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WO2005072743A1 - Broncho-dilatateurs - Google Patents

Broncho-dilatateurs Download PDF

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Publication number
WO2005072743A1
WO2005072743A1 PCT/JP2005/001625 JP2005001625W WO2005072743A1 WO 2005072743 A1 WO2005072743 A1 WO 2005072743A1 JP 2005001625 W JP2005001625 W JP 2005001625W WO 2005072743 A1 WO2005072743 A1 WO 2005072743A1
Authority
WO
WIPO (PCT)
Prior art keywords
general formula
group
compound
salt
prodrug
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP2005/001625
Other languages
English (en)
Japanese (ja)
Inventor
Tsutomu Shiroya
Nao Wakabayashi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ono Pharmaceutical Co Ltd
Original Assignee
Ono 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
Priority claimed from JP2004023995A external-priority patent/JP2007186423A/ja
Priority claimed from JP2004342546A external-priority patent/JP2007186424A/ja
Application filed by Ono Pharmaceutical Co Ltd filed Critical Ono Pharmaceutical Co Ltd
Publication of WO2005072743A1 publication Critical patent/WO2005072743A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • 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
    • A61P11/08—Bronchodilators

Definitions

  • the present invention relates to (1) a general formula (I)
  • a bronchodilator containing a salt thereof, a solvate thereof or a prodrug thereof, or a cyclodextrin inclusion compound thereof and (2) — an inhalant having a bronchodilator effect comprising a compound represented by the general formula (I), a salt thereof, a solvate thereof or a prodrug thereof, or a cyclodextrin clathrate thereof.
  • COPD chronic obstructive pulmonary disease
  • bronchitis chronic bronchitis, emphysema, or a combination of airflow obstruction and a characteristic of airflow restriction that is not completely reversible. It is.
  • Smoking causes bronchial inflammation and alveoli rupture. As a result, symptoms such as cough, sputum, and shortness of breath may occur, and if progressing, hypoxemia may occur.
  • the COPD therapeutic agents, bronchodilators eg example, anticholinergics, 0 2 stimulants or theophylline
  • expectorants steroids
  • antibiotics antibiotics are used.
  • bronchodilators and expectorants are symptoms Can be improved, but it is not a drug that improves the underlying condition. Also, long-term use of steroid drugs is not desirable in terms of side effects. Therefore, a safe and useful therapeutic agent for COPD is eagerly needed.
  • the compound represented by the general formula (I) described below has an EP2 agonist effect, and has immunological diseases (autoimmune diseases, organ transplantation, etc.), asthma, bone formation abnormality, nerve cell death, liver damage, It is disclosed to be useful for prevention and Z or treatment of retinal neuropathy such as premature birth, miscarriage, and glaucoma (see EP860430).
  • immunological diseases autoimmune diseases, organ transplantation, etc.
  • asthma bone formation abnormality
  • nerve cell death CAD
  • liver damage glaucoma
  • An object of the present invention is to provide a drug having a bronchodilator effect and an anti-inflammatory effect, which is safe and useful as a medicament and can treat COPD.
  • the present inventors have for the first time found that the compound represented by the general formula (I) has a surprisingly strong bronchodilator effect. Therefore, it has also been found that the compound represented by the general formula (I) is effective for treating respiratory diseases such as chronic obstructive pulmonary disease, adult respiratory distress syndrome emphysema, cystic fibrosis or chronic bronchitis. . Furthermore, since the compound represented by the general formula (I) also has an anti-inflammatory effect, it can not only improve symptoms but also suppress bronchial inflammation which causes chronic obstructive pulmonary disease.
  • the compound represented by the general formula (I) by inhaling the compound represented by the general formula (I), a bronchodilator effect and an anti-inflammatory effect are locally exerted, and an effect other than the intended effect of the EP2agonist, for example, an effect on the circulatory system is obtained. It can be avoided and used as a safe drug with fewer side effects. Furthermore, they found that the compound represented by the general formula (I) could be a useful therapeutic agent for respiratory diseases by combining the biodegradable polymer and the bronchodilator effect, and completed the present invention. did. That is, the present invention
  • R 1 represents a carboxy group or a hydroxymethyl group
  • R 1 one 1 represents an O Kiso group, methylidene group or a halogen atom
  • R 1 - 2 represents a hydrogen atom, water acid groups or C 1 to 4, It represents an alkoxy group
  • R 1 - 3 is a hydrogen atom, an alkyl group of C l to 8, an alkenyl group of C 2 to 8, alkynyl group of C2-8, groups or the following (1) to (5)
  • a bronchodilator comprising a compound thereof, a salt thereof, a solvate thereof, a prodrug thereof, or a cyclodextrin inclusion compound thereof, 2.
  • the compound represented by the general formula (I) or a salt thereof is (5 Z) — 7— ⁇ (1 R, 2R, 3 R, 5 R) —5-chloro-2-— [(1 E, 4 S ) —4- (1-ethylcyclobutyl) -14-hydroxybutene-11-yl] —3-hydroxycyclopentyl ⁇ hepta-15-enoic acid or a lysine salt thereof according to the above item 1. Bronchodilators,
  • bronchodilator according to the above 1 which is a preventive and / or therapeutic agent for respiratory diseases, or the bronchodilator according to the above 3, wherein the respiratory disease is a chronic obstructive pulmonary disease.
