Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • 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
  • A61P17/00—Drugs for dermatological disorders
• • 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

Definitions

• the invention relates to new benzonaphthyridine N-oxides which are used in the pharmaceutical industry for the manufacture of medicaments.
• the invention thus relates to compounds of the formula I
• R1 is 1-4C-alkyl
• R2 is hydroxy, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or completely or predominantly fluorine-substituted 1-4C-alkoxy
• R3 denotes hydroxy, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or completely or predominantly 1-4C-alkoxy substituted by fluorine, or in which
• R2 and R3 together represent a 1-2C-alkylenedioxy group
• R4 represents a phenyl radical substituted by R5 and R6, where
• R5 is hydrogen, hydroxy, halogen, nitro, 1-4C-alkyl, trifluoromethyl or 1-4C-alkoxy
• R6 is CO-R7 or CO-R8, where
• R7 is hydroxy, 1-8C-alkoxy, 3-7C-cycloalkoxy or 3-7C-cycloalkylmethoxy and R8 is N (R81) R82, where R81 and R82 independently of one another are hydrogen, 1-7C-alkyl,
• 1-4C-alkyl represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples include the butyl, iso-butyl, sec-butyl, tert-butyl, propyl, isopropyl and preferably the ethyl and methyl radical.
• 1-4C-alkoxy represents radicals which, in addition to the oxygen atom, contain a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples include the butoxy, iso-butoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy radicals.
• 3-7C-Cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.
• 3-7C-Cycloalkylmethoxy stands for Cyclopropylmethoxy, Cyclobutylmethoxy, Cyclopentylmethoxy, Cyclohexylmethoxy and Cycloheptylmethoxy, of which Cyclopropylmethoxy, Cyclobutylmethoxy and Cyclopentylmethoxy are preferential.
• fluorine-substituted 1-4C-alkoxy are, for example, 2,2,3,3,3-pentafluoropropoxy, perfluoroethoxy, 1, 1, 2,2-tetrafluoroethoxy, 1, 2.2 -Trifluoreth- oxy-, the trifluoromethoxy, especially the 2,2,2-trifluoroethoxy and preferably the difluoromethoxy called.
• 1-2C-Alkylenedioxy stands for example for the methylenedioxy- (-0-CH 2 -0-) and the ethylenedioxy radical (-0-CH 2 -CH 2 -0-).
• Halogen in the sense of the invention is fluorine, chlorine and bromine.
• 1-8C-alkoxy represents radicals which, in addition to the oxygen atom, contain a straight-chain or branched alkyl radical having 1 to 8 carbon atoms. Examples include octyloxy, heptyloxy, hexyloxy, pentyloxy, methylbutoxy, ethylpropoxy, butoxy, iso-butoxy, sec-butoxy, tert-butoxy, propoxy and preferably isopropoxy -, ethoxy and methoxy.
• 1-7C-Alkyl stands for straight-chain or branched alkyl radicals with 1 to 7 carbon atoms. Examples include heptyl, isoheptyl (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), neohexyl (3,3-dimethylbutyl), pentyl, isopentyl (3-methylbutyl) , Neopentyl (2,2-dimethylpropyl), butyl, iso-butyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl radical.
• 3-7C-Cycloalkyl stands for the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl radical.
• 3-7C-Cycloalkylmethyl stands for a methyl radical which is substituted by one of the 3-7C-Cycloalkyl radicals mentioned above.
• Examples include the cycloalkylmethyl radicals cyclopropylmethyl, cyclobutylmethyl and cyclopentylmethyl.
• Suitable salts for compounds of the formula I - depending on the substitution - are all acid addition salts or all salts with bases. Particular mention should be made of the pharmacologically acceptable salts of the inorganic and organic acids and bases commonly used in galenics.
• Suitable as such are on the one hand water-soluble and water-insoluble acid addition salts with acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, maleic acid , Malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, the acids in the salt production - depending on whether it is a mono- or polybasic acid and depending depending on which salt is desired - in an equimolar or a different quantity ratio.
• acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfur
• salts with bases can also be used.
• alkali lithium, sodium, potassium
• calcium, aluminum, magnesium, titanium, ammonium, meglumine or guanidinium salts may be mentioned, the bases also being used here in salt production equimolar or a different ratio.
• Pharmacologically incompatible salts which may initially be obtained as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art.
• the compounds according to the invention and their salts if they are isolated, for example, in crystalline form, can contain different amounts of solvents.
• the invention therefore also includes all solvates and in particular all hydrates of the compounds of the formula I, and also all solvates and in particular all hydrates of the salts of the compounds of the formula I.
• R1 is 1-4C-alkyl
• Fluorine substituted 1-2C-alkoxy means, R3 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or entirely or predominantly by
• R4 is a phenyl radical substituted by R5 and R6, where
• R5 is hydrogen, hydroxy, halogen, nitro, 1-4C-alkyl, trifluoromethyl or 1-4C-alkoxy
• R6 is CO-R7 or CO-R8, where
• R7 is hydroxy, 1-8C-alkoxy, 3-7C-cycloalkoxy or 3-7C-cycloalkylmethoxy and R8 is N (R81) R82, where R81 and R82 independently of one another are hydrogen, 1-7C-alkyl,
• R1 means methyl
• R2 means 1-4C-alkoxy
• R3 means 1-4C-alkoxy
• R4 represents a phenyl radical substituted by R5 and R6, where
• R5 denotes hydrogen, hydroxy, 1-4C-alkyl or 1-4C-alkoxy
• R6 means CO-R7 or CO-R8, where
• R7 is hydroxy, 1-8C-alkoxy or 3-7C-cycloalkoxy and
