EP0804192A1 - Pharmaceutical preparations for tumour necrosis factor (tnf) inhibition - Google Patents

Pharmaceutical preparations for tumour necrosis factor (tnf) inhibition

Info

Publication number
EP0804192A1
EP0804192A1 EP96902870A EP96902870A EP0804192A1 EP 0804192 A1 EP0804192 A1 EP 0804192A1 EP 96902870 A EP96902870 A EP 96902870A EP 96902870 A EP96902870 A EP 96902870A EP 0804192 A1 EP0804192 A1 EP 0804192A1
Authority
EP
European Patent Office
Prior art keywords
compounds
formula
alkyl
treatment
diseases
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Withdrawn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
EP96902870A
Other languages
German (de)
French (fr)
Inventor
Hermann Graf
Helmut Wachtel
Herbert Schneider
Daryl Faulds
Daniel Perez
Harald Dinter
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.)
Bayer Pharma AG
Original Assignee
Schering AG
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 Schering AG filed Critical Schering AG
Publication of EP0804192A1 publication Critical patent/EP0804192A1/en
Withdrawn legal-status Critical Current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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • 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
    • 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
    • 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
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • 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
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
    • 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 the compounds of the formula I for the production of medicaments for the treatment of diseases which are mediated by activation of the tumor necrosis factor (TNF).
  • TNF tumor necrosis factor
  • the compounds of formula I are described, for example, in USP-4,186,129 and WO 8602268. From these patents it is known that the compounds of the formula I have phosphodiesterase inhibitory activity and have central depressive, antidopaminergic, antinociceptive and anticonvulsive activity and are suitable for the local treatment of inflammation. It is also known from USP -4,824,838 that compounds of the formula I can be used as antidepressants.
  • R ⁇ is hydrogen or C ⁇ .g-alkyl.
  • the compounds of formula I can contain one or more chiral centers and also include the racemic diastereomeric mixtures and the individual optical isomers.
  • Alkyl means in each case straight-chain or branched alkyl groups, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-methyl-butyl, 2,2-dimethylpropyl and hexyl .
  • Alkyl residues with 1 to 4 carbon atoms are to be regarded as preferred.
  • Alkenyl means for example 1-propenyl, 2-propenyl or 3-methyl-2-propenyl and alkynyl means for example propargyl.
  • Cycloalkyl is understood to mean, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, in particular C3_5-cycloalkyls.
  • Aryl or aralkyl each mean an aromatic ring or an aromatic ring system having 6 to 10 carbon atoms, such as, for example, phenyl, benzyl, phenethyl or naphthyl.
  • a monocycle is to be regarded as preferred.
  • Acyl is to be understood as meaning aliphatic and aromatic carboxylic acids, for example C 1-6 -alkanoyl, benzoyl.
  • heterocycle encompasses a 5- or 6-membered saturated heterocycle having an oxygen, sulfur or nitrogen atom, for example 2- or 3-tetrahydropyranyl, 2- or 3-tetrahydrofuranyl, 2- or 3-tetrahydrothienyl, dihydropyranyl , Pyrrolidinyl, pvrrolinyl, piperidinyl and N-alkyl-pyrrolidinyl and N-alkyl-piperidinyl in which the alkyl radical contains 1-4 carbon atoms, preferably tetrahydrofuranyl.
  • Halogen means chlorine, fluorine, bromine and iodine.
  • Rl is methyl and R3 is hydrogen.
  • R ⁇ is hydrogen
  • R 2 is alkyl or cycloalkyl
  • R 3 in the meaning CH 3 being preferred in particular.
  • TNF Diseases that are mediated by TNF are understood to mean both diseases that are triggered by the production of TNF and diseases in which other cytokines such as 11-1 or 11-6 are influenced by TNF.
  • TNF means both TNF- ⁇ and TNF- ⁇ , both of which are antagonized by the compounds of the formula I. TNF- ⁇ is preferably inhibited.
  • the compounds of the formula I are therefore suitable for producing a pharmaceutical preparation which is used for the treatment and prophylaxis of diseases in living things which are triggered by stimulation of TNF.
  • Diseases which are influenced by excessive or unregulated TNF stimulation are, for example, allergic and inflammatory diseases, autoimmune diseases, pulmonary diseases, infectious diseases and bone resorption diseases such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gout, sepsis, septic shock, endotoxin shock, Gram-negative sepsis, toxic shock syndrome, ARDS (acute respiratory distress syndrome), pulmonary sarcoidosis, asthma, silicosis, cachexia, ulcerative colitis, Crohn's disease, osteoporosis, organ damage after reperfusion, inflammatory diseases of the CNS such as cerebral infectious diseases, panalitis, multiple sclerosis, such as multiple sclerosis Mad cow disease, inflammatory skin diseases such as urticaria, psoriasis,
  • the agents are produced by customary processes by bringing the active ingredient into the form of a pharmaceutical preparation with suitable carriers, auxiliaries and / or additives which is suitable for enteral or parenteral administration.
  • the preparations thus obtained can be used as pharmaceuticals in human or veterinary medicine be used.
  • the application can be administered orally or sublingually as a solid in the form of capsules or tablets or as a liquid in the form of solutions, suspensions, elixirs, aerosols or emulsions or rectally in the form of suppositories or in the form of injection solutions which can also be used subcutaneously, intramuscularly or intravenously, or topically or intrathecally.
  • auxiliary organic and inorganic carrier materials are suitable as auxiliaries for the desired pharmaceutical formulation, such as, for. As water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. If necessary, preservatives, stabilizers, wetting agents, emulsifiers or salts for changing the osmotic pressure or buffer may also be included.
  • the pharmaceutical preparations can be in solid form, for example as tablets, dragees, suppositories, capsules or in liquid form, for. B. present as solutions, suspensions or emulsions.
  • Auxiliary materials such as salts, bile acids or animal or vegetable phospholipids and their mixtures as well as liposomes or their components can also be used as carrier systems.
  • tablets, coated tablets or capsules with talc and / or hydrocarbon carrier or binder such as. B. lactose, corn or potato starch, suitable.
  • the application can also be in liquid form, such as. B. as juice to which sweetener may be added.
  • the compounds of formula I are used in doses sufficient to reduce TNF production to normal or lower levels.
  • the dosage of the active ingredients can vary depending on the route of administration, age and weight of the patient, type and severity of the disease to be treated and similar factors.
  • the daily dose is 0.5-50 mg, preferably 0J- 5 mg, whereby the dose can be given as a single dose to be administered once or divided into 2 or more daily doses.
  • the activity of the compounds according to the invention can be demonstrated, for example, in animals suffering from experimental allergic encephalomyelitis (EAE), a CNS disease which is caused by T lymphocytes.
  • EAE allergic encephalomyelitis
  • the illness can be triggered on rodents and primates by immunization and histopathologically and symptomatically resembles the disease states in humans.
  • the course of the disease can be followed using magnetic resonance imaging.
  • Macrophages and microglial cells which have macrophage functions in the brain, mediate the release of TNF- ⁇ during experimental allergic encephalomyelitis (EAE). If macrophages are stimulated, for example by lipopolysaccharide (LPS), TNF- ⁇ is secreted in vitro and in vivo within hours.
  • LPS lipopolysaccharide
  • a urine macrophage Zeil line (RAW 264) was preincubated for 30 minutes in the presence and in the absence of various concentrations of PDE-IV inhibitors and then stimulated with LPS (10 ng / ml). The culture medium was removed 18 hours after stimulation and the TNF- ⁇ release was measured using a specific Elisa test.
  • the test is available from various companies, including British Biotechnology, Genzyme, and is performed as described by the manufacturer.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Diabetes (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Virology (AREA)
  • Pain & Pain Management (AREA)
  • Communicable Diseases (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Dermatology (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Obesity (AREA)
  • Pulmonology (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)