  • the compound represented by the general formula (I) described in the above 1, a salt thereof, a solvate thereof, a prodrug thereof, or a cyclodextrin clathrate thereof, a type 4 phosphodiesterase inhibitor, a steroid drug, / 3 agonists, Roikotoryen receptor antagonists, Toronpokisan synthase inhibitors, thromboxane A 2 receptor antagonist, mediator release inhibitor, antihistamines, xanthine derivatives, anticholinergic phosphorus agents, cytokine inhibitors, prostaglandins, A medicament comprising a combination of at least one selected from forskolin preparations, elastase inhibitors, meta-oral protease inhibitors, expectorants, antibiotics and immunosuppressants,
  • a drug for inhalation having a bronchodilator effect comprising a compound represented by the general formula (I), a salt thereof, a solvate thereof or a prodrug thereof, or a cyclodextrin clathrate thereof according to the above 1.
  • composition for inhalation according to the above 7, which is a microsphere or a nanosphere,
  • a prophylactic and / or therapeutic agent for chronic obstructive pulmonary disease comprising the compound represented by the general formula (I), a salt thereof, a solvate thereof or a prodrug thereof, or a cyclodextrin clathrate thereof according to the above 1.
  • 11. a compound represented by the general formula (I) as described in 1 above, a salt thereof, a solvate thereof or a prodrug thereof, or a cyclodextrin inclusion compound thereof; and (2) a biodegradable polymer Contain chronic obstructive ⁇ ⁇ disease
  • a pharmaceutical composition for inhalation for the prevention and / or treatment of chronic obstructive pulmonary disease comprising (1) ⁇ 2agonist, and (2) a biodegradable polymer;
  • a general formula (I) for producing a prophylactic and / or therapeutic agent for respiratory diseases 14.
  • the C 1-4 alkyl group means methyl, ethyl, propyl, Butyl and their branched isomer groups are meant.
  • the alkyl group of ci-8 means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and their branched isomer groups.
  • the C2-8 alkenyl group means vinyl, propenyl, butyr, pentyl, hexenyl, heptyl, octyl, and their branched isomer groups.
  • the C2-8 alkynyl group means ethynyl, propynyl, butul, pentul, hexynyl, heptul, octynyl and their branched isomer groups.
  • the C1-4 alkoxy group means methoxy, ethoxy, propoxy, butoxy and their branched isomer groups.
  • the C3-7 cycloalkyl group means a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group.
  • the halogen atom means fluorine, chlorine, bromine and iodine.
  • the alkyl group, the alkenyl group, the alkynyl group, the alkoxy group, the alkylthio group, the alkylene group, the alkenylene group and the alkynylene group include straight-chain and branched-chain ones.
  • isomers in double bonds, rings and condensed rings
  • isomers due to the presence of asymmetric carbon R, S, ⁇ , configuration, enantiomers, diastereomers
  • optical rotation Optically active form D, L, d, 1 body
  • polar form by chromatographic separation high polar form
  • Equilibrium compounds Equilibrium compounds, rotamers, mixtures of these in any proportion, and racemic mixtures are all included in the present invention.
  • the compound represented by the general formula (I) is converted into a salt by a known method.
  • a salt a pharmacologically acceptable salt is preferable.
  • the salt examples include an alkali metal salt, an alkaline earth metal salt, an ammonium salt, an amine salt and an acid addition salt.
  • the salt is preferably water-soluble. Suitable salts include salts of alkali metals (such as potassium and sodium), salts of alkaline earth metals (such as calcium and magnesium), ammonium salts, and pharmaceutically acceptable organic amines (tetramethylammonium). , Triethynoleamine, methylamine, dimethylamine, cyclopentynoleamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) amino methane, lysine, arginine, N-methyl-1-D-glucamine, etc. ). Particularly, a lysine salt is preferred.
  • the acid addition salt is preferably water-soluble.
  • Suitable acid addition salts include, for example, mineral salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, or acetate, lactate, tartrate, and the like.
  • Organic salts such as benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, and dalconate.
  • the compound represented by the general formula (I) and a salt thereof can also be converted to a solvate.
  • the solvate is non-toxic and water-soluble.
  • Suitable solvates include, for example, water and solvates such as alcoholic solvents (eg, ethanol and the like).
  • the compound of the present invention may be selected from the group consisting of Using these mixtures, they can be converted to cyclodextrin clathrates by the method described in JP-B-50-3362, JP-B-52-31404 or JP-B-61-52146. Conversion to a cyclodextrin clathrate compound is advantageous when used as a drug because it increases stability and increases water solubility.
  • the prodrug of the compound represented by the general formula (I) refers to a compound which is converted into the compound of the present invention by a reaction with an enzyme, gastric acid or the like in a living body.
  • a prodrug of the compound of the present invention when the compound of the present invention has an amino group, a compound in which the amino group is acylated, alkylated, or phosphorylated (for example, the amino group of the compound of the present invention is eicosanoylated, alanylated, pentyl) Aminocarbonylation, (5-methyl-1-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, vivaloyloxymethylation, acetoxymethylation, When the compound of the present invention has a hydroxyl group, a compound in which the hydroxyl group is acylated, alkylated, phosphorylated,
  • the prodrug of the compound of the present invention may be either a hydrate or a non-hydrate.
  • a salt thereof, a solvate thereof or a prodrug thereof, or a cyclodextrin clathrate thereof preferably, for example, (5Z) -7- ⁇ (1R, 2R , 3 R, 5 R) — 5—Black mouth 2— [(1 E, 4 S) 1-4 1 (1-ethyl butyl mouth) 1-4—Hydroxybuta 1 1 1 1 1-inole] — 3-Hydroxy Cyclopentynole ⁇ Hepta-5-enoic acid or its lysine salt (2S) -2,6-diaminohexanoic acid (5Z) -7- ⁇ (1R, 2R, 3R, 5 R) 1-5-Chloro-2-[[(1E, 4S) -4-1 (1-ethynolecyclobutynole) -4-hydroxybuta-1-ene_1-yl] —3-Hydr
  • EP2 agonist used in the present invention, any compound having an EP2 agonist action may be used, and not only a compound having a known EP2 agonist action but also an EP2 agonist action to be found in the future. All compounds having are included.