• R8 denotes N (R81) R82, where R81 and R82 independently of one another denote hydrogen, 1-7C-alkyl or 3-7C-cycloalkyl, or where R81 and R82 together and including the nitrogen atom to which both are bonded represent a 1- Represent piperidyl, 1-hexahydroazepinyl or 4-morpholinyl radical, as well as the salts of these compounds.
• R1 means methyl
• R2 means methoxy, ethoxy or propoxy
• R3 means methoxy or ethoxy
• R4 represents a phenyl radical substituted by R5 and R6, where
• R5 means hydrogen
• R6 means CO-R7 or CO-R8, where
• R7 is hydroxy or 1-8C-alkoxy
• R8 is N (R81) R82, where R81 and R82 independently of one another are hydrogen or 1-4C-alkyl or 5-7C-cycloalkyl, or where R81 and R82 together and including the nitrogen atom to which both are bonded represent a 1- Piperidyl, 1-hexahydroazepinyl or 4-morpholinyl radical, and the salts of these compounds.
• R1 means methyl
• R2 means methoxy or ethoxy
• R3 means methoxy or ethoxy
• R4 represents a phenyl radical substituted by R5 and R6, where
• R5 means hydrogen
• R6 means CO-R7 or CO-R8, where
• R7 is hydroxy or 1-8C-alkoxy
• R8 is N (R81) R82, where R81 and R82 independently of one another are hydrogen or 1-4C-alkyl or 5-7C-cycloalkyl, or where R81 and R82 together and including the nitrogen atom to which both are attached form a 1- Piperidyl, 1-hexahydroazepinyl or 4-morpholinyl radical, and the salts of these compounds.
• Preferred compounds of formula I are those in which
• R1 means methyl
• R2 means ethoxy or propoxy
• R3 means methoxy or ethoxy
• R4 represents a phenyl radical substituted by R5 and R6, where
• R5 means hydrogen
• R6 means CO-R7 or CO-R8, where R7 means 1-4C-alkoxy and
• R8 denotes N (R81) R82, where R81 and R82 independently of one another denote 1-4C-alkyl or 5-7C-cycloalkyl, or where R81 and R82 together and including the nitrogen atom to which both are attached form a 1-piperidyl- or 1-Hexahydroazepinylrest represent, as well as the salts of these compounds.
• R1 means methyl
• R2 ethoxy means
• R3 means methoxy or ethoxy
• R4 represents a phenyl radical substituted by R5 and R6, where
• R5 means hydrogen
• R6 means CO-R7 or CO-R8, where
• R7 means 1-4C-alkoxy
• R8 denotes N (R81) R82, where R81 and R82 independently of one another denote 1-4C-alkyl or 5-7C-cycloalkyl, or where R81 and R82 together and including the nitrogen atom to which both are attached form a 1- Represent piperidyl or 1-hexahydroazepinylrest, as well as the salts of these compounds.
• R1 means methyl
• R2 means ethoxy or propoxy
• R3 means methoxy
• R4 represents a phenyl radical substituted by R5 and R6, where
• R5 means hydrogen
• R6 means CO-R8,
• R8 is N (R81) R82, where R81 and R82 independently of one another are 1-4C-alkyl, and the salts of these compounds.
• the compounds of the formula I are chiral compounds with chiral centers in positions 2, 4a and 10b Numbering:
• the invention relates to all eight conceivable diastereomers in any mixing ratio to one another.
• Preferred are the compounds of formula I in which the hydrogen atoms in positions 4a and 10b are in the cis position relative to one another.
• the invention further relates to a process for the preparation of the compounds of the formula I, in which R1, R2, R3 and R4 have the meanings indicated above, and their salts.
• the process is characterized in that compounds of the formula II
• R1, R2, R3 and R4 have the meanings given above, subject to N-oxidation and, if desired, subsequently converting the compounds of the formula I obtained into their salts, or if desired subsequently obtained salts of the compounds of the formula I into the free compounds transferred.
• the N-oxidation takes place in a manner familiar to the person skilled in the art, for example with the aid of hydrogen peroxide in methanol or with the aid of m-chloroperoxibenzoic acid in dichloromethane at room temperature.
• the reaction conditions required to carry out the process in detail are familiar to the person skilled in the art on the basis of his specialist knowledge.
• compounds of the formula I obtained can be converted into further compounds of the formula I by derivatization.
• the corresponding acids can be obtained from compounds of the formula I in which R4 is a phenyl radical substituted by R5 and R6 and R6 is an ester group by acidic or alkaline hydrolysis or by reaction with amines of the formula HN (R81) R82, in which R81 and R82 are the have the meanings given above, the corresponding amides are represented.
• the reactions are expediently carried out analogously to methods known to the person skilled in the art.
• R1, R2, R3 and R4 have the meanings given above, are prepared by a cyclocondensation reaction.
• the cyclocondensation is also carried out in a manner known per se to the person skilled in the art according to Bischler-Napieralski (for example as described in J. Chem. Soc, 1956, 4280-4282) in the presence of a suitable condensing agent, such as, for example, polyphosphoric acid, phosphorus pentachloride, phosphorus trichloride, phosphorus pentoxide , Thionyl chloride or preferably phosphorus oxytrichloride, in a suitable inert solvent, for example in a chlorinated hydrocarbon such as chloroform, or in a cyclic hydrocarbon such as toluene or xylene, or another inert solvent such as acetonitrile, or without further solvent using an excess of condensing agent, preferably at elevated temperature, in particular at the boiling point of the solvent or Condensing agent.
• a suitable condensing agent such as, for example, polyphosphoric acid, phosphorus pentachlor
• Enantiomerically pure compounds of the formula II can be separated in a known manner (for example by preparing and separating corresponding diastereoisomeric compounds) or by stereo selective synthesis methods are produced. Such separation processes and synthesis methods are described for example in EP 247 971 and in DE 42 17 401.
