EP1140098A2 - Composes heterocycliques d'azote tricycliques servant d'inhibiteurs de la pde iv - Google Patents

Composes heterocycliques d'azote tricycliques servant d'inhibiteurs de la pde iv

Info

Publication number
EP1140098A2
EP1140098A2 EP99959324A EP99959324A EP1140098A2 EP 1140098 A2 EP1140098 A2 EP 1140098A2 EP 99959324 A EP99959324 A EP 99959324A EP 99959324 A EP99959324 A EP 99959324A EP 1140098 A2 EP1140098 A2 EP 1140098A2
Authority
EP
European Patent Office
Prior art keywords
general formula
optionally
compounds
medicament
pde
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.)
Withdrawn
Application number
EP99959324A
Other languages
German (de)
English (en)
Inventor
Matthias Hoffmann
Birgit Jung
Ulrike Kuefner-Muehl
Christopher John Montague Meade
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.)
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
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 Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Publication of EP1140098A2 publication Critical patent/EP1140098A2/fr
Withdrawn legal-status Critical Current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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive 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
    • 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
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • 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
    • A61P35/00—Antineoplastic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to the use of tricyclic nitrogen heterocycles of the general formula I.
  • radicals R 2 and R 3 may have the meaning given in the following part of the description and in the claims.
  • Cyclic nucleotide phosphodiesterases degrade the second messenger cAMP and cGMP to 5'-AMP and ⁇ '-GMP.
  • the second messengers cAMP and cGMP trigger the activation of protein kinases and thus the phosphorylation of proteins.
  • the hydrolysis of cAMP and cGMP to the inactive nucleotides 5'-AMP and 5'-GMP consequently prevent the activation of the protein kinases.
  • Phosphodiesterases are divided into different PDE isoenzyme classes based on different substrate specificity, different kinetic properties etc.
  • the family of PDE l isoenzymes is activated via the intracellular receptor protein for Ca2 + ions Kalmodulin (Ca 2+ / Kalmodulin-stimulated PDE).
  • PDE II isoenzymes are cGMP-stimulated phosphodiesterases with low affinity for cAMP and cGMP.
  • the family of PDE III isoenzymes (cGMP-inhibited) is characterized by a high affinity for cAMP and cGMP.
  • the phosphodiesterases type IV (PDE IV) are cAMP-specific PDEs which have low affinity for cGMP and high affinity for cAMP.
  • PDE V isoenzymes are cGMP-specific with low affinity for cAMP.
  • PDE inhibitors influence the concentration of intracellular cAMP and cGMP. Of particular interest is the selective inhibition of
  • Phosphodiesterase type IV which leads to an increase in the concentration of intracellular cAMP.
  • Phosphodiesterase (PDE) type IV inhibitors are known from the prior art.
  • PDE Phosphodiesterase
  • One of the most prominent representatives of the compounds that selectively inhibit the PDE IV isoenzyme is rolipram, which has the following chemical structure.
  • PDE IV inhibitors cause vasodilation (reduced tone of the smooth muscles), have a partially inotropic effect and have anti-inflammatory properties. Accordingly, PDE IV inhibitors can have a therapeutic effect in the treatment and prophylaxis of diseases in which the above effects are desired and to be expected by increasing the cAMP concentration.
  • tricyclic heterocycles of the general formula (I) whose radicals R 1 , R 2 and R 3 are as defined below are selective inhibitors of type IV phosphodiesterase.
  • the invention consequently relates to the use of tricyclic nitrogen heterocycles of the general formula I.
  • R 1 Ci-Cs-alkyl, Cs-Cß-cycloalkyl, phenyi, benzyl or a 5- or 6-membered, saturated or unsaturated heterocyclic ring which can contain one or two heteroatoms selected from the group consisting of oxygen and nitrogen;
  • R 2 C-
  • R 3 Cj-Cö-alkyl, which is optionally substituted by C ⁇
  • Cs-Cß-cycloalkyl phenoxy or substituted by a 5- or 6-membered, saturated or unsaturated heterocyclic ring which can contain one or two heteroatoms selected from the group consisting of oxygen and nitrogen,
  • C5-C6-Cycloalkyl or phenyl or benzyl which is optionally substituted by C 1-4 alkoxy can optionally be in the form of their racemates, their enantiomers, in the form of their diastereomers and their mixtures, if appropriate in the form of their tautomers and, if appropriate, their pharmacologically acceptable
  • R 1 C-
  • R 3 C ⁇ -C4-alkyl, which is optionally by C-
  • -C4-alkoxy) phenyloxy, piperazine or pyrrole can be substituted, Cs-Cß-cycloalkyl or optionally substituted by C ⁇ -C4-alkoxy, phenyl or benzyl, can optionally be in the form of them Racemate, yours
  • Enantiomers in the form of their diastereomers and their mixtures, optionally in the form of their tautomers and, if appropriate, their pharmacologically acceptable acid addition salts.
  • R 2 is ethyl, propyl, allyl or butenyl
  • R 3 is ethyl, propyl, butyl, cyclopentyl, cyclohexylmethyl, benzyl, phenylethyl,