  • EP2agonists include the compounds described in EP860430, the compounds described in W099 / 33794, the compounds described in EP974580, the compounds described in W095 / 19964, the compounds described in US5698598, and the compounds described in US6376533.
  • the compound of the present invention represented by the general formula (I) can be produced by improving the method described in EP860430, a method analogous thereto, and the like, and using an appropriate combination thereof.
  • the compound represented by the general formula (I) has a very low toxicity and is sufficiently safe for use as a medicament.
  • a compound represented by the general formula (I), a salt thereof, a solvate thereof, a prodrug thereof, or a cyclodextrin inclusion compound thereof (hereinafter may be abbreviated as a compound represented by the general formula (I), etc.)
  • a compound represented by the general formula (I), etc. has bronchodilator and anti-inflammatory effects, thus preventing and / or treating respiratory diseases such as chronic obstructive pulmonary disease, adult respiratory distress syndrome emphysema, cystic fibrosis or chronic bronchitis, etc. It is effective for treating respiratory diseases such as chronic obstructive pulmonary disease, adult respiratory distress syndrome emphysema, cystic fibrosis or chronic bronchitis, etc. It is effective for
  • the compounds represented by the general formula (I) include: 1) complementing or enhancing the therapeutic effect of the compound; 2) improving the kinetics and absorption of the compound; reducing the dose; and / or 3) It may be administered as a concomitant drug in combination with other drugs to reduce the side effects of the compound.
  • the concomitant use of the compound represented by the general formula (I) and another drug may be administered in the form of a combination preparation in which both components are combined in one preparation, or in the form of separate preparations for administration. May be taken.
  • simultaneous administration and administration at different times are included.
  • the administration according to the time difference may be performed by administering the drug of the present invention first and then administering the other drug later, or administering the other drug first and then administering the agent of the present invention later.
  • the respective administration methods may be the same or different.
  • the other drug may be a low molecular weight compound, a high molecular weight protein, polypeptide, polynucleotide (DNA, RNA, gene), antisense, decoy, antibody, or vaccine. It may be.
  • the dose of the other drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the drug of the present invention to other drugs can be appropriately selected depending on the age and weight of the administration subject, administration method, administration time and the like. For example, 0.01 to 100 parts by mass of another agent is used for 1 part by mass of the agent of the present invention.
  • Other drugs may be administered, for example, in combination of one or more of any of the following homologous groups and heterogeneous groups at appropriate ratios.
  • Other drugs that complement and / or enhance the therapeutic effect of the compound represented by the general formula (I) include not only those that have been found up to now, but also Includes what is found.
  • agents for example, type 4 phosphodiesterase inhibitors, steroids drugs, agonists, Roikotoryen receptor antagonists, thromboxane synthetase inhibition agents, thromboxane A 2 receptor antagonist, mediator release inhibitors, anti Histamine drugs, xanthine derivatives, anticholinergics, cytoforce inhibitors, prostaglandins, forskolin preparations, elastase inhibitors, meta-oral protease inhibitors, expectorants, antibiotics or immunosuppressants .
  • type 4 phosphodiesterase inhibitors for example, type 4 phosphodiesterase inhibitors, steroids drugs, agonists, Roikotoryen receptor antagonists, thromboxane synthetase inhibition agents, thromboxane A 2 receptor antagonist, mediator release inhibitors, anti Histamine drugs, xanthine derivatives, anticholinergics, cytoforce inhibitors, prostaglandins, forskolin preparations, elastase inhibitors, meta-oral prote
  • Examples of the type 4 phosphodiesterase inhibitors include rolipram, cilomilast, Bayl 9-8004, NIK-616, lofunorelast (BY-217), sipamphyrin (BRL-61063), achizolam (CP-80063), SCH — 351591, YM—976, V—11294 A, PD—168787, D—4396, IC—485.
  • Oral steroids oral cortisone, hydrocortisone, sodium hydrocortisone phosphate, sodium succinate sodium cortisone sodium, fludomouth cortisone acetate, prednisolone, acetic acid Prednisolone, prednisolone sodium succinate, prednisolone butyl succinate, prednisolone sodium phosphate, halopredone acetate, methylprednisolone acetate, methylprednisolone acetate, sodium methylprednisolone sodium succinate, triamcinolone, triamcinolone acetate, triamcinozone demethasone dexenamethazone Inhalants such as dexamethasone sodium, dexamethasone palmitate, paramethasone acetate, betamethasone, etc. Nate, mometasone furan carbonate, plasterone sulfonate , Deflazacort, methylprednisolone sulphonate
  • J3 agonists include, for example, pentanoterol hydrobromide, salbutamol sulfate, terbutaline sulfate, formoterol fumarate, salmeterol xinafoate, isoproterenol sulfate, orciprenaline sulfate, chlorprenaline sulfate, epinephrine, trimethoquinol hydrochloride, and sulfuric acid Hexoprenaline mesyl, propoterol hydrochloride, llobuterol hydrochloride, llopterol hydrochloride, pirputerol hydrochloride, clenbuterol hydrochloride, mabuterol hydrochloride, litodrine hydrochloride, panbuterol, doxamine hydrochloride, meradrine tartrate, AR-C68397, reposalbutamol, KUR — 1246, KUL—7211, AR—C89855, S_1319
  • leukotriene receptor antagonists examples include pranlukast hydrate, montelukast, zafirlukast, seratrodast, MCC—847, KCA-757, CS—615, YM—158, L—740515, CP—195494, LM -1484, RS-635, A-93178, S-364 96, BIIL-284, ONO-4057 and the like.
