century. Inc.
  • 1A-1B was used for transtracheal administration to guinea pigs (weight around 400 g, male Hartley guinea pigs).
  • Evansblue 40 mg / 2 m 1 / kg v.
  • Substance P (1 g / 2 m 1 / kg> i.v.
  • mice Fifteen minutes after administration of Substance P, the mice were euthanized with carbon dioxide and the main trachea was removed about 2 cm from the neck.
  • the excised main trachea 0.5 acetone 5,% N a 2 S 0 4 7: 3 by immersing mixture 4m about 2 4 hours 1 extracts the dye extract absorbance of (OD 6 2 0 nm) It was measured.
  • the amount of dye was converted from the calibration curve, and the amount of dye leakage per 0.1 g of trachea was defined as the intensity of vascular permeability enhancement, and the inhibition rate relative to the control (5% glucose transtracheal administration group) was calculated.
  • the 50 % inhibitor dose (ID 50 value) was calculated by linear regression analysis of the logarithmic value of the dose and the inhibition rate of each individual. In this test, when the compound A. (compound of the following structural formula A) was intratracheally administered immediately before Evans Blue administration, the ID 50 value was 5.8 ⁇ gZkg. In addition, when compound B (the following structural formula B) was intratracheally administered 100 tgZkg four hours before administration of Evans blue, the inhibition rate was 5.7%.
  • Healthy guinea pigs (body weight 500 g before and after, Hartley male guinea pigs) using a for inhibiting operation on airway contraction by neurokinin an NK 2 receptor Agonisuto A (NKA) Konzett-Roessier ( Naunyn-Sc miedebergs Arch. Exp. Pathol, Using a modified method of pharmakol. 195.71 (1940), airway pressure was used as an index.
  • NKA NK 2 receptor Agonisuto A
  • the airway pressure during artificial respiration is detected by a pressure transducer (Nihon Kohden Corporation, TP-200T or TP-400T) attached to the side branch of the tracheal force neura and amplified (Nihon Kohden, AP-601G). Recorded on a recorder (Nihon Kohden Kogyo Co., Ltd., WT-645G or WT-685G). After the airway pressure and blood pressure and heart rate were stabilized, airway reactivity was confirmed with Methacholine (100 g / ml, 0.1 l Oml zkg), a standard airway contraction substance.
  • Methacholine 100 g / ml, 0.1 l Oml zkg
  • the prescribed contraction response is obtained If not, airway reactivity was confirmed with Methacholine at 12 / gZkg (120 g / m 1, 0.10 ml / kg). Five minutes after confirmation of airway responsiveness, 4 gZkg of NKA was intravenously administered from a vein force neura to induce airway constriction, and then the airway pressure for 10 minutes was measured.
  • test substance was dissolved in a 5% glucose solution, and 0.5 g 1 g of the solution was intratracheally administered using an intratracheal administration device (1A-1B, manufactured by pemi-century. Itic).
  • the inhibition rate with respect to contro 1 was calculated by taking the increased airway pressure area value for 10 minutes after NKA administration as the strength of NKA-induced airway contraction.
  • the 50% inhibitory drug dose (ID 5. value) was calculated by linear regression analysis of the logarithmic value of the drug dose and the inhibition rate of each individual.
  • ID 5 0 value when the trachea administered via Compound A in 3 0 minutes before the NKA dose was 0. 2 1 jLi g / kg.
  • ID 50 values when administered Keiki tube 4 hours prior to NKA administration of compound B was 1. 8 ⁇ gZkg.
  • NK 3 receptor Agonisuto in Example 2 was adjusted base airway pressure as an index.
  • Example 2 An experiment was performed in the same manner as in Example 2 except that NKB 4.0 gZkg was intravenously administered instead of NKA intravenous administration.
  • the area of increased airway pressure for 10 minutes after NKB administration was defined as the strength of NKB-induced airway contraction, and the inhibition rate against contro 1 (5% glucose transtracheal administration group) was calculated.
  • the 50% inhibitory drug dose (ID5 () value) was calculated by linear regression analysis of the logarithmic value of the drug dose and the inhibition rate of each individual.
  • Guinea pigs anesthetized with bentopalpital (pentobarbi lsodium, 50 mg / ml solution, 0.40-0.5 ml Zbody, sc) were equipped with a tracheal force nebule and an intravenous cannula.
  • gallamine gallamine triethiodide 20 mgZkg, i.v.
  • a platinum electrode for stimulation was connected to the right or left vagus nerve.
  • the airway pressure during artificial respiration was detected by a pressure transducer attached to a side branch of the tracheal force neuron, amplified, and recorded on a recorder.
  • the vagus nerve was stimulated infrequently and briefly (2 Hz, 20 seconds, 5 V, duration 5 msec) from a platinum electrode to confirm airway responsiveness.
  • Five minutes after confirmation of airway responsiveness the vagus nerve was fully stimulated (20 Hz, 60 seconds, 5 V, duration 5 msec) to induce airway constriction, and then the airway pressure for 10 minutes was measured.
  • test substance was dissolved in a 5% glucose solution on the day of the test, and 0.5 ml of a 0.5 kg solution was inoculated 30 minutes before the main stimulation of the vagus nerve using an intratracheal administration device (1A_1B, penn-century. Inc.). It was administered in a tube.
  • the increased airway pressure area value for 10 minutes after the main stimulation of the vagus nerve was defined as the intensity of airway contraction induced by vagus nerve stimulation, and the inhibition rate against contro (5% glucose solution administration group) was calculated.
  • the inhibitory rate after transtracheal administration of 10 kg of Compound A was 51%.
  • Receptor antagonist test oral administration
  • the experiment was performed in the same manner as in Example 1 except that the test compound was orally administered.
  • the test substance was administered orally in suspension in 5% tragacanth versus solution.
  • ID 5 Q value when orally administered one hour before the compound A Evans blue administration was 3. 6mgZk g.
  • the inhibitory rate when 1 Omg / kg was orally administered 2 hours before the administration of Evans blue was -25%, and the inhibitory rate when 33 mg / kg was orally administered was 31%.
  • Example 2 The experiment was performed in the same manner as in Example 2, except that the test compound was orally administered.
  • the test substance was administered orally in suspension in 5% tragacanth versus solution.
  • the experiment was performed in the same manner as in Example 3, except that the test compound was orally administered.
  • the test substance was orally administered by suspending it in a 5% tragacanth-solution.
  • ID 5 0 value when Compound A was tracheal administered through one hour before NKB administration was 0. 89mgZkg. Further, ID 5 0 value when orally administered 2 hours prior to NKB administration of compound B was 1. SmgZk g.
  • the compound having the above general formula (1) exerts a drug effect by a smaller dose than that administered orally by intratracheal administration.
  • the medicinal effect is expressed with a smaller number of active ingredients, and the degree of side effects of the neurokinin antagonist can be reduced.
  • it is useful as a medicament for the prevention or treatment of respiratory diseases (eg, chronic obstructive pulmonary disease, bronchitis and asthma, etc.), analgesia, expectoration, and prevention or treatment of rhinitis. '
  • the inhalant of the present invention can be used in combination with i32 agonist and Z or a steroid.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pulmonology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Otolaryngology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un produit pour inhalation qui contient comme principe actif un composé de la formule générale (1) suivante ou un sel pharmacologiquement acceptable de ce dernier. Le produit pour inhalation de l'invention est utilisé, par exemple, dans les traitements de maladies respiratoires. (1) (Ar1 est facultativement phényle substitué ; Ar2 est halophényle ; X est CH(OH), SO, ou SO2 ; et n est 1 ou 2).
PCT/JP2004/010237 2003-07-14 2004-07-12 Composition medicinale a administration pulmonaire WO2005004875A1 (fr)