• R1, R2 and R3 have the meanings given above
• R4-CO-X in which R4 has the meaning given above
• X represents a suitable leaving group, preferably a chlorine atom.
• benzoylation is carried out by the Einhorn method, the Schotten-Baumann variant or as described in J. Chem. Soc. (C), 1971, 1805-1808.
• the substances according to the invention are isolated and purified in a manner known per se, e.g. such that the solvent is distilled off in vacuo and the residue obtained is recrystallized from a suitable solvent or subjected to one of the customary purification methods, such as, for example, column chromatography on a suitable carrier material.
• Salts are obtained by dissolving the free compound in a suitable solvent (e.g. a ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as ethanol or isopropanol), which contains the desired acid or base, or to which the desired acid or base is then added.
• the salts are removed by filtering, falling over, precipitating with a non-solvent for the Rungssalz or obtained by evaporation of the solvent.
• the salts obtained can be converted into the free compounds by alkalization or acidification, which in turn can be converted into salts. In this way, pharmacologically incompatible salts can be converted into pharmacologically acceptable salts.
• mp stands for melting point, h for hour (s), RT for room temperature, SF for molecular formula, MG for molecular weight, Ber. for calculated, found for found.
• s melting point
• RT room temperature
• SF molecular formula
• MG molecular weight
• Ber. calculated, found for found.
• the free base is obtained from the hydrochloride by extraction with dichloromethane after treatment with dilute sodium hydroxide solution.
• the compounds according to the invention have valuable pharmacological properties which make them commercially useful.
• selective inhibitors of types 3 and 4 of cyclic nucleotide phosphodiesterase PDE3, PDE4
• they are suitable on the one hand as bronchial therapeutic agents (for the treatment of airway obstructions due to their dilating and celiac stimulating effects, but also on the other hand, due to their respiratory rate or respiratory-enhancing effects), however, primarily for the treatment of diseases of an inflammatory nature, for example the respiratory tract (asthma prophylaxis), the skin, the intestine, the eyes and the joints, which are mediated by mediators such as interferons, members the tumor necrosis factor family, interleukins, chemokines, colony stimulating factors, growth factors, lipid mediators (e.g.
• PAF platelet activating factor
• bacterial factors e.g. LPS
• immunoglobulms oxygen radicals and relatives (e.g. nitrogen monoxide NO)
• biogenic nurses e.g. histamine, seroton in
• kinins e.g bradykinin
• neurogenic mediators such as substance P, neurokinin
• proteins such as granule constituents of leukocytes (including cationic proteins from eosinophils) and adherence proteins (eg integrins).
• the compounds according to the invention have smooth muscle cell relaxing effects, Eg in the area of the bronchial system, the blood circulation, and the urinary tract
• the compounds according to the invention are notable for low toxicity, good human acceptance, good enteral absorption and high bioavailability, a wide therapeutic range, the absence of essential side effects and good solubility in water
• the compounds according to the invention can be used as therapeutic agents in human and veterinary medicine, for example for the treatment and prophylaxis of the following diseases: acute and chronic (in particular inflammatory and allergen-induced) respiratory diseases of various origins (bronchitis, allergic bronchitis) , Bronchial asthma, emphysema, COPD), diseases with a restricted ciatality or increased requirements for ciliary clearance (bronchitis, cystic fibrosis), dermatoses (especially proliferative, inflammatory and allergic type) such as Pso ⁇ asis (vulga ⁇ s), toxic and allergic Contact eczema, atopic eczema, seborrheic eczema, lying simplex, sunburn, genital canal pruntus, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and flat-like pyoderma,
• the compounds according to the invention can also be used to treat hypertension disorders of various origins, such as pulmonary hypertension and the associated side effects, for the treatment of erectile dysfunction or colic of the kidneys and ureters in connection with kidney stones.
• cAMP-increasing effect they can also be used for diseases of the heart that can be treated by PDE inhibitors, such as heart failure, and as anti-thrombotic substances that inhibit platelet aggregation.
• Another object of the invention is a method for the treatment of mammals, including humans, who are suffering from one of the abovementioned diseases.
• the method is characterized in that the sick mammal is administered a therapeutically effective and pharmacologically acceptable amount of one or more of the compounds according to the invention.
• the invention further relates to the compounds according to the invention for use in the treatment and / or prophylaxis of diseases, in particular the diseases mentioned.
• the invention also relates to the use of the compounds according to the invention for the production of medicaments which are used for the treatment and / or prophylaxis of the diseases mentioned.
• the invention furthermore relates to medicaments for the treatment and / or prophylaxis of the diseases mentioned, which contain one or more of the compounds according to the invention.