  • the Toronpokisan A 2 receptor antagonists for example, seratrodast, llama Toroban, domitroban pan calcium hydrate, KT 2-962 etc. Ru mentioned.
  • mediator release inhibitor examples include tranilast, sodium cromoglycate, amlexanox, revilinast, ibudilast, dazanolast, potassium milolast, and the like.
  • Antihistamines include, for example, ketotifen fumarate, mequitazine, azelastine hydrochloride, oxatomide, terfenadine, emedastin fumarate, epinastine hydrochloride, astemizole, ebastine, cetirizine hydrochloride, bepotastine, fexofenadine, mouth Ratadine, olopatadine hydrochloride, TAK-427, ZCR-2060, NIP-530, mometasone proate, mizolastine, BP-294, andlast, auranofin, atarivastin and the like.
  • xanthine derivative examples include aminophylline, theophylline, doxophylline, sipamphylline, diprofylline and the like.
  • Anticholinergic agents include, for example, iprat bromide, oxitropium bromide, furtium bromide, simetropium bromide, temiverine, pium bromide bromide, revatropate (UK-1 12166) and the like. .
  • cytokine inhibitors examples include sublatast tosilate and the like.
  • elastase inhibitors examples include sivelestat, ONO-6818, MR-889, PBI-1101, EPI-HNE-4, R-665 and the like.
  • expectorants include ammonia wisdom, sodium bicarbonate, bromhexine hydrochloride, carbocistein, amproxol hydrochloride, amploxol hydrochloride sustained-release agent, methyl cysteine hydrochloride, acetyl cysteine, and salt. Acid L-ethyl cysteine, tyloxapol and the like.
  • Antibiotics include, for example, cefuroxime sodium, meropenem trihydrate, netilmicin sulfate, sisomycin sulfate, ceftibutene, PA-1806, IB-367, topramycin, PA-1420, Doxonolevicin, astromycin sulfate, cefetamethopipoxyl hydrochloride and the like.
  • inhaled antibiotics include PA-1806, IB-367, tobramycin, PA-1420, doxorubicin, astromycin sulfate, cefetametopivoxil hydrochloride and the like.
  • immunosuppressant examples include cyclosporin, tacrolimus, azathioprine, methotrexate, cyclophosphamide and the like.
  • compounds such as the compounds represented by the general formula (I) have been found to date for the prevention and Z or other agents that enhance or prevent Z or therapeutic effects based on the mechanism described above. This includes not only things but also things that will be discovered in the future.
  • the compound represented by the general formula (I) or the like can be formulated as a single preparation or a blended preparation using a technique widely used, if necessary, by adding a pharmaceutically acceptable additive.
  • the whole or topical is used. It is administered in oral or parenteral form.
  • Dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is generally from 1 ng to 100 mg per adult per dose, from once a day.
  • the dose varies depending on various conditions, so a smaller dose than the above-mentioned dose may be sufficient in some cases. In some cases.
  • oral preparations include liquids for internal use (eg, elixirs, syrups, pharmaceutically acceptable solutions, suspensions, and emulsions) and solids for internal use (eg, tablets (sublingual tablets, oral cavity Pills, capsules (including hard capsules, soft capsules, gelatin capsules, microcapsules, etc.), powders, granules, troches and the like).
  • liquids for internal use eg, elixirs, syrups, pharmaceutically acceptable solutions, suspensions, and emulsions
  • solids for internal use eg, tablets (sublingual tablets, oral cavity Pills, capsules (including hard capsules, soft capsules, gelatin capsules, microcapsules, etc.), powders, granules, troches and the like).
  • Parenteral preparations include, for example, liquid preparations (for example, injections (subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, infusions, etc.), inhalants, nasal preparations, eye drops, Skin preparations, ointments, suppositories, etc. These preparations may be release controlling agents such as immediate release preparations, sustained release preparations, etc. These preparations can be prepared by known methods, for example, the Japanese Pharmacopoeia. And the like.
  • Liquid preparations for oral administration are manufactured, for example, by dissolving, suspending or emulsifying the active ingredient in a commonly used diluent (for example, purified water, ethanol or a mixture thereof). You. Further, the liquid preparation may contain a humectant, a suspending agent, an emulsifier, a sweetener, a flavor, an aromatic, a preservative, a buffer, and the like.
  • a humectant for example, purified water, ethanol or a mixture thereof.
  • Solid preparations for oral administration include tablets, pills, capsules, powders, granules and the like.
  • Capsules include hard capsules and soft capsules.
  • Tablets include sublingual tablets, buccal patches, and buccally disintegrating tablets.
  • one or more of the active substances may be intact or excipients (ratatose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (hydroxypropylcellulose, polypropylpyrroli). Don, magnesium metasilicate aluminate, etc.), disintegrant (fiber calcium calcium dalycholate, etc.), lubricant (magnesium stearate, etc.), stabilizer, dissolution aid (glutamic acid, aspartic acid, etc.) And always It is used in the form of a pharmaceutical preparation according to the law. .
  • cocoating agent ((sucrose, sugar, zegeratitin ,, hydridoxyloxysippropropinopinoresesenorenorerorosesu, hihidodorolo
  • capcapserul which is a substance that can be absorbed and absorbed, such as zelaratitin, is also included. .