Abstract

The disclosure concerns the use of compounds of formula I for treating conditions associated with tumour necrosis factor (TNF).

Description

Pharmazeutische Präparate zur TNF-Inhibition Pharmaceutical preparations for TNF inhibition
Die Erfindung betrifft die Verwendung der Verbindungen der Formel I zur Herstellung von Arzneimitteln zur Behandlung von Krankheiten, die durch Aktivierung des Tumomekrosefactors (TNF) vermittelt werden.The invention relates to the use of the compounds of the formula I for the production of medicaments for the treatment of diseases which are mediated by activation of the tumor necrosis factor (TNF).
Die Verbindungen der Formel I werden beispielsweise in USP-4.186.129 und WO 8602268 beschrieben. Aus diesen Patentschriften ist bekannt, daß die Verbindungen der Formel I phosphodiesterasehemmende Wirksamkeit besitzen und zentral-depressive, antidopaminerge, antinoziceptive und antikonvulsive Wirksamkeit aufweisen und zur lokalen Behandlung von Entzündungen geeignet sind. Ferner ist aus USP -4.824.838 bekannt, daß Verbindungen der Formel I als Antidepressiva verwendet werden können.The compounds of formula I are described, for example, in USP-4,186,129 and WO 8602268. From these patents it is known that the compounds of the formula I have phosphodiesterase inhibitory activity and have central depressive, antidopaminergic, antinociceptive and anticonvulsive activity and are suitable for the local treatment of inflammation. It is also known from USP -4,824,838 that compounds of the formula I can be used as antidepressants.
Es wurde nun gefunden, daß die Verbindungen der Formel I die TNF Produktion inhibieren und daher zur Behandlung von Krankheiten, die über die Aktivierung von TNF vermittelt werden, verwendet werden können.It has now been found that the compounds of the formula I inhibit TNF production and can therefore be used for the treatment of diseases which are mediated by the activation of TNF.
Erfindungsgemäß geeignet sind die razemischen und optisch aktiven Verbindungen der Formel IThe racemic and optically active compounds of the formula I are suitable according to the invention
worinwherein
R1 Cι _4-Alkyl,R 1 Cι- 4 alkyl,
R2 Ci _6-Alkyl, C3_7-Cycloalkyl, C3_7-Cycloalkyl-Cι _2-alkyl, C2_6-Alkenyl, C3.7- Alkinyl, ein Heterocyclus oder Cj.ö-Alkyl, das mit einem oder mehreren Halogenen, Hydroxy, Carboxy, Cι- -Alkoxy, C1.4-Alkoxycarbonyl oder einer gegebenenfalls mit C1 _4-Alkyl stubstituierten Aminogruppe substituiert ist, R3 Wasserstoff, Cj.g-Alkyl, Acyl, Aryl, Aralkyl, Aryl substituiert mit 1 oder 2 Methylgruppen undR 2 Ci _ 6 alkyl, C3_ 7 cycloalkyl, C3_7 cycloalkyl-Cι _ 2 alkyl, C 2 _6-alkenyl, C3.7-alkynyl, a heterocycle or C j .ö-alkyl, with one or more Halogens, hydroxy, carboxy, C 1 -C alkoxy, C1.4-alkoxycarbonyl or an amino group which is optionally substituted by C1-4-alkyl is substituted, R3 is hydrogen, Cj.g-alkyl, acyl, aryl, aralkyl, aryl substituted with 1 or 2 methyl groups and
R^ Wasserstoff oder C^.g-Alkyl bedeuten.R ^ is hydrogen or C ^ .g-alkyl.
Die Verbindungen der Formel I können ein oder mehrere chirale Zentren enthalten und umfassen auch die razemisch diastereomeren Gemische sowie die einzelnen optischen Isomeren.The compounds of formula I can contain one or more chiral centers and also include the racemic diastereomeric mixtures and the individual optical isomers.
Alkyl bedeutet jeweils geradkettige oder verzweigte Alkylgruppen wie beispielsweise Methyl, Ethyl, n-Propyl, Isopropyl, n-Butyl, sek.-Butyl, Isobutyl, tert.-Butyl, Pentyl, 2- Methyl-butyl, 2,2-Dimethylpropyl und Hexyl. Alkylreste mit 1 - 4 Kohlenstoffatomen sind als bevorzugt zu betrachten.Alkyl means in each case straight-chain or branched alkyl groups, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-methyl-butyl, 2,2-dimethylpropyl and hexyl . Alkyl residues with 1 to 4 carbon atoms are to be regarded as preferred.
Alkenyl bedeutet beispielsweise 1-Propenyl, 2-Propenyl oder 3-Methyl-2-propenyl und Alkinyl beispielsweise Propargyl.Alkenyl means for example 1-propenyl, 2-propenyl or 3-methyl-2-propenyl and alkynyl means for example propargyl.
Unter Cycloalkyl ist beispielsweise Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl oder Cycloheptyl zu verstehen, insbesondere C3_5-Cycloalkyle.Cycloalkyl is understood to mean, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, in particular C3_5-cycloalkyls.
