EP1474398A1 - N-allyloxyethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines and the use of the same as pharmaceuticals - Google Patents

N-allyloxyethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines and the use of the same as pharmaceuticals

Info

Publication number
EP1474398A1
EP1474398A1 EP03737261A EP03737261A EP1474398A1 EP 1474398 A1 EP1474398 A1 EP 1474398A1 EP 03737261 A EP03737261 A EP 03737261A EP 03737261 A EP03737261 A EP 03737261A EP 1474398 A1 EP1474398 A1 EP 1474398A1
Authority
EP
European Patent Office
Prior art keywords
methyl
hydrogen
compounds
optionally
different
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Withdrawn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
EP03737261A
Other languages
German (de)
French (fr)
Inventor
Adrian Carter
Helmut Ensinger
Matthias Grauert
Detlef Andre Stiller
Thomas Weiser
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 EP1474398A1 publication Critical patent/EP1474398A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • 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
    • A61P7/10—Antioedematous agents; Diuretics
    • 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
    • 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
    • A61P9/06—Antiarrhythmics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22—Bridged ring systems
    • C07D221/26—Benzomorphans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • R1, R 2 and R 3 are identical or different, are hydrogen, methyl or ethyl;
  • R 4 is hydrogen, methyl or ethyl;
  • R5, R6 and R7 are the same or different, are hydrogen, methyl or ethyl
  • R 9 and R 9 are identical or different and are hydrogen, fluorine, chlorine, bromine, methyl,
  • the compounds of the general formula I, wherein R 1, R 2 and R 3 are identical or different, are hydrogen or methyl;
  • R 4 is hydrogen or methyl;
  • R 8, R 6 and R 7 are identical or different, hydrogen or methyl, preferably
  • Methyl; R ⁇ is hydrogen, methyl, hydroxy or methoxy, preferred
  • R 9 may be hydrogen or methyl, optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their pharmacologically acceptable acid addition salts.
  • the compounds of general formula ⁇ wherein R 1 , R 2 and R 3 are identical or different, are hydrogen or methyl; R4 is hydrogen or methyl;
  • R 5 , R 6 and R 7 are methyl;
  • R 8 is hydrogen or methyl, preferably hydrogen;
  • R 9 may be hydrogen or methyl, optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their pharmacologically acceptable
  • R 1 , R 2 , R 3 , R, R 5 , R 8, R 7 , R 3 and R 9 may have the abovementioned meanings represent.
  • the compounds of general formula (1) can be converted into their salts, in particular for pharmaceutical use, into their pharmacologically acceptable acid addition salts with an inorganic or organic acid.
  • suitable acids are 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 abovementioned acids can be used.
  • the claimed compounds are blockers of the voltage-dependent sodium channel. These are compounds which have high affinity batrachotoxin (BTX) (Kj ⁇ 500 nM) competitively or non-competitively from the binding site on the sodium channel. Such substances show a "use-dependency" in the blockade of the sodium channels, ie for the binding of the substances to the sodium channel, the sodium channels must first be activated. The maximum blockade of the sodium channels is only achieved after repeated stimulation of the sodium channels. As a result, the substances bind preferentially
  • the compounds of the general formula according to the invention can thus be used in diseases whose cause is due to an overexcitation-caused dysfunction. These include diseases such as arrhythmias, spasms, cardiac and cerebral ischemia, pain and neurodegenerative diseases of various origins.
  • epilepsy hypoglycemia, hypoxia, anoxia, brain trauma, brain edema, cerebral stroke, perinatal asphyxia, cerebellar degeneration, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotension, cardiac infarction, cardiac arrhythmia, angina pectoris, chronic pain, neuropathic pain and local anesthesia.
  • a further aspect of the invention is therefore directed to the use of compounds of general formula I as pharmaceuticals, in particular as medicaments, in which the blockage of the voltage-dependent sodium channel can develop a therapeutic benefit.
  • the compounds of general formula 1 according to the invention for the preparation of a medicament for the prevention or treatment of epilepsy, hypoglycemia, hypoxia, anoxia, brain trauma, brain edema, brain stroke, perinatal asphyxia, degenerations of the cerebellum, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotension, cardiac infarction, cardiac arrhythmia, angina pectoris, chronic pain, neuropathic pain and local anesthesia.
  • BTX binding to the sodium channel [SW Postma & WA Catterall, Mol.
  • the sodium channel blocking property of the compounds of the invention can be demonstrated by the blockade of veratridine-induced glutamate release [S. Villauneva, P. Frenz, Y. Dragnic, F. Orrego, Brain Res. 461, 377-380 (1988)].
  • Veratridine is a toxin that permanently opens the sodium channel, which leads to increased influx of sodium ions into the cell, and this sodium influx leads to an increased release of glutamate in neuronal tissue, which can be antagonized by the compounds of this invention.