  • the sublingual sublingual tablets are manufactured and manufactured according to a method known in the art.
  • the excipients ((Lalactoctose, Mamanninitotoul) can be added to more than one active substance.
  • Guggulcocoseus micro-crystallized cercerol lorose, cocoloroidadulsicilirica, dedenpumpun, etc.
  • binding agent ((hydrhydroxy xypsiprolopipirulose)
  • Disintegration disintegrant ((dendenpumpun, LL—hydodoloroxycysprolopipiril cercellulose, kacarrubovoxysimimetylyl cecerulololose, cuculoscacarmellose) Nanatto trillium,, fiber fiber glycolicocholate coco norelesium, etc.), lubricating agents ((magnesium sulphate) Ummum, etc.), swelling and swelling agents ((hydddroloxycyssipprolo pipyril cercerolloose, hydridoloxoxysipprolopipinoreleme methinoinoreresesenonorellorose, Carbobo Popo Norrele, Power Lulu Poppoxisimethytyl Rusecellulose Loose, Poporibibiururuaruarukoko Le ,, Kiki Sasan down the other end Nga gum-time ,, Guguaa
  • a padlock is manufactured and manufactured according to a method known in the art.
  • excipients ((Laratatatotothose, Mamanninitotoul) may be added to the active substance of more than one level. ,, Guggulcocoseus, Micro-crystallized crystal , Colloidal silica, starch, etc.), binders (hydroxypropyl cellulose, polybutylpyrrolidone, magnesium aluminate metasilicate, etc.), disintegrants (starch, L-hydroxypropyl cellulose, carboxymethyl cellulose, cloth) Carmellose sodium, calcium cellulose glycolate, etc.), lubricants (magnesium stearate, etc.), adhesives (hydroxypropinoresenorelose, hydroxypropinolemethinoresenorelose, carboponole, pyrenoxoxymethylsenorelose, polyvinylinole) Anoreconore, xanthan gum, guar gum, etc., adh
  • a coating agent sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc.
  • additives such as preservatives, antioxidants, coloring agents, sweeteners and the like which are commonly used can be added.
  • the orally rapidly disintegrating tablet is produced according to a known method.
  • one or more active substances may be used as is, or as a coating agent suitable for bulk powder or granulated bulk powder (ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methacrylic acid copolymer, etc.)
  • An active substance coated with a plasticizer polyethylene glycol, triethyl citrate, etc.
  • excipients lactose, mannitol, glucose, microcrystalline cellulose, colloidal silica, starch, etc.
  • a binder hydroxypropyl cellulose
  • disintegrant starch, L-hydroxypropylcellulose, carboxy) Methylcellulose, croscarmellose sodium, cellulose glycolate, lubricating acid, etc., lubricants (magnesium stearate, etc.), dispersing aids (glucoher
  • a coating agent such as sucrose, gelatin, hydroxypropinoresenorelose, hydroxypropinolemethinoresenolerose phthalate
  • additives such as preservatives, antioxidants, coloring agents, sweeteners and the like which are commonly used can be added.
  • Liquid preparations for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs and the like.
  • one or more active substances are dissolved, suspended or emulsified in a commonly used diluent (such as purified water, ethanol or a mixture thereof).
  • this liquid preparation may contain a wetting agent, a suspending agent, an emulsifying agent, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like.
  • Injections for parenteral administration include solutions, suspensions, emulsions, and solid injections that are used by dissolving or suspending in a solvent for use. Injectables are used by dissolving, suspending or emulsifying one or more active substances in a solvent.
  • the solvent for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol and the like, and combinations thereof are used.
  • this injection contains a stabilizer, a solubilizing agent (daltamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), a suspending agent, an emulsifier, a soothing agent, a buffer, a preservative, and the like. Is also good. This Are prepared by sterilization or aseptic operation in the final step.
  • a sterile solid preparation for example, a lyophilized product, can be manufactured and then used after dissolving in sterilized or sterile distilled water for injection or other solvents before use.
  • Topical dosage forms for parenteral administration include, for example, ointments, gels, creams, compresses, patches, liniments, nebulizers (sprays), aerosols, inhalants, Nasal preparations and eye drops are included. These contain one or more active substances and are manufactured by known methods or commonly used formulations.
  • the ointment is manufactured by a known or commonly used formulation. For example, it is produced by grinding or melting one or more active substances in a base.
  • the ointment base is selected from known or commonly used ones. For example, higher fatty acids or higher fatty acid esters (adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristate ester, panolemitic acid ester, stenoate esterol, oleic ester, etc.), Waxes (beeswax, spermaceti, ceresin, etc.), surfactants (polyoxyethylene alkyl ether phosphate, etc.), higher alcohols (cetano monole, stearyl alcohol, cetostearyl alcohol, etc.), silicon oil (dimethyl polysiloxane) ), Hydrocarbons (hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), glyco
  • the gel is produced by a known or commonly used formulation. For example, it is produced by melting one or more active substances in a base.
  • Gel base Is selected from known or commonly used ones. For example, lower alcohols (ethanol, isopropyl alcohol, etc.), gelling agents (carboxymethinoresenolerose, hydroxyxechinoresenorelose, hydroxypropinoresenololose, ethylcellulose, etc.), medium A single agent or a mixture of two or more selected from a wetting agent (triethanolamine, diisopropanolamine, etc.), a surfactant (polyethylene glycol monostearate, etc.), gums, water, an absorption promoter, and a rash inhibitor Used as Further, they may contain preservatives, antioxidants, flavoring agents and the like.