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Cited By (1)

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CN102266181A (zh) * 2011-09-08 2011-12-07 鲁杨 一种具有保健功能的枕头

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JPH1143490A (ja) * 1997-05-30 1999-02-16 Sankyo Co Ltd 光学活性スルホキシド誘導体の塩
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JPH09235275A (ja) * 1995-12-01 1997-09-09 Sankyo Co Ltd 飽和複素環化合物
JPH1143490A (ja) * 1997-05-30 1999-02-16 Sankyo Co Ltd 光学活性スルホキシド誘導体の塩
WO1999027911A1 (fr) * 1997-12-03 1999-06-10 Fujisawa Pharmaceutical Co., Ltd. Medicament en pastilles souples et procede de fabrication
JP2000034288A (ja) * 1998-01-23 2000-02-02 Sankyo Co Ltd スピロピペリジン誘導体
JP2003519102A (ja) * 1999-12-02 2003-06-17 オーエスアイ・ファーマスーティカルズ・インコーポレーテッド アデノシンａ▲下１▼、ａ▲下２ａ▼およびａ▲下３▼受容体に対して特異的な化合物並びにその使用
WO2002069944A2 (fr) * 2001-03-08 2002-09-12 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouvelles compositions medicamenteuses a base d'anticholinergiques et d'antagonistes de recepteurs nk1

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