  • the compounds of the invention can be prepared in analogy to known synthesis methods.
  • One possible synthetic route is shown in Scheme 1.
  • the 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine-10-ols (2) characterized as starting compounds in Scheme 1 are obtainable according to synthetic methods known from the prior art. This will be on see also European Patent Application EP-A-521422 and International Patent Applications WO 97/06146 and WO 99/14199.
  • the synthesis unit 3 contains a leaving group X, which is preferably chlorine, bromine, hydroxyl or a methoxy or ethoxy radical.
  • a leaving group X which is preferably chlorine, bromine, hydroxyl or a methoxy or ethoxy radical.
  • Example 5 (2R) -N-r2-Allyloxyethvn-1, 2,3,4,5,6-hexahydro-6,9,11,11-tetramethyl-2,6-methano-3-benzazocin-10-ol hydrochloride
  • the residue is dissolved in 20 ml of dichloromethane and 1.5 g of SOCl 2 are added dropwise at RT. After 30 min. will i.Vak. concentrated, the residue taken up in 20 ml of THF and added dropwise under nitrogen to a suspension of 0.5 g of lithium aluminum hydride in 20 ml of terahydrofuran. The mixture is then heated to 50 ° C for 2 h, cooled, 1, 5mL 4N NaOH was added dropwise and stirred for 30 min. The precipitate is filtered off with suction and the mother liquor i.Vak. concentrated. The residue is filtered through a short silica gel column (about 30 mL silica gel, about 250 mL ethyl acetate).
  • the compounds according to the invention can be administered orally, transdermally, by inhalation or parenterally.
  • the compounds of the invention are present as active ingredients in conventional dosage forms, for example in compositions consisting essentially of an inert pharmaceutical carrier and an effective dose of the active ingredient, such as tablets, dragees, capsules, wafers, powders, solutions, suspensions, emulsions , Syrups, suppositories, transdermal systems etc.
  • An effective dose of the compounds according to the invention is between 1 and 1000, preferably between 1 and 500, more preferably between 5-300 mg / dose when administered orally, when administered intravenously, subcutaneously or intramuscularly 0.001 and 50, preferably between 0.1 and 10 mg / dose.
  • inhalation solutions are suitable according to the invention containing 0.01 to 1, 0, preferably 0.1 to 0.5% active ingredient.
  • the use of powders is preferred.
  • infusion solution preferably in a physiological saline solution or nutrient salt solution.
  • 10-100 mg / h, preferably 25-60 mg / h could be used. The latter application form is of outstanding importance according to the invention.
  • the compounds according to the invention can be used alone or in combination with other active compounds according to the invention, if appropriate also in combination with other pharmacologically active substances.
  • Suitable application forms are, for example, tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders.
  • Corresponding tablets can be prepared, for example, by mixing the active substance (s) with known excipients, 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 carboxymethylcellulose,
  • Cellulose acetate phthalate or polyvinyl acetate.
  • the tablets can also consist of several layers.
  • Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the core can also consist of several layers.
  • the dragee cover to achieve a depot effect from several layers can be used wherein the above mentioned in the tablets excipients can be used.
  • Juices of the active compounds or active compound combinations according to the invention may additionally contain a sweetener, such as saccharin, cycamate, glycerol or sugar, as well as a taste-improving agent, e.g. Flavorings such as vanillin or orange extract. They may also contain suspending aids or thickening agents, such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
  • a sweetener such as saccharin, cycamate, glycerol or sugar
  • a taste-improving agent e.g. Flavorings such as vanillin or orange extract.
  • suspending aids or thickening agents such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
  • Injection solutions are prepared in the usual manner, e.g. prepared 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 substances can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatine capsules.
  • inert carriers such as lactose or sorbitol
  • Suitable suppositories can be prepared, for example, by mixing with suitable carriers, such as neutral fats or polyethylene glycol or its derivatives.
  • a therapeutically effective daily dose is between 1 and 2500 mg, preferably 100-1000 mg per adult.
  • Active ingredient 100 mg lactose 140 mg corn starch 240 mg
  • the finely ground active substance, lactose and part of the corn starch are mixed together.
  • the mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet granulated and dried.
  • the granules, the remainder of the corn starch and the magnesium stearate are sieved and mixed together.
  • the mixture is compressed into tablets of suitable shape and size.
  • the finely ground active ingredient, a portion of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and processed with the remainder of the corn starch and water to a granulate which is dried and sieved. To this is added the sodium carboxymethyl starch and the magnesium stearate, mixed and pressed the mixture into tablets of suitable size.
  • the active ingredient, corn starch, lactose and polyvinylpyrrolidone are mixed well and moistened with water.
  • the moist mass is forced through a sieve with 1 mm mesh size, dried at about 45 ° C and then strikes the granules through the same sieve.
  • curved tablet cores having a diameter of 6 mm are pressed on a tableting machine.