  • the cream is produced by a known or commonly used formulation. For example, it is produced by melting or emulsifying one or more active substances in a base.
  • the cream base is selected from known or commonly used ones. For example, higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (2-hexyldecanol, cetanol, etc.), emulsifiers (polyoxyethylene) Alkyl ethers, fatty acid esters, etc.), water, absorption promoters, and rash inhibitors are used alone or as a mixture of two or more. Further, they may contain preservatives, antioxidants, flavoring agents and the like.
  • the poultice is produced by a known or commonly used formulation. For example, it is produced by melting one or more active substances in a base material, spreading the mixture on a support as a kneaded product, and producing the mixture.
  • the compress base is selected from known or commonly used ones. For example, thickeners (polyacrylic acid, polybutylpyrrolidone, gum arabic, starch, gelatin, methylcellulose, etc.), wetting agents (urea, glycerin, propylene glycol, etc.), fillers (kaolin, zinc oxide, talc, calcium) , Magnesium, etc.), water, dissolution aids, tackifiers, antifoggants, or a mixture of two or more.
  • thickeners polyacrylic acid, polybutylpyrrolidone, gum arabic, starch, gelatin, methylcellulose, etc.
  • wetting agents urea, glycerin, propylene glycol, etc.
  • fillers kaolin, zinc
  • the patch is produced by a known or commonly used formulation. For example, it is produced by melting one or more active substances in a base material and spreading and applying the resulting mixture on a support.
  • the base for the patch is selected from those known or commonly used. For example, one selected from a polymer base, oils and fats, higher fatty acids, tackifiers and rash preventive agents may be used alone or in combination of two or more. Further, it may contain a preservative, an antioxidant, a flavoring agent and the like.
  • the liniment is manufactured by a known or commonly used formulation.
  • one or more active substances may be dissolved or suspended in one or more selected from water, alcohols (ethanol, polyethylene glycol, etc.), higher fatty acids, glycerin, soap, emulsifiers, suspending agents, etc. It is manufactured by turbidity or emulsification. Further, they may contain preservatives, antioxidants, flavoring agents and the like.
  • Inhalants for parenteral administration include aerosols, powders for inhalation, solutions for inhalation (eg, solutions for inhalation, suspensions for inhalation, etc.), and forcepsell inhalations
  • the inhalation solution may be in the form of being dissolved or suspended in water or another suitable medium before use.
  • These inhalants can be applied using an appropriate inhalation container.
  • a nebulizer atomizer, nebulizer
  • an inhaler for powdered medicine can be used.
  • inhalants are manufactured according to a known method. For example, it is produced by mixing a compound or the like represented by the general formula (I) into a powder or a liquid, blending it into an inhalable propellant and Z or a carrier, and filling an appropriate inhaler container.
  • the compound represented by the general formula (I) or the like is powdered, it is powdered according to a conventional method.
  • a powder is prepared by pulverizing with lactose, starch, magnesium stearate, etc. into a fine powder and forming a uniform mixture or granulating.
  • the compound represented by the general formula (I) or the like When the compound represented by the general formula (I) or the like is liquefied, for example, the compound may be dissolved in a liquid carrier such as water, physiological saline or an organic solvent.
  • a conventionally known propellant for example, alternative CFCs, liquefied gas propellants (eg, fluorocarbons, liquefied petroleum, getyl ether, dimethyl ether, etc.), compressed gas (eg, soluble gas)
  • insoluble gas eg, nitrogen gas, etc.
  • the inhaler may further contain additives as needed. Any additive can be used as long as it is a commonly used additive, such as solid excipients (eg, sucrose, lactose, glucose, mannitol, sorbitol, maltose, cellulose, etc.), liquid excipients Agents (eg, propylene glycol), binders (starch, dextrin, methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyethylene glycol, sucrose, etc.), lubricants (eg, magnesium stearate, light silicic anhydride, talc, Flavoring agents (for example, citrate, menthol, daritylritin ammonium salt, glycine, orange powder, etc.), preservatives (for example, sodium benzoate, sodium bisulfite, methylparaben, propylparaben, etc.) ) , Stabilizers (eg, citrate, sodium citrate, etc.), suspending
  • a liquid for inhalation it is prepared by appropriately selecting a preservative, a coloring agent, a buffering agent, a tonicity agent, a thickening agent, an absorption promoter and the like as needed.
  • a preservative for example, lubricants, binders, excipients, coloring agents, preservatives, absorption enhancers (bile salts, chitosan, etc.) are appropriately selected as necessary.
  • the inhalant may contain a biodegradable polymer.
  • Biodegradable polymers include fatty acid ester polymers or copolymers thereof, polyacrylates, polyhydroxybutyrate, polyalkylene oxalates, polyorthoesters, polycarbonate and polyamino acids. These may be used alone or in admixture of one or more. Further, a phospholipid such as egg yolk lecithin, chitosan, or the like may be used.
  • Fatty acid ester polymers or copolymers thereof include polylactic acid, polydaricholic acid, polycuenic acid, polymalic acid and lactic acid-dalicholic acid copolymer, and one or more of these may be used in combination. it can.
  • polyanoacrylic acid ester polymonohydroxybutyric acid, polytrimethylene oxalate, polyorthoesterol, polyonoresocarbonate, polyethylenecarbonate, polyy-benzyl-L-glutamic acid and poly-L —
  • alanine is polylactic acid, polydarcholate, or lactic acid-glycolic acid copolymer, and more preferably, lactic acid-glycolic acid copolymer.