Aryl oder Aralkyl bedeuten jeweils einen aromatischen Ring oder ein aromatisches Ringsystem mit 6 bis 10 Kohlenstoffatomen wie beispielsweise Phenyl, Benzyl, Phenethyl oder Naphthyl. Als bevorzugt ist ein Monocyclus zu betrachten.Aryl or aralkyl each mean an aromatic ring or an aromatic ring system having 6 to 10 carbon atoms, such as, for example, phenyl, benzyl, phenethyl or naphthyl. A monocycle is to be regarded as preferred.
Unter Acyl sind aliphatische und aromatische Carbonsäuren zu verstehen wie beispiels¬ weise C^.g-Alkanoyl, Benzoyl.Acyl is to be understood as meaning aliphatic and aromatic carboxylic acids, for example C 1-6 -alkanoyl, benzoyl.
Der Ausdruck "Heterocyclus" umfaßt einen 5- oder 6-gliedrigen gesättigten Heterocyclus mit einem Sauerstoff-, Schwefel- oder Stickstoffatom wie beispielsweise 2- oder 3-Tetra- hydropyranyl, 2- oder 3-Tetrahydrofuranyl, 2- oder 3-Tetrahydrothienyl, Dihydropyranyl, Pyrrolidinyl, Pvrrolinyl, Piperidinyl sowie N-Alkyl-Pyrrolidinyl und N-Alkyl-Piperidinyl worin der Alkylrest 1-4 Kohlenstoffatome enthält, vorzugsweise Tetrahydrofuranyl.The term "heterocycle" encompasses a 5- or 6-membered saturated heterocycle having an oxygen, sulfur or nitrogen atom, for example 2- or 3-tetrahydropyranyl, 2- or 3-tetrahydrofuranyl, 2- or 3-tetrahydrothienyl, dihydropyranyl , Pyrrolidinyl, pvrrolinyl, piperidinyl and N-alkyl-pyrrolidinyl and N-alkyl-piperidinyl in which the alkyl radical contains 1-4 carbon atoms, preferably tetrahydrofuranyl.
Unter Halogen ist Chlor, Fluor, Brom und Jod zu verstehen.Halogen means chlorine, fluorine, bromine and iodine.
Erfindungsgemäß bevorzugt sind die Verbindungen der Formel I, worin Rl Methyl und R3 Wasserstoff bedeutet. Besonders geeignet sind Verbindungen, worin R^ Wasserstoff oder Methyl und R2 Alkyl oder Cycloalkyl bedeuten, wobei insbesondere R^ in der Bedeutung CH3 bevorzugt ist.According to the invention, preference is given to the compounds of the formula I in which Rl is methyl and R3 is hydrogen. Compounds in which R ^ is hydrogen are particularly suitable or methyl and R 2 is alkyl or cycloalkyl, with R 3 in the meaning CH 3 being preferred in particular.
Die Herstellung der Verbindungen der Formel I, deren Isomere und Gemische derselben erfolgt nach an sich bekannten Methoden, die beispielsweise in dem vorne genannten Stand der Technik beschrieben sind.The compounds of the formula I, their isomers and mixtures thereof are prepared by methods known per se, which are described, for example, in the prior art mentioned above.
Unter Krankheiten, die durch TNF vermittelt werden, sind sowohl Krankheiten zu verstehen, die durch Produktion von TNF ausgelöst werden wie auch Krankheiten, bei denen durch TNF andere Cytokine wie beispielsweise 11-1 oder 11-6 beeinflußt werden.Diseases that are mediated by TNF are understood to mean both diseases that are triggered by the production of TNF and diseases in which other cytokines such as 11-1 or 11-6 are influenced by TNF.
Unter TNF ist sowohl TNF-α als auch TNF-ß zu verstehen, die beide durch die Verbindungen der Formel I antagonisiert werden. Bevorzugt wird TNF-α inhibiert.TNF means both TNF-α and TNF-β, both of which are antagonized by the compounds of the formula I. TNF-α is preferably inhibited.
Die Verbindungen der Formel I eignen sich daher zur Herstellung eines pharmazeutischen Präparates, das zur Behandlung und Prophylaxe von Erkrankungen in Lebewesen verwendet wird, die durch Stimulation von TNF ausgelöst werden. Als Erkrankungen, die durch excessive oder unregulierte TNF-Stimulation beeinflußt werden sind beispielsweise allergische und inflammatorische Erkrankungen, Autoimmunerkrankungen, pulmonare Erkrankungen, infektiöse Erkrankungen und Knochenresorptionserkrankungen bekannt wie Rheumatoide Arthritis, Rheumatoide Spondylitis, Osteoarthritis, Gicht, Sepsis, septischer Schock, Endotoxin-Schock, Gramnegative Sepsis, Toxisches Schocksyndrom, ARDS (Akutes Atemnotsyndrom), Pulmonare Sarkoidose, Asthma, Silikose, Kachexie.Colitis ulcerosa, Morbus Crohn, Osteoporose, Organschädigung nach Reperfusion, inflammatorische Erkrankungen des ZNS wie Cerebrale Malaria, Multiple Sklerosis, Panencephalitis, Infektionserkrankungen wie AIDS, Rinderwahnsinn, inflammatorische Erkrankungen der Haut wie Urticaria, Psoriasis, Atopische Dermatitis, Kontaktdermatitis, Lupus Erythematosus sowie Diabetes Insipidus, Neuroprotection z.B. bei Morbus Parkinson, Demenz