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WO2003008396A1 - Derive d'oxazine actif sur le plan optique - Google Patents

Derive d'oxazine actif sur le plan optique Download PDF

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Publication number
WO2003008396A1
WO2003008396A1 PCT/JP2002/007171 JP0207171W WO03008396A1 WO 2003008396 A1 WO2003008396 A1 WO 2003008396A1 JP 0207171 W JP0207171 W JP 0207171W WO 03008396 A1 WO03008396 A1 WO 03008396A1
Authority
WO
WIPO (PCT)
Prior art keywords
tetrahydro
methoxyphenyl
preventing
substance
methyl
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/JP2002/007171
Other languages
English (en)
Japanese (ja)
Inventor
Shinji Ina
Kenjiro Yamana
Naomi Suzuki
Takeshi Otani
Mayumi Iino
Akane Takahama
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.)
Kowa Co Ltd
Original Assignee
Nikken Chemicals 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 Nikken Chemicals Co Ltd filed Critical Nikken Chemicals Co Ltd
Publication of WO2003008396A1 publication Critical patent/WO2003008396A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K31/33—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
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
    • C07D265/08—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D265/10—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen atoms directly attached to ring carbon atoms

Definitions

  • the present invention relates to a novel compound having a phosphodiesterase (PDE) IV inhibitory activity and a pharmaceutical composition containing the same.
  • PDE phosphodiesterase
  • the 2-one does not have an acidic or basic functional group, and its separation cannot be achieved by a diastereomer optical resolution method using an optically active organic base or organic acid. Therefore, the difference in the phosphodiesterase (PDE) IV inhibitory action and the side effect was not known and could not be examined.
  • PDE phosphodiesterase
  • the present invention relates to (1) 16- [3- (2-Indanyloxy) -14-methoxyphenyl] —6-methyl-1,3,4,5,6-tetrahydro-1 2H—1,3—o It relates to xazin-1-one or a hydrate or a solvate thereof.
  • the present invention also relates to (1) 16- [3- (2-Indanyloxy) -14-methoxyphenyl] -16-methyl-1,3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one And a pharmaceutical comprising, as an active ingredient, a substance selected from the group consisting of hydrates and solvates thereof.
  • a pharmaceutical comprising, as an active ingredient, a substance selected from the group consisting of hydrates and solvates thereof.
  • PDE phosphodiesterase
  • the medicaments of the present invention provide inflammatory diseases such as asthma, dermatitis, chronic obstructive pulmonary disease; multiple sclerosis; It is useful as a medicament for treating and / or preventing or preventing autoimmune diseases such as rheumatism.
  • the compound of the present invention has an ameliorating effect on allergic conjunctivitis, and based on this, the medicament of the present invention is used for the treatment and / or treatment of allergic eye diseases such as allergic conjunctivitis, spring catarrh, and spring keratoconjunctivitis. Useful as a medicament for prevention.
  • the compound of the present invention exhibits an inhibitory effect on TNF- ⁇ production.
  • the medicament of the present invention is useful for treating allergy, bronchial asthma, sepsis, arthritis (rheumatoid arthritis, osteoarthritis, etc.), diabetes, It is useful as a medicament for treating and / or preventing psoriasis, Crohn's disease and ulcerative colitis.
  • the compound of the present invention exhibits NKi receptor antagonism.
  • the medicament of the present invention provides pain; vomiting; asthma, chronic obstructive pulmonary disease, dermatitis (atopic dermatitis, contact dermatitis) , Deprived measles, etc.), and is useful as a medicament for treating and preventing or preventing inflammatory diseases such as allergic eye disease and arthritis.
  • the present invention provides (1) -6- [3- (2-indanyloxy) -14-methoxyphenyl] -16-methyl-3,4,5, Use of a substance selected from the group consisting of 6-tetrahydro-2H-1,3-oxazin-12-one and hydrates and solvates thereof; a phosphodiesterase (PDE) IV inhibitor containing the above substance; An ameliorating agent for allergic conjunctivitis containing the above substance; a TNF-a production inhibitor containing the above substance; and an NI ⁇ receptor antagonist containing the above substance are provided.