• Another object of the invention is a commercial product, consisting of a customary seconding: därpacksch, a primary pack containing the medicament (for example an ampoule or a blister pack) and, if desired, a pack insert, the medicament exhibiting antagonistic action against cyclic nucleotide phosphodiesterases of type 3 and 4 shows and alleviates the symptoms of diseases which are associated with cyclic nucleotide phosphodiesterases of types 3 and 4, and on the secondary packaging and / or on the package insert of the commercial product on the suitability of the medicament for the prophylaxis or treatment of diseases, which are associated with cyclic nucleotide phosphodiesterases of types 3 and 4, is pointed out, and wherein the medicament contains one or more compounds of the formula I according to the invention.
• the substances according to the invention are also advantageously suitable for combination with other substances which stimulate cAMP, such as prostaglandins (PGE2, PGI2 or prostacyclin) and their derivatives, direct adenylate cyclase stimulators such as forskolin and related substances, or adenylate cyclase indirectly stimulating substances such as catecholamines and adrenergic receptor agonists, in particular beta-mimetics.
• PGE2 prostaglandins
• PGI2 or prostacyclin prostacyclin
• adenylate cyclase stimulators such as forskolin and related substances
• adenylate cyclase indirectly stimulating substances such as catecholamines and adrenergic receptor agonists, in particular beta-mimetics.
• they develop a synergistic, superadditive effect due to their cAMP degradation-inhibiting effect. This comes e.g. when used in combination with PGE2 to treat pulmonary hypertension.
• the pharmaceuticals are produced by methods known per se and familiar to the person skilled in the art.
• auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
• solvents for example antioxidants, dispersants, emulsifiers, preservatives, solubilizers or permeation promoters can be used.
• the compounds according to the invention are preferably also administered by inhalation.
• these are administered either directly as a powder (preferably in micronized form) or by atomizing solutions or suspensions containing them.
• the compounds according to the invention are used in particular in the form of those medicaments which are suitable for topical application.
• suitable pharmaceutical formulations include, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels or solutions.
• the pharmaceuticals according to the invention are produced by methods known per se.
• the active ingredients are dosed in the order of magnitude customary for PDE inhibitors.
• topical forms of application such as ointments
• the dose for inhalation is usually between 0.1 and 3 mg per day.
• the usual dose for systemic therapy is between 0.01 and 10 mg per kilogram and day.
• Activation of inflammatory cells is of particular importance when studying PDE4 inhibition at the cellular level.
• An example is the FMLP (N-formyl-methionylleucyl-phenyl-alanine) -induced superoxide production of neutrophil granulocytes, which can be measured as luminol-enhanced chemiluminescence.
• FMLP N-formyl-methionylleucyl-phenyl-alanine
• Substances which inhibit chemiluminescence as well as cytokine secretion and the secretion of inflammation-increasing mediators on inflammatory cells are those which inhibit PDE4 or PDE3 and PDE4.
• the latter isoenzyme of the phosphodiesterase families is particularly represented in granulocytes. Its inhibition leads to an increase in the intracellular cyclic AMP concentration and thus to the inhibition of cellular activation.
• the PDE4 inhibition by the substances according to the invention is thus a central indicator for the suppression of inflammatory processes.
• PDE activity was determined according to Thompson et al. (1) with some modifications (2).
• the test samples contained 40 mM Tris-HCl (pH 7.4), 5 mM MgCl 2 , 0.5 ⁇ M cAMP or cGMP, [ 3 H] cAMP or
• [ 3 H] cGMP (approx. 50,000 cpm / sample), the PDE isoenzyme-specific additives described in more detail below, the indicated concentrations of inhibitor and an aliquot of the enzyme solution for a total sample volume of 200 ⁇ l.
• Stock solutions of the compounds to be examined in DMSO were prepared in such concentrations that the DMSO content - to avoid influencing the PDE activity - did not exceed 1% by volume in the test samples. After 5 minutes of pre-incubation at 37 ° C, the reaction was started by adding the substrate (cAMP or cGMP). The samples were incubated for a further 15 min at 37 ° C. The reaction was stopped by adding 50 ⁇ l of 0.2 N HCl.
• Bovine brain PDE1 (Ca 2+ / calmodulin-dependent): The inhibition of this isoenzyme was investigated in the presence of Ca 2+ (1 mM) and calmodulin (100 nM) using cGMP as substrate (3).
• PDE2 (cGMP-stimulated) from rat hearts was purified chromatographically [Schudt et al. (4)] and in the presence of cGMP (5 ⁇ M) using cAMP as substrate.
• PDE3 cGMP-inhibited
• PDE5 cGMP-specific
• PDE4 cAMP-specific
• PMNL human polymorphonuclear leukocytes
• the PDE3 inhibitor motapizon (1 ⁇ M) was used to suppress the PDE3 activity emanating from contaminating platelets.
• the IC 50 values were taken from the concentration-inhibition curves by nonlinear regression
• Table 1 shows the inhibitory concentrations determined according to point A1 [inhibitory concentrations as -log IC 50 (mol / l)] for some compounds according to the invention.
• the numbers of the connections correspond to the numbers of the examples.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Pulmonology (AREA)
• Dermatology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Plural Heterocyclic Compounds (AREA)
• Pyridine Compounds (AREA)
• Glass Compositions (AREA)
• Saccharide Compounds (AREA)