beispielsweise nach Multiinfarkten und Schlaganfall.The compounds of the formula I are therefore suitable for producing a pharmaceutical preparation which is used for the treatment and prophylaxis of diseases in living things which are triggered by stimulation of TNF. Diseases which are influenced by excessive or unregulated TNF stimulation are, for example, allergic and inflammatory diseases, autoimmune diseases, pulmonary diseases, infectious diseases and bone resorption diseases such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gout, sepsis, septic shock, endotoxin shock, Gram-negative sepsis, toxic shock syndrome, ARDS (acute respiratory distress syndrome), pulmonary sarcoidosis, asthma, silicosis, cachexia, ulcerative colitis, Crohn's disease, osteoporosis, organ damage after reperfusion, inflammatory diseases of the CNS such as cerebral infectious diseases, panalitis, multiple sclerosis, such as multiple sclerosis Mad cow disease, inflammatory skin diseases such as urticaria, psoriasis, atopic dermatitis, contact dermatitis, lupus erythematosus and diabetes insipidus, neuroprotection, for example in Parkinson's disease, dementia, for example, after multi-infarction and stroke.
Die Wirksamkeit der Verbindungen der Formel I in den genannten Indikationen kann durch entsprechende übliche pharmakologische Teste gezeigt werden.The effectiveness of the compounds of the formula I in the indications mentioned can be shown by corresponding customary pharmacological tests.
Die Mittel werden nach üblichen Verfahren hergestellt, indem man den Wirkstoff mit geeigneten Träger-, Hilfs- und/oder Zusatzstoffen in die Form eines pharmazeutischen Präparates bringt, das für die enterale oder parenterale Applikation geeignet ist. Die so erhaltenen Zubereitungen können als Arzneimittel in der Human- oder Veterinärmedizin eingesetzt werden. Die Applikation kann oral oder sublingual als Feststoff in Form von Kapseln oder Tabletten oder als Flüssigkeit in Form von Lösungen, Suspensionen, Elexieren, Aerosolen oder Emulsionen oder rektal in Form von Suppositorien oder in Form von gegebenenfalls auch subcutan intramuskulär bzw. intravenös anwendbaren Injektionslösungen oder topisch oder intrathekal erfolgen. Als Hilfsstoffe für die gewünschte Arzneimittelformulierung sind die dem Fachmann bekannten inerten organischen und anorganischen Trägermaterialien geeignet wie z. B. Wasser, Gelantine, Gummmi arabicum, Milchzucker, Stärke, Magnesiumstearat, Talk, pflanzliche Öle, Polyalkylenglykole usw.. Gegebenenfalls können darüberhinaus Konservierungs-, Stabilisierungs-, Netzmittel, Emulgatoren oder Salze zur Veränderung des osmotischen Druckes oder Puffer enthalten sein.The agents are produced by customary processes by bringing the active ingredient into the form of a pharmaceutical preparation with suitable carriers, auxiliaries and / or additives which is suitable for enteral or parenteral administration. The preparations thus obtained can be used as pharmaceuticals in human or veterinary medicine be used. The application can be administered orally or sublingually as a solid in the form of capsules or tablets or as a liquid in the form of solutions, suspensions, elixirs, aerosols or emulsions or rectally in the form of suppositories or in the form of injection solutions which can also be used subcutaneously, intramuscularly or intravenously, or topically or intrathecally. The auxiliary organic and inorganic carrier materials known to the person skilled in the art are suitable as auxiliaries for the desired pharmaceutical formulation, such as, for. As water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. If necessary, preservatives, stabilizers, wetting agents, emulsifiers or salts for changing the osmotic pressure or buffer may also be included.
Die pharmazeutischen Präparate können in fester Form zum Beispiel als Tabletten, Dragees, Suppositoren, Kapseln oder in flüssiger Form z. B. als Lösungen, Suspensionen oder Emulsionen vorliegen.The pharmaceutical preparations can be in solid form, for example as tablets, dragees, suppositories, capsules or in liquid form, for. B. present as solutions, suspensions or emulsions.
Als Trägersysteme können auch grenzflächennahe Hilfsstoffe wie Salze, Gallensäuren oder tierische oder pflanzliche Phospholipide und deren Mischungen sowie Liposome oder deren Bestandteile verwendet werden.Auxiliary materials such as salts, bile acids or animal or vegetable phospholipids and their mixtures as well as liposomes or their components can also be used as carrier systems.