  • the coated dragee cores are coated in a known manner with a layer which consists essentially of sugar and talc.
  • the finished dragees are polished with wax.
  • Substance and cornstarch are mixed and moistened with water.
  • the moist mass is sieved and dried.
  • the dry granules are sieved and mixed with magnesium stearate.
  • the final mixture is filled into hard gelatine capsules size 1.
  • the active ingredient is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and treated with sodium chloride as isotonic, the resulting solution is filtered pyrogen-free and the filtrate under aseptic conditions in ampoules bottled, which are then sterilized and sealed.
  • the vials contain 5 mg, 25 mg and 50 mg active ingredient.
  • the hard fat is melted.
  • the ground active substance is dispersed homogeneously. It is cooled to 38 ° C and poured into slightly pre-cooled suppository molds.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Diabetes (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Pain & Pain Management (AREA)
  • Cardiology (AREA)
  • Obesity (AREA)
  • Anesthesiology (AREA)
  • Emergency Medicine (AREA)
  • Vascular Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Urology & Nephrology (AREA)
  • Psychology (AREA)
  • Endocrinology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The invention relates to 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-10-ols of general formula (1) wherein the radicals R1, R2, R3, R4, R5, R6, R7, R8 and R9 can have the designations cited in the description and in the claims. The invention also relates to methods for the production thereof and to the use of the same as pharmaceuticals.

Description

N-Allyloxyethyl-1 ,2^4 A6-Hexahydro-2,6-methano-3-benzazocine und ihre N-Allyloxyethyl-1,2A4A6-hexahydro-2,6-methano-3-benzazocine and its
Verwendung als ArzneimittelUse as a medicine
Gegenstand der geplanten Patentanmeldung sind substituierte N-Allyloxyethyl- 1 ,2,3,4,5,6-Hexahydro-2,6-methano-3-benzazocin-10-ole der allgemeinen Formel ±Subject of the proposed patent application are substituted N-Allyloxyethyl- 1, 2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-10-ols of the general formula ±
worin wherein
R1 , R2 und R3 gleich oder verschieden, Wasserstoff, Methyl oder Ethyl; R4 Wasserstoff, Methyl oder Ethyl;R1, R 2 and R 3 are identical or different, are hydrogen, methyl or ethyl; R 4 is hydrogen, methyl or ethyl;
R5, R6 und R7 gleich oder verschieden, Wasserstoff, Methyl oder Ethyl;R5, R6 and R7 are the same or different, are hydrogen, methyl or ethyl;
RÖ und R9 gleich oder verschieden Wasserstoff, Fluor, Chlor, Brom, Methyl,R 9 and R 9 are identical or different and are hydrogen, fluorine, chlorine, bromine, methyl,
Ethyl, Hydroxy oder Methoxy bedeuten können, gegebenenfalls in Form ihrer Racemate, ihrer Enantiomere, ihrer Diastereomere und ihrer Gemische, sowie gegebenenfalls ihrer pharmakologisch unbedenklichenEthyl, hydroxy or methoxy, optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their pharmacologically acceptable
Säureadditionssalze.Acid addition salts.
Bevorzugt sind die Verbindungen der allgemeinen Formel I, worin R1 , R2 und R3 gleich oder verschieden, Wasserstoff oder Methyl; R4 Wasserstoff oder Methyl;Preferably, the compounds of the general formula I, wherein R 1, R 2 and R 3 are identical or different, are hydrogen or methyl; R 4 is hydrogen or methyl;
Rδ, R6 und R7 gleich oder verschieden, Wasserstoff oder Methyl, vorzugsweiseR 8, R 6 and R 7 are identical or different, hydrogen or methyl, preferably
Methyl; Rδ Wasserstoff, Methyl, Hydroxy oder Methoxy, bevorzugtMethyl; Rδ is hydrogen, methyl, hydroxy or methoxy, preferred
Wasserstoff oder Methyl bedeuten können,Can mean hydrogen or methyl,
R9 Wasserstoff oder Methyl bedeuten können, gegebenenfalls in Form ihrer Racemate, ihrer Enantiomere, ihrer Diastereomere und ihrer Gemische, sowie gegebenenfalls ihrer pharmakologisch unbedenklichen Säureadditionssalze.R 9 may be hydrogen or methyl, optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their pharmacologically acceptable acid addition salts.
Besonders sind die Verbindungen der allgemeinen Formel Λ , worin R1 , R2 und R3 gleich oder verschieden, Wasserstoff oder Methyl; R4 Wasserstoff oder Methyl;Particularly, the compounds of general formula Λ, wherein R 1 , R 2 and R 3 are identical or different, are hydrogen or methyl; R4 is hydrogen or methyl;
R5, R6 und R7 Methyl; R8 Wasserstoff oder Methyl, bevorzugt Wasserstoff; R9 Wasserstoff oder Methyl bedeuten können, gegebenenfalls in Form ihrer Racemate, ihrer Enantiomere, ihrer Diastereomere und ihrer Gemische, sowie gegebenenfalls ihrer pharmakologisch unbedenklichenR 5 , R 6 and R 7 are methyl; R 8 is hydrogen or methyl, preferably hydrogen; R 9 may be hydrogen or methyl, optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their pharmacologically acceptable
Säureadditionssalze.Acid addition salts.