  • PDE phosphodiesterase
  • a method for treating and / or preventing an inflammatory disease such as asthma, dermatitis, or chronic obstructive pulmonary disease, multiple sclerosis, or an autoimmune disease such as rheumatism Administering to a mammal, including a human, an amount;
  • a method for ameliorating allergic conjunctivitis in a mammal, including a human comprising the step of administering an effective amount of the above substance to a mammal, including a human;
  • a method for treating and / or preventing allergic eye diseases such as allergic conjunctivitis, spring catarrhal, and spring keratoconjunctivitis, comprising the steps of treating the above substance and administering a Z or prophylactically effective amount to mammals including humans. ;
  • a method for suppressing the production of TNF-a in a mammal including a human comprising a step of administering an effective amount of the above substance to a mammal including a human;
  • a method for antagonizing ⁇ ⁇ receptor in a mammal L including mammals comprising a step of administering an effective amount of the above substance to mammals including humans;
  • Methods for treating and / or preventing inflammatory diseases such as pain, vomiting, or asthma, chronic obstructive pulmonary disease, dermatitis (atopic dermatitis, contact dermatitis, juniper, etc.), allergic eye disease, or arthritis
  • administering a therapeutic and / or prophylactically effective amount of said substance to a mammal, including a human.
  • optically pure compound of the present invention can be prepared, for example, by using a high-performance liquid chromatography (HPLC) to prepare a racemic product produced by the method described in International Publication WO98 / 05344 in the following Examples.
  • HPLC high-performance liquid chromatography
  • two types of optically active forms [ie, (1) 16- [3- (2-indanyloxy) -14-methoxyphenyl] -16-methyl-3,4 , 5,6-Tetrahydro-2H-1,3-oxazine-12-one and (+)-6- [3- (2-Indanyloxy) —4-methoxypheninole] -16-methyl-3,4,5 , 6-tetrahydro-2H-1,3-oxazine-1-2-one]. Further, by recrystallizing the obtained optically active substance with various solvents as needed, it is possible to obtain an optically active substance with higher purity.
  • Recrystallization of the optically active substance is performed using a single solvent such as methanol, ethanol, isopropanol, ptanol, acetone, ethynole acetate, chlorophonolem, n-hexane, cyclohexane, etc., or a mixed solvent combining two or more solvents.
  • a single solvent such as methanol, ethanol, isopropanol, ptanol, acetone, ethynole acetate, chlorophonolem, n-hexane, cyclohexane, etc., or a mixed solvent combining two or more solvents.
  • the optically active substance obtained by the above method is (1) one-piece [(one) one 6- [3- (2-indanyloxy) -14-methoxyethoxy-nore] 16-methyl-3,4,5,6-te Abbreviations for trahydro-2H—1, .3-oxazin-1-one] and (+) — body [(+)-16] [3- (2-indanoleoxy) -14-methoxyphenyl] 16— Methylo
  • (1) one body has PDE IV inhibitory activity and anti-asthmatic effect about twice that of racemic body, whereas (+) — body has about 1/3 of racemic body Has an anti-asthmatic effect of about 1/4 or less, and has a pharmacological activity that is considerably weaker, but shows toxicity similar to that of the racemic form.
  • the monolith is preferable because it has a significantly higher solubility in water than the racemic form, which increases the possibility of being used as various liquid preparations, and may also improve the absorption in the digestive tract and the like.
  • the monotherapy has an improving effect on allergic conjunctivitis, a TNF-a production inhibitory effect, and an NK; ⁇ receptor antagonistic effect.
  • the usefulness of the racemate as a PDE IV inhibitor and an anti-asthmatic drug is disclosed in International Publication WO98 / 045354, but (1) a drug for treating allergic eye diseases, It is not suggested or taught to be useful as a TNF-production inhibitor or an NKI receptor antagonist.