Für die orale Anwendung sind insbesondere Tabletten, Dragees oder Kapseln mit Talkum und/oder Kohlenwasserstoffträger oder -binder, wie z. B. Lactose, Mais- oder Kartoffelstärke, geeignet. Die Anwendung kann auch in flüssiger Form erfolgen, wie z. B. als Saft, dem gegebenenfalls Süßstoff beigefügt wird.For oral use, tablets, coated tablets or capsules with talc and / or hydrocarbon carrier or binder, such as. B. lactose, corn or potato starch, suitable. The application can also be in liquid form, such as. B. as juice to which sweetener may be added.
Die Verbindungen der Formel I werden in Dosierungen angewendet, die ausreichend sind, die TNF-Produktion auf normale oder geringere Werte herabzusetzen.The compounds of formula I are used in doses sufficient to reduce TNF production to normal or lower levels.
Die Dosierung der Wirkstoffe kann je nach Verabfolgungsweg, Alter und Gewicht des Patienten, Art und Schwere der zu behandelnden Erkrankung und ähnlichen Faktoren variieren. Die tägliche Dosis beträgt 0,5 - 50 mg, vorzugsweise 0J- 5 mg, wobei die Dosis als einmal zu verabreichende Einzeldosis oder unterteilt in 2 oder mehrere Tagesdosen gegeben werden kann.The dosage of the active ingredients can vary depending on the route of administration, age and weight of the patient, type and severity of the disease to be treated and similar factors. The daily dose is 0.5-50 mg, preferably 0J- 5 mg, whereby the dose can be given as a single dose to be administered once or divided into 2 or more daily doses.
Die Wirksamkeit der erfindungsgemäßen Verbindungen kann beispielsweise an Tieren gezeigt werden, die an experimenteller allergischer Encephalomyelitis leiden (EAE), einer Erkrankung des ZNS, die durch T-Lymphocyten hervorgerufen wird. Die Erkrankung kann an Nagetieren und Primaten durch Immunisierung ausgelöst werden und ähnelt histopathologisch und symptomatisch den Krankheitszuständen beim Menschen. Der Krankheitsverlauf kann mit Hilfe der Kernspintomographie verfolgt werden.The activity of the compounds according to the invention can be demonstrated, for example, in animals suffering from experimental allergic encephalomyelitis (EAE), a CNS disease which is caused by T lymphocytes. The illness can be triggered on rodents and primates by immunization and histopathologically and symptomatically resembles the disease states in humans. The course of the disease can be followed using magnetic resonance imaging.
Makrophagen und Mikrogliazellen, welche Makrophagenfunktionen im Gehirn ausüben, vermitteln die Freisetzung von TNF-α während experimenteller allergischer Encephalomyelitis (EAE). Werden Makrophagen stimuliert beispielsweise durch Lipopolysaccharid (LPS), erfolgt eine Sekretion von TNF-α in vitro und in vivo innerhalb von Stunden.Macrophages and microglial cells, which have macrophage functions in the brain, mediate the release of TNF-α during experimental allergic encephalomyelitis (EAE). If macrophages are stimulated, for example by lipopolysaccharide (LPS), TNF-α is secreted in vitro and in vivo within hours.
Eine urine Makrophagen Zeil -Linie (RAW 264) wurde 30 Minuten preinkubiert in Gegenwart und in Abwesenheit von verschiedenen Konzentrationen von PDE-IV- Inhibitoren und anschließend mit LPS (10 ng/ml) stimuliert. 18 Stunden nach Stimulation wurde das Kulturmedium entfernt und die TNF-α-Freisetzung mit einem spezifischen Elisa-Test gemessen.A urine macrophage Zeil line (RAW 264) was preincubated for 30 minutes in the presence and in the absence of various concentrations of PDE-IV inhibitors and then stimulated with LPS (10 ng / ml). The culture medium was removed 18 hours after stimulation and the TNF-α release was measured using a specific Elisa test.
Der Test ist von verschiedenen Firmen erhältlich, unter anderem von der Firma British Biotechnology, Genzyme, und wird durchgeführt, wie es vom Hersteller beschrieben wird.The test is available from various companies, including British Biotechnology, Genzyme, and is performed as described by the manufacturer.
5-(3-Propoxy-4-methoxyphenyl)-5-methyl-2-oxazolidinon inhibierte die LPS-induzierte TNF-α-Freisetzung durch RAW-Zellen mit IC50 = 0,50 (μM). 5- (3-Propoxy-4-methoxyphenyl) -5-methyl-2-oxazolidinone inhibited LPS-induced TNF-α release by RAW cells with IC50 = 0.50 (μM).