  • microcapsules, microspheres or nanospheres in which a drug is encapsulated may be prepared using a biodegradable polymer such as a lactic acid-glycolic acid copolymer.
  • Fibers for parenteral administration include one or more active substances, including suppositories for rectal administration and pessaries for vaginal administration, formulated in a conventional manner. .
  • the agent of the present invention has a bronchodilator effect, it preferably acts specifically on the bronchi or on the peritracheal tissues such as the trachea and lungs.
  • the form of the drug of the present invention is preferably, for example, an inhalant.
  • the compound represented by the general formula (I) has a strong bronchodilator effect and an anti-inflammatory effect. Have. Therefore, it is effective in preventing and / or treating respiratory diseases (eg, chronic obstructive pulmonary disease, adult respiratory distress syndrome emphysema, cystic fibrosis or chronic bronchitis, etc.).
  • respiratory diseases eg, chronic obstructive pulmonary disease, adult respiratory distress syndrome emphysema, cystic fibrosis or chronic bronchitis, etc.
  • Figure 1 shows that (2 S)-2,6-diaminohexanoic acid (5 Z)-7- ⁇ (1 R, 2R, 3R, 5R)-5-black mouth-2-[(1 E, 4 S ) —4— (1-ethylcyclobutyl) 4-hydroxy-1-pent-1-yl] -13-hydroxycyclopentyl ⁇ hepta-5-enoate (Compound A) It shows a contraction suppressing action.
  • FIG. 2 shows the inhibitory action of Compound A on TNF- ⁇ production.
  • FIG. 3 shows the elastase release inhibitory effect of Compound II.
  • FIG. 4 shows the airway contraction inhibitory effect of Compound A by inhalation administration.
  • FIG. 5 shows the airway contraction inhibitory effect of a microsphere preparation containing Compound A (Formulation A (Formulation Example 7)) by intratracheal administration.
  • FIG. 6 shows the drug residual rate in the lung over time after intratracheal administration of Formulation A (Formulation Example 7) and a physiological saline solution containing Compound A (Formulation B).
  • Guinea pigs anesthetized with pentoparbital sodium (75 mg / kg, ip) were treated with gallamine (10 mg / kg, iv), and the experiments were performed under artificial respiration.
  • Methacholine (10 zg / kg, iv) was used as an airway contraction-inducing substance, and the airway contraction response was determined by Konzett & Roessler fe (Konzett H, Roessler R. tenuicessenowskissen zu Arch Exp Pathol Pharmacol 1940; 195: 71-74).
  • Methacholine was induced 10 minutes before (pre), 15 minutes, 30 minutes, and 45 minutes after administration, and 15 minutes and 30 minutes after administration of the drug solution.
  • the control group (Control) was continuously administered with physiological saline intravenously.
  • the airway constriction was calculated as the airway constriction rate (% of pre), taking the methacholine-induced airway constriction before the start of administration as 100%.
  • the results are shown in Figure 1.
  • Compound A suppressed the metacholine-induced airway constriction in a dose-dependent manner. This indicates that the compound of the present invention has an airway dilating action.
  • Compound A is added to whole blood of humans collected with heparin (final concentration: 10 U / mL), pre-incubated at 37 ° C for 10 minutes, and then lipopolysaccharide (hereinafter abbreviated as LPS). (100 ng / mL).
  • LPS lipopolysaccharide
  • the blood was centrifuged, and TNF- ⁇ in the plasma was measured by the ELISA method. The result is shown in figure 2.
  • Compound A suppressed TNF- ⁇ production depending on the concentration. This indicates that the compound of the present invention has an anti-inflammatory effect.
  • Neutrophils obtained from heparin-collected human blood (final concentration 10 U / mL) by the density gradient method were used in the experiment.
  • the isolated neutrophils were resuspended in Hanks buffer.
  • fMLP N-honoleminole methionyl-leucyl-phenylalanine
  • cytochalasin B (final) Concentration: 0.1 / z mol / L / l / mol L).
  • the reaction was stopped by ice cooling, and the elastase activity in the supernatant after centrifugation was measured.
  • the results are shown in Figure 3.
  • Compound A suppressed the release of neutrophil elastase induced by fMLPZ cytochalasin B depending on the concentration. This indicated that the compound of the present invention has an anti-inflammatory effect.
  • Guinea pigs anesthetized with sodium pentopalbital (75 mg / kg, ip) were treated with gallamine (10 mg / kg , iv) and the experiments were performed under artificial respiration.
  • Methacholine (10 g / kg, iv) was used as an airway contraction-inducing substance, and the airway contraction response was measured by the Konzett & Roessler method.
  • the compound A solution (100 ⁇ g / mL) or physiological saline was atomized using an ultrasonic nebulizer and inhaled directly into the trachea for 5 minutes using a mechanical ventilator.
  • methacholine was administered at 5, 10, 15, 25, 35, 45 and 55 minutes after the end of compound inhalation to induce airway constriction.
  • the airway response obtained by obstructing the three-way cock attached to the upper part of the force neuron inserted into the trachea of the guinea pig was 100%, and the airway contraction rate (% of maximum) was calculated.
  • Fig. 4 shows the results. Compound A inhibited methacholine-induced airway constriction.
  • guinea pigs were anesthetized with sodium pentobarbital (50 mg / kg, ip), treated with gallamine (10 mg / kg, iv), and the airway contraction response was measured under artificial respiration.
  • the response was measured by the Konzett & Roessler method.
  • Airway contraction rate (% of maximum) was calculated assuming that the airway reaction obtained by closing the three-way cock attached to the upper part of the force inserted into the guinea pig trachea was 100%.
  • Fig. 5 shows the results.