  • Phenoxymethyl, methoxybenzyl or N-pyrolylmethyl can mean optionally in the form of their racemates, their enantiomers, in the form of their diastereomers and their mixtures, optionally in the form of their tautomers and, if appropriate, their pharmacologically acceptable acid addition salts.
  • R 1 is ethyl, n-propyl, tert-butyl, cyclopentyl, 3-tetrahydrofuryl, N-morpholinyl or phenyl;
  • R 2 is ethyl or n-propyl
  • R 3 is ethyl, i-propyl, n-propyl, n-butyl, t-butyl, cyclopentyl, cyclohexylmethyl, benzyl, phenylethyl, phenoxymethyl, 4-methoxybenzyl or
  • N-Pyrollylmethyl can optionally be in the form of their racemates, their enantiomers, in the form of their diastereomers and their mixtures, optionally in the form of their tautomers and, if appropriate, their pharmacologically acceptable acid addition salts.
  • the compounds of the general formula (I) can be converted into their salts, in particular for pharmaceutical use, into their physiologically compatible salts with an inorganic or organic acid.
  • an inorganic or organic acid for example, succinic acid
  • Hydrobromic acid acetic acid, fumaric acid, maleic acid, methanesulfonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulfuric acid, tartaric acid or citric acid. Mixtures of the aforementioned acids can also be used.
  • alkyl groups also insofar as they are part of other radicals
  • branched and unbranched alkyl groups with 1 to 5 carbon atoms are considered, for example the following are mentioned: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. Butyl , tert-butyl, n-pentyl, isopentyl or neopentyl.
  • the abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. are also used for the groups mentioned above.
  • Cycloalkyl radicals with 5 or 6 carbon atoms are called cyclopentyl or cyclohexyl.
  • 5- or 6-membered, saturated or unsaturated Heterocyclic rings which may contain one or two heteroatoms selected from the group consisting of oxygen and nitrogen are mentioned: furan, tetrahydrofuran, tetrahydrofuranone, ⁇ -butylrolactone, ⁇ -pyran, ⁇ -pyran, dioxolane, tetrahydropyran, dioxane, pyrrole, pyrroline, Pyrrolidine, pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, morpholine, oxazole, isoxazole, oxazine, pyrazolidine.
  • the present invention aims at the use of the previously defined compounds of the general formula (I) for the manufacture of medicaments for the treatment or prophylaxis of diseases in which the selective inhibition of the PDE IV enzyme is indicated.
  • the present invention further aims at the use of compounds of the general formula (I) for the treatment or prophylaxis of diseases in which a therapeutically desired effect can be achieved by increasing the concentration of intracellular cAMP.
  • the present invention aims at the use of compounds of the general formula (I) as defined above for increasing the concentration of intracellular cAMP.
  • the use of the compounds of general formula (I) according to the above. Definitions for the manufacture of a medicament for increasing the concentration of intracellular cAMP is another aspect of the present invention.
  • PDE IV inhibitors have bronchodilatory or even anti-inflammatory effects in the lungs.
  • the compounds of general formula (I) according to the above. Definitions can therefore be used to treat asthma or CO. P.D. (chronic obstructive pulmonary disease).
  • PDE IV inhibitors inhibit eosinophil influx after allergic irritation.
  • the compounds of general formula (I) as defined above can consequently be used in the treatment of allergic diseases such as, for example, allergic rhinitis, allergic conjunctivitis and allergic eye diseases. Since PDE IV inhibitors also inhibit the release of cytokines such as TNF-alpha from macrophages, the compounds of general formula (I) defined above are effective in the treatment of diseases such as adult respiratory distress syndrome or inflammatory arthritis, where TNF release is a Role plays, to be expected.
  • the compounds of general formula (I) defined above can also be of therapeutic use for the treatment and prophylaxis of the diseases mentioned below: asthma, in particular asthma in the case of inflammation of the lungs, inflammation of the lungs and the respiratory tract, CO.
  • PD chronic obstructive pulmonary disease
  • cystic fibrosis chronic bronchitis
  • eosinophilic granuloma inflammatory skin diseases such as psoriasis, ischemia, endotoxic or septic shock, ulcerative colitis, Crohn's disease, rheumatoid arthritis, chronic glomerulonephritis, urticivitis vertebralitis, urticivitis, con Arteriosclerosis.
  • Table 1 summarizes the pharmacological data obtained for the compounds of the general formula (I). Based on Torphy et al. (1992) J. Pharmacol. Exp. Ther. 263: 1195.
  • Final volume of the assay 0.1 ml; Protein: between 2 ⁇ g / measuring point and 6 ⁇ g / measuring point (depending on the degree of purification of the enzyme); Incubation buffer: 40mM Tris-HCl (pH 7.8), 3mM MgCl2; Radioligand: 1 ⁇ Ci / ml [3H] cAMP; Incubation: 30 min at 30 ° C; Reference inhibitor: rolipram
  • the compounds of the general formula (I) can be used alone or in combination with other active compounds according to the invention, optionally also in combination with other pharmacologically active compounds.
  • Suitable forms of use are, for example, tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders.