Von erfindungegmäß herausragender Bedeutung sind solche Verbindungen der Formel i, die in der 1 R und, sofern R4 nicht Wasserstoff bedeutet, 2"S-Konfiguration vorliegen. Diese erfindungsgemäß bevorzugten Stereoisomere lassen sich auch durch die allgemeine Formel VOutstandingly important in the invention are those compounds of the formula I which are in the 1 R and, if R 4 is not hydrogen, 2 "S configuration These stereoisomers which are preferred according to the invention can also be represented by the general formula V
in der die Reste R1 , R2, R3, R , R5, Rß, R7, R3 und R9 die vorstehend genannten Bedeutungen aufweisen können, darstellen.in which the radicals R 1 , R 2 , R 3 , R, R 5 , R 8, R 7 , R 3 and R 9 may have the abovementioned meanings represent.
Von besonderem Interesse sind die nachfolgenden Verbindungen der allgemeinen Formel V.Of particular interest are the following compounds of general formula V.
(2R)-N-Allyloxyethyl-1 ,2,3,4,5,6-hexahydro-6,11 ,11 -trimethyl-2,6-methano-3- benzazocin-10-ol-hydrochlorid; - (2R,2"S)-N-(2-Allyloxy-propyl)-1 ,2,3,4,5,6-hexahydro-6,11 ,11-trimethyl-2,6- methano-3-benzazocin-10-ol-hydrochlorid;(2R) -N-Allyloxyethyl-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocin-10-ol hydrochloride; - (2R, 2 "S) -N- (2-Allyloxy-propyl) -1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocine -10-ol hydrochloride;
Gegebenenfalls können die Verbindungen der allgemeinen Formel (1 ) in ihre Salze, insbesondere für die pharmazeutische Anwendung, in ihre pharmakologisch unbedenklichen Säureadditionssalze mit einer anorganischen oder organischen Säure, überführt werden. Als Säuren kommen hierfür beispielsweise Bernsteinsäure, Bromwasserstoffsäure, Essigsäure, Fumarsäure, Maleinsäure, Methansulfonsäure, Milchsäure, Phosphorsäure, Salzsäure, Schwefelsäure, Weinsäure oder Zitronensäure in Betracht. Ferner können Mischungen der vorgenannten Säuren eingesetzt werden.Optionally, the compounds of general formula (1) can be converted into their salts, in particular for pharmaceutical use, into their pharmacologically acceptable acid addition salts with an inorganic or organic acid. Examples of suitable acids are 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. Furthermore, mixtures of the abovementioned acids can be used.
Die beanspruchten Verbindungen sind Blocker des spannungsabhängigen Natriumkanals. Es handelt sich dabei um Verbindungen, die Batrachotoxin (BTX) mit hoher Affinität (Kj < 500 nM) kompetitiv oder nicht-kompetitiv von der Bindungsstelle am Natriumkanal verdrängen. Solche Substanzen zeigen eine "use-dependency" bei der Blockade der Natriumkanäle, d.h. für die Bindung der Substanzen an dem Natriumkanal müssen die Natriumkanäle zunächst aktiviert werden. Die maximale Blockade der Natriumkanäle wird erst nach wiederholter Stimulation der Natriumkanäle erreicht. Demzufolge binden die Substanzen bevorzugt anThe claimed compounds are blockers of the voltage-dependent sodium channel. These are compounds which have high affinity batrachotoxin (BTX) (Kj <500 nM) competitively or non-competitively from the binding site on the sodium channel. Such substances show a "use-dependency" in the blockade of the sodium channels, ie for the binding of the substances to the sodium channel, the sodium channels must first be activated. The maximum blockade of the sodium channels is only achieved after repeated stimulation of the sodium channels. As a result, the substances bind preferentially
Natriumkanäle, die vermehrt aktiviert werden. Dadurch sind die Substanzen in der Lage, bevorzugt in den Körperregionen wirksam zu werden, die pathologisch überstimuliert sind. Die erfindungsgemäßen Verbindungen der allgemeinen Formel können somit bei Erkrankungen, deren Ursache auf eine durch Übererregung bedingte Funktionsstörung beruhen, eingesetztwerden. Darunterfallen Erkrankungen wie Arrhythmien, Spasmen, kardiale und Gehirnischämien, Schmerzen sowie neurodegenerative Erkrankungen verschiedener Genese. Beispielsweise kann genannt werden: Epilepsie, Hypoglykämie, Hypoxie, Anoxie, Gehirntrauma, Gehirnoedem, Gehirn-Schlaganfall, perinatale Asphyxie, Degenerationen des Cerebellums, amyotrope laterale Sklerose, Morbus Huntington, Morbus Alzheimer, Morbus Parkinson, Zyklophrenie, Hypotonie, Herzinfakt, Herzrhythmusstörungen, Angina pectoris, chronischer Schmerz, neuropathischer Schmerz sowie Lokalanaesthesie.Sodium channels that are increasingly activated. As a result, the substances are able to be effective preferably in the body regions that are pathologically overstimulated. The compounds of the general formula according to the invention can thus be used in diseases whose cause is due to an overexcitation-caused dysfunction. These include diseases such as arrhythmias, spasms, cardiac and cerebral ischemia, pain and neurodegenerative diseases of various origins. For example: epilepsy, hypoglycemia, hypoxia, anoxia, brain trauma, brain edema, cerebral stroke, perinatal asphyxia, cerebellar degeneration, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotension, cardiac infarction, cardiac arrhythmia, angina pectoris, chronic pain, neuropathic pain and local anesthesia.