Claims

Patentansprüche claims
1.) Verwendung von optisch aktiven oder razemischen Verbindungen der Formel I1.) Use of optically active or racemic compounds of the formula I.
worin wherein
R1 C^-Alkyl,R 1 C ^ alkyl,
R2 Cι _6-Alkyl, C3_7-Cycloalkyl, C3_7-Cycloalkyl-Cι _2-alkyl, C2.6-Alkenyl, C3.7- Alkinyl, ein Heterocyclus oder C1 _6-Alkyl, das mit einem oder mehreren Halogenen, Hydroxy, Carboxy, Cι- -Alkoxy, Cι_4-Alkoxycarbonyl oder einer gegebenenfalls mit Cj_4-Alkyl stubstituierten Aminogruppe substituiert ist,R 2 C _ _6-alkyl, C 3 _7-cycloalkyl, C3_7-cycloalkyl-Cι _ 2 -alkyl, C 2 .6-alkenyl, C3.7-alkynyl, a heterocycle or C1 _6-alkyl, with one or more halogens , Hydroxy, carboxy, C 1 -C alkoxy, C 4 alkoxy carbonyl or an amino group optionally substituted with C 4 alkyl is substituted,
R^ Wasserstoff, C1.g-Alkyl, Acyl, Aryl, Aralkyl, Aryl substituiert mit 1 oder 2 Methylgruppen undR ^ hydrogen, C1.g-alkyl, acyl, aryl, aralkyl, aryl substituted with 1 or 2 methyl groups and
R^ Wasserstoff oder Ci .g-Alkyl bedeuten zur Herstellung eines Arzneimittels zur Behandlung von Krankheiten, die durch Aktivierung des Tumornekrosefaktors vermittelt werden.R ^ is hydrogen or Ci .g-alkyl mean for the manufacture of a medicament for the treatment of diseases which are mediated by activation of the tumor necrosis factor.
2.) Verwendung von 5-(3-Cyclopentyloxy-4-methoxyphenyl)-5-methyl-2-oxazolidinon gemäß Anspruch 1.2.) Use of 5- (3-cyclopentyloxy-4-methoxyphenyl) -5-methyl-2-oxazolidinone according to claim 1.
3.) Verwendung von 5-(3-Propoxy-4-methoxyphenyl)-5-methyl-2-oxazolidinon gemäß Anspruch 1.3.) Use of 5- (3-propoxy-4-methoxyphenyl) -5-methyl-2-oxazolidinone according to claim 1.
4.) Verwendung von Verbindungen der Formel I gemäß Anspruch 1 zur Herstellung eines Arzneimittels zur Behandlung entzündlicher Erkrankungen des ZNS . 4.) Use of compounds of formula I according to claim 1 for the manufacture of a medicament for the treatment of inflammatory diseases of the CNS.
5.) Verwendung von Verbindungen der Formel I gemäß Anspruch 1 zur Herstellung eines Arzneimittels zur Behandlung von Multipler Sklerose.5.) Use of compounds of formula I according to claim 1 for the manufacture of a medicament for the treatment of multiple sclerosis.
6.) Verwendung von Verbindungen der Formel I gemäß Anspruch 1 zur Herstellung eines Arzneimittels zur Behandlung von infektiösen Erkrankungen.6.) Use of compounds of formula I according to claim 1 for the manufacture of a medicament for the treatment of infectious diseases.
7.) Verwendung von Verbindungen der Formel I gemäß Anspruch 1 zur Herstellung eines Arzneimittels zur Behandlung von Knochenresorptionserkrankungen.7.) Use of compounds of formula I according to claim 1 for the manufacture of a medicament for the treatment of bone resorption diseases.
8.) Verwendung von Verbindungen der Formel I gemäß Anspruch 1 zur Herstellung eines Arzneimittels zur Behandlung pulmonarer Erkrankungen.8.) Use of compounds of formula I according to claim 1 for the manufacture of a medicament for the treatment of pulmonary diseases.
9.) Verwendung von Verbindungen der Formel I gemäß Anspruch 1 zur Behandlung inflammatorischer Erkrankungen der Haut9.) Use of compounds of formula I according to claim 1 for the treatment of inflammatory diseases of the skin
10.) Verwendung von Verbindungen der Formel I gemäß Anspruch 1 zur Behandlung von Autoimmunerkrankungen. 10.) Use of compounds of formula I according to claim 1 for the treatment of autoimmune diseases.
EP96902870A 1995-02-10 1996-02-09 Pharmaceutical preparations for tumour necrosis factor (tnf) inhibition Withdrawn EP0804192A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19505516 1995-02-10
DE19505516 1995-02-10
PCT/DE1996/000257 WO1996024350A1 (en) 1995-02-10 1996-02-09 Pharmaceutical preparations for tumour necrosis factor (tnf) inhibition