  • Corresponding tablets can be obtained, for example, by mixing the active ingredient (s) with known auxiliaries, for example inert diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrants, such as corn starch or alginic acid, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc, and / or agents to achieve the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • auxiliaries for example inert diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrants, such as corn starch or alginic acid, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc,
  • coated tablets can be produced by coating cores produced analogously to the tablets with agents commonly used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the core can also consist of several layers in order to achieve a depot effect or to avoid incompatibilities.
  • the coated tablet to achieve a depot effect can consist of several layers, wherein the auxiliaries mentioned above for the tablets can be used.
  • Juices of the active substances or combinations of active substances according to the invention can additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar as well as a taste-improving agent, e.g. Flavorings, such as vanillin or orange extract, contain. They can also contain suspending aids or thickeners, such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
  • a sweetener such as saccharin, cyclamate, glycerol or sugar
  • a taste-improving agent e.g.
  • Flavorings such as vanillin or orange extract
  • suspending aids or thickeners such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
  • Injection solutions are used in the usual way, e.g. with the addition of preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, and filled into injection bottles or ampoules.
  • preservatives such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, and filled into injection bottles or ampoules.
  • the capsules containing one or more active ingredients or combinations of active ingredients can be produced, for example, by mixing the active ingredients with inert carriers, such as milk sugar or sorbitol, and encapsulating them in gelatin capsules.
  • Suitable suppositories can be produced, for example, by mixing them with carrier agents such as neutral fats or polyethylene glycol or its derivatives.
  • a therapeutically effective daily dose is between 1 and 800 mg, preferably 10-300 mg per adult.
  • the finely ground active ingredient, milk sugar and part of the corn starch are mixed together.
  • the mixture is sieved, whereupon it is moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried.
  • the granules, the rest of the corn starch and the magnesium stearate are sieved and mixed together.
  • the mixture is compressed into tablets of a suitable shape and size.
  • the finely ground active ingredient, part of the corn starch, milk sugar, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and processed with the rest of the corn starch and water to form a granulate, which is dried and sieved.
  • the sodium carboxymethyl starch and the magnesium stearate are added, and the mixture is mixed and pressed into tablets of a suitable size.
  • the active ingredient, corn starch, milk sugar and polyvinylpyrrolidone are mixed well and moistened with water.
  • the moist mass is pressed through a sieve with a 1 mm mesh size, dried at approx. 45 ° C and then the granules are passed through the same sieve.
  • domed dragee cores with a diameter of 6 mm are pressed on a tablet machine.
  • the dragee cores thus produced are coated in a known manner with a layer consisting essentially of sugar and talc.
  • the finished coated tablets are polished with wax.
  • the active ingredient is dissolved in water at its own pH or, if appropriate, at pH 5.5 to 6.5, and sodium chloride is added as the isotonic agent, the solution obtained is filtered pyrogen-free and the filtrate is filled into ampoules under aseptic conditions, which are then sterilized and sealed .
  • the ampoules contain 5 mg, 25 mg and 50 mg of active ingredient.
  • the hard fat is melted.
  • the milled active substance is homogeneously dispersed at 40 ° C. It is cooled to 38 ° C and poured into weakly pre-cooled suppository molds.
  • Distilled water is heated to 70 ° C. Hydroxyethyl cellulose is dissolved therein with stirring. After adding sorbitol solution and glycerin, the mixture is cooled to room temperature. Sorbic acid, aroma and substance are added at room temperature. To vent the suspension, evacuate with stirring.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Urology & Nephrology (AREA)
  • Rheumatology (AREA)
  • Cardiology (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Ophthalmology & Optometry (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Vascular Medicine (AREA)
  • Otolaryngology (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation de composés hétérocycliques d'azote tricycliques de formule générale (I) comme médicament à effet inhibiteur de la PDE IV, les radicaux R<1>, R<2> et R<3> possédant la signification donnée dans la description et dans les revendications.
EP99959324A 1998-12-17 1999-11-24 Composes heterocycliques d'azote tricycliques servant d'inhibiteurs de la pde iv Withdrawn EP1140098A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19858331A DE19858331A1 (de) 1998-12-17 1998-12-17 Tricyclische Stickstoffheterocyclen als PDE IV Inhibitoren
DE19858331 1998-12-17
PCT/EP1999/009086 WO2000035428A2 (fr) 1998-12-17 1999-11-24 Composes heterocycliques d'azote tricycliques servant d'inhibiteurs de la pde iv