Ein weiterer Aspekt der Erfindung zielt folglich auf die Verwendung von Verbindungen der allgemeinen Formel 1_, als Arzneimittel, insbesondere als Arzneimittel, in denen die Blockade des spannungsabhängigen Natriumkanals einen therapeutischen Nutzen entfalten kann.A further aspect of the invention is therefore directed to the use of compounds of general formula I as pharmaceuticals, in particular as medicaments, in which the blockage of the voltage-dependent sodium channel can develop a therapeutic benefit.
Bevorzugt ist die Verwendung der erfindungsgemäßen Verbindungen der allgemeinen Fornel 1 zur Herstellung eines Arzneimittels zur Vorbeugung oder Behandlung von Arrhythmien, Spasmen, kardialen und Gehirnischämien, Schmerzen sowie neurodegenerative Erkrankungen.Preference is given to the use of the compounds according to the invention of general formula 1 for the preparation of a medicament for the prevention or treatment of arrhythmias, spasms, cardiac and brain ischemia, pain and neurodegenerative diseases.
Besonders bevorzugt ist die vorstehend genannte Verwendung der erfindungsgemäßen Verbindungen der allgemeinen Formel 1 zur Herstellung eines Arzneimittels zur Vorbeugung oder Behandlung von Epilepsie, Hypoglykämie, Hypoxie, Anoxie, Gehirntrauma, Gehirnoedem, Gehirn-Schlaganfall, perinatale Asphyxie, Degenerationen des Cerebellums, amyotrope laterale Sklerose, Morbus Huntington, Morbus Alzheimer, Morbus Parkinson, Zyklophrenie, Hypotonie, Herzinfakt, Herzrhythmusstörungen, Angina pectoris, chronischer Schmerz, neuropathischer Schmerz sowie Lokalanaesthesie. Als Testsystem für den Nachweis der Natriumkanal blockierenden Wirkung dient die BTX-Bindung am Natriumkanal [S.W. Postma & W.A. Catterall, Mol. Pharmacol 25, 219-227 (1984)] sowie patch-clamp Experimente, in denen gezeigt werden kann, daß die erfindungsgemäßen Verbindungen den elektrisch stimulierten Natriumkanal in einer "use-dependent" Art und Weise blockieren [W.A. Catterall, Trends Pharmacol. Sei., 8, 57-65 (1987)]. Durch die Auswahl des Zellsystems (z.B. neuronale, kardiale, DRG Zellen) kann die Wirkung der Substanzen auf verschiedene Natriumkanalsubtypen untersucht werden.Particularly preferred is the above-mentioned use of the compounds of general formula 1 according to the invention for the preparation of a medicament for the prevention or treatment of epilepsy, hypoglycemia, hypoxia, anoxia, brain trauma, brain edema, brain stroke, perinatal asphyxia, degenerations of the cerebellum, amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotension, cardiac infarction, cardiac arrhythmia, angina pectoris, chronic pain, neuropathic pain and local anesthesia. BTX binding to the sodium channel [SW Postma & WA Catterall, Mol. Pharmacol 25, 219-227 (1984)] as well as patch-clamp experiments in which it can be shown that the present invention is used as a test system for the detection of the sodium channel blocking effect Compounds block the electrically stimulated sodium channel in a "use-dependent" manner [WA Catterall, Trends Pharmacol. Sci., 8, 57-65 (1987)]. By selecting the cell system (eg neuronal, cardiac, DRG cells), the effect of the substances on different sodium channel subtypes can be investigated.