Publications (1)

Publication Number Publication Date
EP0804192A1 true EP0804192A1 (en) 1997-11-05

Family

ID=7754327

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96902870A Withdrawn EP0804192A1 (en) 1995-02-10 1996-02-09 Pharmaceutical preparations for tumour necrosis factor (tnf) inhibition

Country Status (14)

Country Link
US (1) US6117895A (en)
EP (1) EP0804192A1 (en)
JP (1) JPH11500110A (en)
KR (1) KR19980702116A (en)
CN (1) CN1173818A (en)
AU (1) AU706159B2 (en)
CZ (1) CZ290671B6 (en)
FI (1) FI973277A0 (en)
HU (1) HUP9702408A3 (en)
IL (1) IL117090A (en)
MX (1) MX9706086A (en)
SK (1) SK283821B6 (en)
WO (1) WO1996024350A1 (en)
ZA (1) ZA961081B (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1007038A2 (en) * 1997-08-21 2000-06-14 Takeda Chemical Industries, Ltd. Anti-inflammatory agent
US20040220103A1 (en) * 1999-04-19 2004-11-04 Immunex Corporation Soluble tumor necrosis factor receptor treatment of medical disorders
DOP2005000123A (en) * 2004-07-02 2011-07-15 Merck Sharp & Dohme CETP INHIBITORS
TW200732313A (en) * 2005-12-15 2007-09-01 Astrazeneca Ab Oxazolidinone compounds and their use as metabotropic glutamate receptor potentiators

Family Cites Families (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2413935A1 (en) * 1974-03-20 1975-10-16 Schering Ag 4- (POLYALCOXY-PHENYL) -2-PYRROLIDONE
DE2541855A1 (en) * 1975-09-18 1977-03-31 Schering Ag 4- (POLYALCOXY-PHENYL) -2-PYRROLIDONE II
FR2358155A1 (en) * 1976-07-15 1978-02-10 Lapinet Eugene COMPOSITION FOR THE TREATMENT AND PREVENTION OF IRRITATION AND INFLAMMATION OF THE SKIN, EYE AND MUCOSAUSES
DE2655369A1 (en) * 1976-12-03 1978-06-08 Schering Ag 5- (SUBST. PHENYL) -OXAZOLIDINONE AND THEIR SULFUR ANALOGS AND PROCESS FOR THEIR PRODUCTION
US5783591A (en) * 1984-10-19 1998-07-21 Schering Aktiengesellschaft Administration of oxazolidinone and pyrolidinone compounds for the treatment of inflammation
DE3438839A1 (en) * 1984-10-19 1986-04-24 Schering AG, 1000 Berlin und 4709 Bergkamen PHARMACEUTICAL PREPARATIONS
US5310732A (en) * 1986-02-03 1994-05-10 The Scripps Research Institute 2-halo-2'-deoxyadenosines in the treatment of rheumatoid arthritis
DE3639225A1 (en) * 1986-11-14 1988-05-19 Schering Ag USE OF 5- (SUBST. PHENYL) -OXAZOLIDINONE DERIATES AS PSYCHOPHARMAKA
CA2060309A1 (en) * 1989-06-13 1990-12-14 Alison M. Badger Inhibition of interleukin-1 and tumor necrosis factor production by monocytes and/or macrophages
CA2088352A1 (en) * 1990-08-03 1992-02-04 Klaus M. Esser Tnf inhibitors
PT100441A (en) * 1991-05-02 1993-09-30 Smithkline Beecham Corp PIRROLIDINONES, ITS PREPARATION PROCESS, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM AND USE
US5227369A (en) * 1991-07-11 1993-07-13 The Regents Of The University Of California Compositions and methods for inhibiting leukocyte adhesion to cns myelin
GB9204808D0 (en) * 1992-03-04 1992-04-15 Rhone Poulenc Rorer Ltd Novel compositions of matter
US5264437A (en) * 1992-03-20 1993-11-23 Syntex (U.S.A.) Inc. Optionally substituted pyrido[2,3-d]pyridine-2,4(1H,3H)-diones and pyrido[2,]pyrimidine-2(1H,3H)-ones
US5672622A (en) * 1994-04-21 1997-09-30 Berlex Laboratories, Inc. Treatment of multiple sclerosis