  • a medicine containing the compound of the present invention as an active ingredient a substance selected from the group consisting of optically active compounds obtained by the above method and hydrates and solvates thereof may be used alone. Alternatively, the above substance can be mixed with a pharmaceutically acceptable carrier to prepare a pharmaceutical composition in an appropriate form.
  • compositions suitable for systemic administration include, for example, pharmaceutical compositions suitable for oral administration such as granules, powders, tablets, pills, hard capsules, soft capsules, syrups, emulsions, suspensions, or liquids And pharmaceutical compositions suitable for parenteral administration such as injections (intravenous, intramuscular, subcutaneous), drops, ointments, suppositories, aerosols, inhalants and the like.
  • pharmaceutical compositions suitable for topical administration include eye drops, eye ointments, ointments, suppositories, aerosols, inhalants and the like.
  • one or more additives for pharmaceutical preparations as necessary, for example, a binder, a lubricant, a disintegrant, a preservative, a buffer, a thickener, and a dissolution agent
  • a binder for example, a binder, a lubricant, a disintegrant, a preservative, a buffer, a thickener, and a dissolution agent
  • additives for preparations such as auxiliaries, chelating agents, stabilizers, pH adjusters, and isotonic agents may be used.
  • compositions for oral administration include: Excipients such as sucrose, microcrystalline cellulose, glucose, corn starch, sucrose, sorbitol, mannitol, erythritol, disintegrants such as calcium carboxymethylcellulose, hydroxypropylcellulose, calcium stearate, magnesium stearate, talc Lubricants such as polyethylene glycol, hydrogenated oil, hydroxypropyl cellulose, hydroxypropinolemethinoresenolellose, canoleboximetinolesenorelose, polyvinylinoleanolol, gelatin, gum arabic
  • a desired dosage form can be prepared using a humectant such as, for example, a surfactant or a flavoring agent, if necessary.
  • a diluent such as water, ethanol, glycerin, propylene glycol, polyethylene glycol, agar, or tragacanth is used, and if necessary, a solubilizing agent (polybutylene) is used.
  • Pyrrolidone polyoxyethylene hydrogenated castor oil, polyethylene glycol, polysorbate 80, polyoxyethylene monostearate, etc.
  • preservatives chlorobutanol, sodium dehydroacetate, Benzalkonium chloride, chlorinated cetylpyridinium, phenyl alcohol, paraoxybenzoic acid esters, bezetonium chloride, etc.
  • buffers borate buffer, phosphate buffer, carbonate buffer, acetate buffer
  • Agents citrate buffer, etc.
  • stabilizers sodium edetate, sodium bisulfite, etc.
  • pH adjusters sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, acetic acid, citrate, phosphorus Acids, etc.
  • isotonic agents sodium chloride, sodium chloride, glycerin, polyhydric alcohol, sorbitol, mannitol, glucose, etc.
  • the dose of the medicament of the present invention when orally administered as a preparation for systemic administration, is usually 0.01 to 1000 mg per day based on the weight of the compound of the present invention for an adult, and is preferably Is 0.01 to 100 mg. It is preferable that the dosage be appropriately increased or decreased depending on the age, medical condition, symptom, presence / absence of co-administered drug, and the like.
  • the daily dose may be administered once a day or divided into two or three times a day at appropriate intervals, or may be administered intermittently every few days. When used as an injection for systemic administration, it is preferred that the compound of the present invention be administered continuously or intermittently to adults in a single dose of 0.001 to 100 mg.
  • the daily dose for an inhalant is usually 0.001 to 300 mg, preferably 0.001 to 30 mg, for an adult.
  • the daily dose for an inhalant is usually 0.001 to 300 mg, preferably 0.001 to 30 mg, for an adult.
  • it is usually used at a concentration of 0.01 to 3.0 ⁇ /%, and in the case of eye ointment, it is usually used at a concentration of 0.01 to 10.0 wZ v%.
  • the dosage is preferably increased or decreased as appropriate depending on the age, medical condition, symptom, presence / absence of co-administered drug, and the like.
  • it can be administered once or several times a day.
  • PDE phosphodiesterase
  • PDE isozymes type I, type III, type IV and type V
  • the type I PDE used was purchased from Sigma.