Die Natriumkanal blockierende Eigenschaft der"erfindungsgemäßen Verbindungen kann durch die Blockade des Veratridin induzierten Glutamat-releases nachgewiesen werden [S. Villauneva, P. Frenz, Y. Dragnic, F. Orrego, Brain Res. 461 , 377-380 (1988)]. Veratridin ist ein Toxin, das den Natriumkanal permanent öffnet. Dadurch kommt es, zu einem erhöhten Einstrom von Natriumionen in die Zelle. Dieser Natriumeinstrom führt in neuronalem Gewebe zu einer gesteigerten Freisetzung von Glutamat. Durch die erfindungsgemäßen Verbindungen läßt sich diese Glutamatfreisetzung antagonisieren.The sodium channel blocking property of the compounds of the invention can be demonstrated by the blockade of veratridine-induced glutamate release [S. Villauneva, P. Frenz, Y. Dragnic, F. Orrego, Brain Res. 461, 377-380 (1988)]. Veratridine is a toxin that permanently opens the sodium channel, which leads to increased influx of sodium ions into the cell, and this sodium influx leads to an increased release of glutamate in neuronal tissue, which can be antagonized by the compounds of this invention.
Neuroprotective Eigenschaften wurden durch protektive Wirkung in einem Ratten- MCAO-Modell [U. Pschorn & A. J. Carter, J. Stroke Cerebrovascular Diseases, 6, 93- 99 (1996)] sowie einem Malonat induziertem Läsionsmodel [ M.F. Beal, Annais of Neurology, 38, 357-366 (1995) und J.B. Schulz, R.T. Matthews, D.R. Henshaw und M.F. Beal, Neuroscience, 71. 1043-1048 (1996)] belegt.Neuroprotective properties were demonstrated by protective action in a rat MCAO model [U. Pschorn & A.J. Carter, J. Stroke Cerebrovascular Diseases, 6, 93-99 (1996)] and a malonate-induced lesion model [M.F. Beal, Annais of Neurology, 38, 357-366 (1995) and J.B. Schulz, R.T. Matthews, D.R. Henshaw and M.F. Beal, Neuroscience, 71. 1043-1048 (1996)].
Analgetische Wirkung lassen sich in Modellen der diabetischen Neuropathie sowie in einem Ligatur-Modell belegen [C. Courteix, M. Bardin, C. Chantelauze, J. Lavarenne, A. Eschalier, Pain 57, 153-160 (1994); C. Courteix, A. Eschalier, J. Lavarenne, Pain 53, 81-88 (1993); G. J. Bennett & Y.-K. Xie, Pain 33, 87-107 (1988)]. Ferner wurde beschrieben, daß Natriumkanalblocker zur Therapie der Zyklophrenie (manisch depressive Erkrankung) eingesetzt werden können [J. R. Calabrese, C. Bowden, M.J. Woyshville; in: Psychopharmacology: The Fourth Generation of Progress (Eds.: D. E. Bloom and D. J. Kupfer) 1099-1111. New York: Raveη Press Ltd.].Analgesic effects can be demonstrated in models of diabetic neuropathy and in a ligature model [C. Courteix, M. Bardin, C. Chantelauze, J. Lavarenne, A. Eschalier, Pain 57, 153-160 (1994); C. Courteix, A. Eschalier, J. Lavarenne, Pain 53, 81-88 (1993); G.J. Bennett & Y.-K. Xie, Pain 33, 87-107 (1988)]. It has also been described that sodium channel blockers can be used for the therapy of cyclophrenia (manic depressive illness) [J. R. Calabrese, C. Bowden, M.J. Woyshville; in: Psychopharmacology: The Fourth Generation of Progress (Ed .: D.E. Bloom and D.J. Kupfer) 1099-1111. New York: Raveη Press Ltd.].
Die erfindungsgemäßen Verbindungen lassen sich in Analogie zu an sich bekannten Synthesemethoden herstellen. Ein möglicher Syntheseweg ist in Schema 1 dargestellt. Die in Schema 1 als Ausgangsverbindungen gekennzeichneten 1 ,2,3,4, 5, 6-Hexahydro-2,6-methano-3-benzazocin-10-ole (2) sind gemäß aus dem Stand der Technik bekannten Syntheseverfahren erhältlich. Diesbezüglich wird an dieser Stelle auf die Europäische Patentanmeldung EP-A-521422 sowie auf die Internationalen Patentanmeldungen WO 97/06146 und WO 99/14199 verwiesen.The compounds of the invention can be prepared in analogy to known synthesis methods. One possible synthetic route is shown in Scheme 1. The 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine-10-ols (2) characterized as starting compounds in Scheme 1 are obtainable according to synthetic methods known from the prior art. This will be on see also European Patent Application EP-A-521422 and International Patent Applications WO 97/06146 and WO 99/14199.