  • Mike's mouth spheroid formulation containing Compound A used as a test substance (100 g / kg, Formulation Example 7 described below; hereinafter abbreviated as Formulation A) suppresses bronchoconstriction due to methacholine, and its effect is Lasted more than 6 hours.
  • Formulation A Compound A used as a test substance
  • the blood was killed by exsanguination, and the lungs including the bronchi were removed and frozen in liquid nitrogen. Under ice-cooling, acetonitrile in an amount 5 times the weight of the organ was added to the mixture, and the mixture was minced with scissors and crushed with a homogenizer (15000 rpm, 2 minutes). This homogenate solution was appropriately diluted with acetonitrile, and the supernatant was recovered by centrifugation.
  • Fig. 6 shows the results.
  • Formulation A When Formulation A was administered, the drug remained in the lungs for a longer time than in the case of administration of a physiological saline containing Compound A (10 / zgkg, hereinafter abbreviated as Formulation B).
  • the following components were mixed in a conventional manner, and the mixture was tableted to give 1,000 tablets each containing 5 mg of compound A and having a diameter of 6.5 mm, a thickness of 3 mm, and a weight of 100 mg.
  • the W / OZW emulsion was desolvated for about 3 hours with gentle stirring (drying in water).
  • the obtained microspheres were separated by filtration or centrifugation. This was washed with distilled water to remove free drug and PVA, freeze-dried, and sieved to obtain microsphere powder. Purified water was added to the powder and mixed to obtain a suspension for inhalation.
  • PVA polyvinyl alcohol
  • a homomixer (Em'Technic Co., Ltd.) was used to emulsify at a mixer rotation speed of about 15,000 rpm.
  • the WZOZW emulsion was desolvated for about 3 hours while gently stirring (drying in water).
  • the obtained microspheres were separated by filtration or centrifugation. This was washed with a 0.2% polysorbate 80 aqueous solution or distilled water to remove free drugs and PVA, freeze-dried, and sieved and pulverized to obtain microsphere powder.
  • a physiological saline solution was added to the powder and mixed to obtain a suspension.
  • the compounds represented by the general formula (I) have strong bronchodilator and anti-inflammatory effects. It is effective in preventing and / or treating respiratory diseases, for example, chronic obstructive pulmonary disease, adult respiratory distress syndrome emphysema, cystic fibrosis or chronic bronchitis.
  • respiratory diseases for example, chronic obstructive pulmonary disease, adult respiratory distress syndrome emphysema, cystic fibrosis or chronic bronchitis.
  • a bronchodilator effect and an anti-inflammatory effect are locally exerted, and side effects based on other effects can be avoided.
  • the bronchodilator effect is maintained by combining the biodegradable polymer. Therefore, a pharmaceutical composition for inhalation containing the compound represented by the general formula (I) and the like is also very useful.

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  • Veterinary Medicine (AREA)
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  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Pulmonology (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
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  • Otolaryngology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Broncho-dilatateurs, compositions pharmaceutiques pour inhalation et agents de prévention et/ou à visée thérapeutique des maladies pulmonaires obstructives chroniques, à base de composants détaillés dans la formule générale (I) qui ont des propriétés anti-inflammatoires et potentiellement broncho-dilatatrices, ainsi que de sels ou de promédicaments qui en sont dérivés, ou de composants de clathrate et de cyclodextrine ; ou à base d’autres médicaments dont les composants divers sont détaillés dans la formule générale (I) et combinés à un ou plusieurs autres médicaments (I) [chaque symbole correspond à sa description]. Les médicaments dont les composants sont détaillés dans la formule générale (I) sont efficaces dans le traitement des maladies respiratoires comme les maladies pulmonaires obstructives chroniques, le syndrome de détresse respiratoire de l’adulte, l’emphysème, la mucoviscidose et la bronchite chronique.
PCT/JP2005/001625 2004-01-30 2005-01-28 Broncho-dilatateurs Ceased WO2005072743A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2004023995A JP2007186423A (ja) 2004-01-30 2004-01-30 気管支拡張剤
JP2004-23995 2004-01-30
JP2004342546A JP2007186424A (ja) 2004-11-26 2004-11-26 気管支拡張剤
JP2004-342546 2004-11-26

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8648097B2 (en) 2008-03-12 2014-02-11 Ube Industries, Ltd. Pyridylaminoacetic acid compound
US8685986B2 (en) 2009-03-30 2014-04-01 Ube Industries, Ltd. Medical composition for treatment or prophylaxis of glaucoma

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WO2003009872A1 (fr) * 2001-07-23 2003-02-06 Ono Pharmaceutical Co., Ltd. Medicaments contenant un agoniste de ep4 en tant que principe actif destines aux maladies associees a une perte de la masse osseuse
JP2003171264A (ja) * 2001-12-07 2003-06-17 Taiyo Yakuhin Kogyo Kk マイクロカプセル及びその製造方法
WO2003074483A1 (fr) * 2002-03-05 2003-09-12 Ono Pharmaceutical Co., Ltd. Composes derives de 8 azaprostaglandine et medicaments contenant ceux-ci comme principe actif
WO2004032965A1 (fr) * 2002-10-10 2004-04-22 Ono Pharmaceutical Co., Ltd. Promoteurs de production de facteurs de reparation endogenes

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8648097B2 (en) 2008-03-12 2014-02-11 Ube Industries, Ltd. Pyridylaminoacetic acid compound
US8685986B2 (en) 2009-03-30 2014-04-01 Ube Industries, Ltd. Medical composition for treatment or prophylaxis of glaucoma

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