  • PDE isozymes of types III, IV and V were partially purified from platelets (types III and V) or neutrophils (type IV) collected from rats.
  • Each enzyme source was 2 OmM bistris, EDTA (ethylenediamine tetraacetic acid) 2 mM N PMSF (Fermethylsulfonylfluoride) 0.1 mM, 2-mercaptoethanol 5 mM, Pepstatin 0.000 lmM, Roy Peptin is homogenized in a buffer ( ⁇ 6.5) containing 0.01 mM, centrifuged at 300000 XG for 30 minutes, and the centrifuged supernatant obtained is subjected to an exchange column (Q Sepharose Fast). Flow, manufactured by FANOLEMASIA), and eluted with 0-1% sodium acetate. Partially purified isozymes were identified by examining the effect of each known selective inhibitor.
  • test substance was dissolved in DMS O (dimethyl sulfoxide) and added to 5 OmM Tris-HCl buffer containing 5 mM magnesium chloride. Additional PDE Aisozaimu and 3 H- c AMP in the reaction solution (III type, when the type IV PDE) or 3 H- c GMP (I-type, when the V-PDE) was added as a substrate, at 3 0 ° C The reaction was performed for 30 minutes. After the reaction, the reaction was stopped by immersing it in a boiling solution at 100 degrees for 5 minutes.
  • Antigen-induced airway contraction inhibitory action anti-asthmatic action
  • Wistar rats (Clear Japan) were used for the experiment. It albumen albumin which was suspended (OA, Sigma) 1 0 0 mu ⁇ and 1 0 mg Mizusani ⁇ aluminum (Alum, manufactured by PIERCE Co.) in physiological saline of 1 m L, administered intraperitoneally to rats Sensitized by A Lergogenic conjunctivitis was induced by instillation of 10 ⁇ L of OA adjusted to a concentration of 3 OmgZniL with physiological saline in rats 3 weeks or more after the sensitization day.
  • OA albumen albumin which was suspended
  • OA 1 0 0 mu ⁇
  • Mizusani ⁇ aluminum Alum, manufactured by PIERCE Co.
  • the drug was suspended in saline at a concentration of 1.0% (w / v) and instilled 10 minutes before OA induced conjunctivitis (diphenhydramine was added as a positive control at 0.3% (w / v). ) was suspended in physiological saline and instilled 10 minutes before conjunctivitis was induced by OA).
  • the effect of the drug was measured by counting the number of gestures (Itch-Scratch response: considered to be an index of itch) observed in the hind limb during 20 minutes after instillation of OA. The suppression rate was determined.
  • Control group physiological saline was instilled 10 minutes before inducing conjunctivitis with ⁇ A in rats sensitized beforehand. '
  • Rats were bled into heparin-treated test tubes under pentobarbital anesthesia. Add an equal volume of RPMI-1640 medium to the collected blood, aliquot into 24 liters, add solvent (DMSO) or test drug dissolved in solvent, and add 30 minutes at 37 ° C, 5% . ⁇ ⁇ Pre-incubation was performed in 2 .
  • the reaction LP S a Li Po polysaccharide
  • Start by ⁇ Ka ⁇ 4 hours, subjected to incubation at 37 ° C, 5% C_ ⁇ 2
  • the reaction was stopped by ice bath. After stopping the reaction, the mixture was centrifuged at 3000 rpm at 4 ° C for 15 minutes, and TNF- ⁇ in the supernatant was measured by ELISA. Study drug The activity was evaluated by determining the production inhibition rate with respect to the solvent control group, and the test drug concentration that inhibited TNF- ⁇ production by 50%.
  • Affinity for the receptor was determined by measuring the inhibition of [3 ⁇ 4] SR140333 binding.
  • the test substance dissolved in DMS0 and [3 ⁇ 4] SR140333 (final concentration 0.25 nM) were added to the NK receptor sample described above, and 25. After incubating for 90 minutes at C, the solution was suction-filtered with a glass filter, washed three times with 1 mL of 50 mM Tris-HC1 buffer pH 7.4, and the radioactivity on the filter was measured with a liquid scintillation counter.
  • the test substance was added to the final concentration of 10 ⁇ M of caffeine, and the binding inhibitory activity of [3 ⁇ 4] SR140333 was measured. '
  • the compound of the present invention has about twice the phosphodiesterase (PDE) IV inhibitory action and anti-asthmatic action as compared to the racemic form, and has a remarkably higher solubility in water as compared to the racemic form. It is extremely useful as an active ingredient of a medicament for treating and / or treating inflammatory diseases such as chronic obstructive pulmonary disease.
  • PDE phosphodiesterase