Schema 1 :Scheme 1:
Der Synthesebaustein 3 enthält eine Abgangsgruppe X, die bevorzugt Chlor, Brom, Hydroxy oder ein Methoxy- oder Ethoxy-Rest ist. Zur detaillierten Erläuterung der Synthese der erfindungsgemäßen Verbindungen der Formel 1 wird auf die nachstehend beschriebenen experimentellen Arbeitsvorschriften verwiesen.The synthesis unit 3 contains a leaving group X, which is preferably chlorine, bromine, hydroxyl or a methoxy or ethoxy radical. For a detailed explanation of the synthesis of the compounds of the formula 1 according to the invention, reference is made to the experimental working instructions described below.
Ein möglicher Zugang zu Verbindungen der Formel , in denen R9 Methyl bedeutet, ist in Schema 2 skizziert.A possible access to compounds of the formula in which R 9 is methyl is outlined in Scheme 2.
1 (mit R9= Methyl) Zur detaillierten Erläuterung der Synthese der erfindungsgemäßen Verbindungen der Formel 1 gemäß Schema 2 wird ebenfalls auf die nachstehend beschriebenen experimentellen Arbeitsvorschriften verwiesen.1 (with R 9 = methyl) For a detailed explanation of the synthesis of the compounds of formula 1 according to Scheme 2 according to the invention, reference is also made to the experimental working instructions described below.
Die nachfolgenden Beispiele dienen der näheren Erläuterung der Erfindung, ohne diese jedoch auf die beispielhaft offenbarten Verbindungen und Verfahren zu beschränken.The following examples serve to illustrate the invention without, however, limiting it to the compounds and methods disclosed by way of example.
Beispiel 1 : (2R)-N-Allyloxyethyl-1 ,2,3,4,5,6-hexahvdro-6,11 ,11-trimethyl-2,6- methano-3-benzazocin-10-ol-hydrochloridExample 1: (2R) -N-Allyloxyethyl-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocin-10-ol hydrochloride
1 ,8 g Allyloxyessigsäure werden in 15 mL Dichlormethan vorgelegt, mit 4,8 g TBTU und 7,5 mL Ethyldiisopropylamin versetzt und 15 Min. bei RT gerührt. Anschließend wird auf -5QC abgekühlt und 3.1 g 1 ,2,3,4,5,6-Hexahydro-6,11 ,11-trimethyl-2,6- methano-3-benzazocin-10-ol zugegeben. Man läßt 30 Min bei 0°C rühren, und 1 h bei RT. Anschließend wird je einmal mit 100ml 2nHCL und 100ml 10%iger Kaliumcarbonatlösung gewaschen, getrocknet und i.Vak. eingeengt. Der Rückstand wird in 50 mL THF aufgenommen und unter Stickstoff zu einer Suspension von 1 ,0 g Lithiumaluminiumhydrid in 50ml THF zugetropft. (Temp. steigt auf 35°C an) Anschließend wird auf 50°C erwärmt, 1 h gerührt, abgekühlt und bei 0 -10°C 1 ml Wasser zugetropft, 30 Min gerührt, 3ml NaOH zugegeben und 30 Min gerührt. Der Niederschlag wird abgesaugt, die Mutterlauge i.Vak. eingeengt und der Rückstand über eine kurze Säule filtriert. ( ca 75 ml Kieselgel; Dichlormehan 70, Essigester 20, Methanol 10). Die geeignete Fraktionen werden i.V. eingeengt, aus Aceton + eth.HCI kristallisiert. Ausbeute 2.8 g (77%), Schmp.: 236 °C; [ ]D 20= -78,3 ° (c = 1 ; Methanol). Beispiel 2: (2R,2"S)-N-(2-Allyloxy-propyl)-1 ,2,3,4,5,6-hexahvdro-6.11.11-trimethyl- 2,6-methano-3-benzazocin-10-ol-hvdrochlorid 1.18 g of allyloxyacetic acid are initially charged in 15 ml of dichloromethane, treated with 4.8 g of TBTU and 7.5 ml of ethyldiisopropylamine and stirred at RT for 15 min. It is then cooled to -5 ° C. and 3.1 g of 1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocin-10-ol are added. The mixture is stirred for 30 min at 0 ° C, and 1 h at RT. The mixture is then washed once each with 100 ml of 2NHCL and 100 ml of 10% potassium carbonate solution, dried and concentrated by evaporation in vacuo. concentrated. The residue is taken up in 50 ml THF and added dropwise under nitrogen to a suspension of 1, 0 g lithium aluminum hydride in 50 ml THF. (Temp. Rises to 35 ° C) Then it is warmed to 50 ° C, stirred for 1 h, cooled and added dropwise at 0 -10 ° C 1 ml of water, stirred for 30 min, added 3ml NaOH and stirred for 30 min. The precipitate is filtered off, the mother liquor i.Vak. concentrated and the residue filtered through a short column. (About 75 ml of silica gel, dichloromethane 70, ethyl acetate 20, methanol 10). The appropriate fractions are evaporated down iV, crystallized from acetone + eth. HCl. Yield 2.8 g (77%), mp: 236 ° C; [ D 20 = -78.3 ° (c = 1, methanol). Example 2: (2R, 2 "S) -N- (2-Allyloxy-propyl) -1,2,3,4,5,6-hexahydro-6,11,1-trimethyl-2,6-methano-3-benzazocine -10-ol hvdrochlorid
Die Darstellung erfolgt analog zur Durchführung nach Beispiel 1. Ausbeute 56%, Schmp.: 239 °C; [α]D 20= -33,9 ° (c = 1 ; Methanol).The preparation is analogous to the procedure of Example 1. Yield 56%, mp.: 239 ° C; [α] D 20 = -33.9 ° (c = 1, methanol).