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9624350A1 *

Also Published As

Publication number Publication date
HUP9702408A2 (en) 1998-05-28
AU4712296A (en) 1996-08-27
JPH11500110A (en) 1999-01-06
CZ290671B6 (en) 2002-09-11
SK283821B6 (en) 2004-02-03
HUP9702408A3 (en) 2000-08-28
CN1173818A (en) 1998-02-18
FI973277A (en) 1997-08-08
MX9706086A (en) 1997-10-31
IL117090A (en) 2000-07-26
KR19980702116A (en) 1998-07-15
IL117090A0 (en) 1996-06-18
FI973277A0 (en) 1997-08-08
US6117895A (en) 2000-09-12
SK107397A3 (en) 1997-12-10
WO1996024350A1 (en) 1996-08-15
CZ251397A3 (en) 1997-12-17
AU706159B2 (en) 1999-06-10
ZA961081B (en) 1996-10-15

Similar Documents

Publication Publication Date Title
DE69815090T2 (en) USE OF CHOLINESTERASE INHIBITORS FOR TREATING CONCENTRATIONAL DISORDER
EP0859766B1 (en) Chiral methyl phenyl oxazolidinones
Aoyama et al. Neural networks applied to structure-activity relationships
DE69034223T2 (en) Sertraline for the treatment of social phobia
DE60029634T2 (en) Substituted piperazine and piperidine calcium channel blockers
EP0038438B1 (en) Substituted 1,2,5-oxadiazole-2-oxides for use as medicaments and medicaments containing them
WO1996024350A1 (en) Pharmaceutical preparations for tumour necrosis factor (tnf) inhibition
EP0003602B1 (en) Pyrrolidine derivatives for use as therapeutically active substances and medicaments containing them
DE2359128C2 (en)
DE60123528T2 (en) Use of an agent for improving astrocyte function for the treatment of Parkinson's disease
EP0900212B1 (en) Chiral phenyldihydrofuranones as pde-iv inhibitors
EP0224810A1 (en) Antihypertensive preparation containing a mixture
EP0270482B1 (en) Use of 5-(substituted phenyl-)oxazolidinones in the treatment of depressions
EP0821960B1 (en) Use of xanthine derivatives combined with a 5-substituted-isoxazole-4-carboxamide derivative and/or a 2-cyano-3-hydroxycrotonamide derivative for the modulation of apoptosis
Loeb et al. Liposome‐entrapped γ‐aminobutyric acid inhibits isoniazid‐induced epileptogenic activity in rats
EP1040838A1 (en) Stable aqueous EM 12 solution
DE3906214A1 (en) USE OF MACROLACTONE AS ANTIALLERGICA
EP0524512A2 (en) Antihypertensive combinations
DE60005526T2 (en) USE OF 2-AMINO-4- (4-FLUORONAPHTH-1-YL) -6-ISOPROPYLPYRIMIDINE FOR THE TREATMENT OF DISEASES OF THE STOMESTYLE
DE2213028B2 (en) DL-3-FORMYLAMINOTHIACYCLOPENTAN-2-ON, PROCESS FOR THE PRODUCTION THEREOF, AND DL-3-FORMYLAMINO-THIACYCLOPENTAN-2-ON AND OTHER PHARMACEUTICAL COMPOSITIONS CONTAINING ACYLDER DERIVATIVES
DE2815878A1 (en) NEW PHARMACEUTICAL COMPOSITIONS SPECIFICALLY INTENDED FOR THE TREATMENT OF FUNCTIONAL CEREBRAL DISORDERS
EP0001061B1 (en) Polypeptides, their preparation and pharmaceutical compositions containing them
DE2029756A1 (en)
WO1993000326A1 (en) Omega-3 polyunsaturated fatty-acid derivatives, their preparation and their use
DE4120917A1 (en) ESTERS OF FATTY ACIDS WITH AMINO ALCOHOLS FOR USE IN THE FIGHT AGAINST DISEASES

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19970701

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL PT SE

17Q First examination report despatched

Effective date: 20040205

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

RIC1 Information provided on ipc code assigned before grant

Ipc: A61P 1/00 20060101ALI20060328BHEP

Ipc: A61P 19/10 20060101ALI20060328BHEP

Ipc: A61P 9/10 20060101ALI20060328BHEP

Ipc: A61P 25/28 20060101ALI20060328BHEP

Ipc: A61P 7/12 20060101ALI20060328BHEP

Ipc: A61P 31/18 20060101ALI20060328BHEP

Ipc: A61P 17/00 20060101ALI20060328BHEP

Ipc: A61P 25/00 20060101ALI20060328BHEP

Ipc: A61P 3/00 20060101ALI20060328BHEP

Ipc: A61P 11/00 20060101ALI20060328BHEP

Ipc: A61P 31/00 20060101ALI20060328BHEP

Ipc: A61P 19/06 20060101ALI20060328BHEP

Ipc: A61P 19/08 20060101ALI20060328BHEP

Ipc: A61P 19/02 20060101ALI20060328BHEP

Ipc: A61P 37/00 20060101ALI20060328BHEP

Ipc: A61K 31/00 20060101ALI20060328BHEP

Ipc: A61K 31/421 20060101AFI20060328BHEP

RTI1 Title (correction)

Free format text: USE OF 2-OXAZOLIDINON DERIVATIVES AS TNF-INHIBITORS

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20060823