Publications (1)

Publication Number Publication Date
EP1140098A2 true EP1140098A2 (fr) 2001-10-10

Family

ID=7891477

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99959324A Withdrawn EP1140098A2 (fr) 1998-12-17 1999-11-24 Composes heterocycliques d'azote tricycliques servant d'inhibiteurs de la pde iv

Country Status (5)

Country Link
EP (1) EP1140098A2 (fr)
JP (1) JP2002532411A (fr)
CA (1) CA2345752A1 (fr)
DE (1) DE19858331A1 (fr)
WO (1) WO2000035428A2 (fr)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7776315B2 (en) 2000-10-31 2010-08-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pharmaceutical compositions based on anticholinergics and additional active ingredients
MY140561A (en) 2002-02-20 2009-12-31 Nycomed Gmbh Dosage form containing pde 4 inhibitor as active ingredient
DE10207160A1 (de) * 2002-02-20 2003-12-18 Altana Pharma Ag Darreichungsform enthaltend PDE 4-Hemmer als Wirkstoff
US7071333B2 (en) 2003-07-30 2006-07-04 Bristol-Myers Squibb Company Triazolopurine-based tricyclic compounds and pharmaceutical compositions comprising same
WO2006075748A1 (fr) * 2005-01-17 2006-07-20 Santen Pharmaceutical Co., Ltd. Agent therapeutique pour maladie conjonctivale allergique
WO2008103357A1 (fr) * 2007-02-21 2008-08-28 E. I. Du Pont De Nemours And Company 1,2,4-triazoles tricycliques fongicides
AR107456A1 (es) * 2016-02-12 2018-05-02 Lilly Co Eli Inhibidor de pde1

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5744473A (en) * 1996-09-16 1998-04-28 Euro-Celtique, S.A. PDE IV inhibitors: "bis-compounds"
DE19826843A1 (de) * 1998-06-16 1999-12-23 Boehringer Ingelheim Pharma Neue Imidazotriazolopyrimidine, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
AU9347498A (en) * 1998-08-27 2000-03-21 Boehringer Ingelheim Pharma Kg Imidazotriazolopyrimidines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0035428A2 *

Also Published As

Publication number Publication date
CA2345752A1 (fr) 2000-06-22
JP2002532411A (ja) 2002-10-02
WO2000035428A3 (fr) 2000-09-28
WO2000035428A2 (fr) 2000-06-22
DE19858331A1 (de) 2000-06-21

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