Priority Applications (9)

Applications Claiming Priority (2)

Publications (1)

Family

ID=8231880

Family Applications (1)

Country Status (12)

Cited By (11)

Families Citing this family (19)

Citations (1)

Family Cites Families (1)

• 1999
  • 1999-04-27 DK DK99922133T patent/DK1075477T3/da active
  • 1999-04-27 US US09/673,649 patent/US6306869B1/en not_active Expired - Fee Related
  • 1999-04-27 EP EP99922133A patent/EP1075477B1/de not_active Expired - Lifetime
  • 1999-04-27 SI SI9930279T patent/SI1075477T1/xx unknown
  • 1999-04-27 WO PCT/EP1999/002827 patent/WO1999057118A1/de not_active Ceased
  • 1999-04-27 ES ES99922133T patent/ES2195571T3/es not_active Expired - Lifetime
  • 1999-04-27 AT AT99922133T patent/ATE234301T1/de not_active IP Right Cessation
  • 1999-04-27 JP JP2000547088A patent/JP2002513793A/ja not_active Withdrawn
  • 1999-04-27 AU AU39289/99A patent/AU3928999A/en not_active Abandoned
  • 1999-04-27 DE DE59904535T patent/DE59904535D1/de not_active Expired - Fee Related
  • 1999-04-27 CA CA002330738A patent/CA2330738A1/en not_active Abandoned
  • 1999-04-27 PT PT99922133T patent/PT1075477E/pt unknown

Patent Citations (1)

Also Published As

Similar Documents

Legal Events