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Immunology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne (-)-6-(3-(2-indanyloxy)-4-méthoxyphényl)-6-méthyl-3,4,5,6-tétrahydro-2H-1,3-oxazin-2-one, un hydrate et solvate associés ; ainsi que des médicaments renfermant le composé susmentionné comme principe actif, ces médicaments étant utiles dans le traitement et/ou la prévention de maladies inflammatoires, telles que l'asthme et la broncho-pneumopathie chronique obstructive.
PCT/JP2002/007171 2001-07-16 2002-07-15 Derive d'oxazine actif sur le plan optique Ceased WO2003008396A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP2001214650 2001-07-16
JP2001-214650 2001-07-16
JP2001-279632 2001-09-14
JP2001279632 2001-09-14
JP2002105569 2002-04-08
JP2002-105569 2002-04-08

Publications (1)

Publication Number Publication Date
WO2003008396A1 true WO2003008396A1 (fr) 2003-01-30

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PCT/JP2002/007171 Ceased WO2003008396A1 (fr) 2001-07-16 2002-07-15 Derive d'oxazine actif sur le plan optique

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Country Link
WO (1) WO2003008396A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9120788B2 (en) 2013-02-19 2015-09-01 Pfizer Inc. Azabenzimidazole compounds
US9598421B2 (en) 2014-08-06 2017-03-21 Pfizer Inc. Imidazopyridazine compounds
US10131669B2 (en) 2014-07-24 2018-11-20 Pfizer Inc. Pyrazolopyrimidine compounds

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5728686A (en) * 1995-11-02 1998-03-17 Hoechst Aktiengesellschaft Alkylxanthine phosphonates and alkylxanthine phosphine oxides and their use as pharmaceuticals
EP0928789A1 (fr) * 1996-07-31 1999-07-14 Nikken Chemicals Company, Limited Derives de 6-phenyltetrahydro-1,3-oxazine-2-one et compositions medicinales a base de ces composes
WO1999047505A1 (fr) * 1998-03-14 1999-09-23 Byk Gulden Lomberg Chemische Fabrik Gmbh Inhibiteurs de pde iii/iv a base de phtalazinones
JP2001151673A (ja) * 1999-09-06 2001-06-05 Nikken Chem Co Ltd 吸入用粉末製剤の製造方法
JP2002179572A (ja) * 2000-10-06 2002-06-26 Nikken Chem Co Ltd アレルギー性眼疾患治療剤

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5728686A (en) * 1995-11-02 1998-03-17 Hoechst Aktiengesellschaft Alkylxanthine phosphonates and alkylxanthine phosphine oxides and their use as pharmaceuticals
EP0928789A1 (fr) * 1996-07-31 1999-07-14 Nikken Chemicals Company, Limited Derives de 6-phenyltetrahydro-1,3-oxazine-2-one et compositions medicinales a base de ces composes
WO1999047505A1 (fr) * 1998-03-14 1999-09-23 Byk Gulden Lomberg Chemische Fabrik Gmbh Inhibiteurs de pde iii/iv a base de phtalazinones
JP2001151673A (ja) * 1999-09-06 2001-06-05 Nikken Chem Co Ltd 吸入用粉末製剤の製造方法
JP2002179572A (ja) * 2000-10-06 2002-06-26 Nikken Chem Co Ltd アレルギー性眼疾患治療剤

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TOMOAKI YOSHIMURA: "Hito tankakukyu yurai cytokine sansei no yakubutsu ni yoru seigyo ni kansuru kenkyu", JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, vol. 120, no. 12, 1 December 2000 (2000-12-01), pages 1277 - 1290, XP002960783 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9120788B2 (en) 2013-02-19 2015-09-01 Pfizer Inc. Azabenzimidazole compounds
US9815832B2 (en) 2013-02-19 2017-11-14 Pfizer Inc. Azabenzimidazole compounds
US10131669B2 (en) 2014-07-24 2018-11-20 Pfizer Inc. Pyrazolopyrimidine compounds
US9598421B2 (en) 2014-08-06 2017-03-21 Pfizer Inc. Imidazopyridazine compounds
US10077269B2 (en) 2014-08-06 2018-09-18 Pfizer Inc. Imidazopyridazine compounds
US10669279B2 (en) 2014-08-06 2020-06-02 Pfizer Inc. Imidazopyridazine compounds

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