Beispiel 3: (2R,2"S)-N-(2-But-2-enoxy-propyn-1 ,2,3,4,5,6-hexahvdro-6,11.11- trimethyl-2.6-methano-3-benzazocin-10-ol-hvdrochloridExample 3: (2R, 2 "S) -N- (2-But-2-enoxy-propyn-1, 2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-one benzazocin-10-ol-hvdrochlorid
Die Darstellung erfolgt analog zur Durchführung nach Beispiel 1. Ausbeute 47%, Schmp.: 205 °CThe preparation is analogous to the procedure of Example 1. Yield 47%, mp.: 205 ° C.
Beispiel 4: (2R.2"S)-N-r2-(2-Methyl-propenoxy)-propyll-1 ,2.3,4,5,6-hexahvdro- 6.11 ,11-trimethyl-2,6-methano-3-benzazocin-10-ol-hvdrochloridExample 4: (2R.2 "S) -N-r2- (2-methyl-propenoxy) -propyl-1, 2,3,4,5,6-hexahydro-6,11,1-trimethyl-2,6-methano-3 -benzazocin-10-ol-hvdrochlorid
Die Darstellung erfolgt analog zur Durchführung nach Beispiel 1. Ausbeute 12%, Schmp.: 240 °C; [α]D 20= -29,6 ° (c = 1 ; Methanol). Beispiel 5: (2R)-N-r2-Allyloxyethvn-1 ,2,3,4,5,6-hexahvdro-6,9,11 ,11-tetramethyl-2.6- methano-3-benzazocin-10-ol-hvdrochloridThe preparation is analogous to the procedure of Example 1. Yield 12%, mp. 240 ° C; [α] D 20 = -29.6 ° (c = 1, methanol). Example 5: (2R) -N-r2-Allyloxyethvn-1, 2,3,4,5,6-hexahydro-6,9,11,11-tetramethyl-2,6-methano-3-benzazocin-10-ol hydrochloride
1 ,9 g (2R)-N-Allyloxyethyl-1 ,2,3,4,5,6-hexahydro-6,11 ,11-trimethyl-2,6-methano-3- benzazocin-10-ol-hydrochlorid (Beispiel 1 ) werden in 40 mL Methanol gelöst und mit 3 g 30%iger Formalinlösung und 3 mL 4 N NaOH versetzt. Man erhitzt 12 Std auf 50 °C, zieht das Lösungsmittel i.Vak. ab, versetzt den Rückstand mit 100 mL Wasser und extrahiert 2 mal mit je 200ml Ether. Die organische Phase wird mit Wasser gewaschen, getrocknet und i.Vak. eingeengt. Der Rückstand wird in 20 mL Dichlormethan gelöst und bei RT 1,5 g SOCl2 zugetropft. Nach 30 min. wird i.Vak. eingeengt, der Rückstand in 20 ml THF aufgenommen und unter Sickstoff zu einer Suspension von 0,5 g Lithiumaluminiumhydrid in 20ml Terahydrofuran zugetropft. Anschließend wird 2 h auf 50 °C erwärmt, abgekühlt, 1 ,5mL 4N NaOH zugetropft und 30 min gerührt.Der Niederschlag wird abgesaugt und die Mutterlauge i.Vak. eingeengt. Der Rückstand wird über eine kurze Kieselgelsäule filtriert (ca 30 mL Kieselgel, ca 250 mL Essigester). ). Die geeignete Fraktionen werden i.V. eingeengt, aus Aceton + eth.HCI kristallisiert. Ausbeute 1.1 g (56%), Schmp.: 212 °C, [α]D 20= - 71 ,6 ° (c = 1 ; Methanol).1.9 g of (2R) -N-allyloxyethyl-1,2,3,4,5,6-hexahydro-6,11,11-trimethyl-2,6-methano-3-benzazocin-10-ol hydrochloride ( Example 1) are dissolved in 40 mL of methanol and treated with 3 g of 30% formalin solution and 3 mL of 4 N NaOH. The mixture is heated for 12 hours at 50 ° C, the solvent is drawn i.Vak. , the residue is combined with 100 ml of water and extracted twice with 200 ml of ether. The organic phase is washed with water, dried and i.vac. concentrated. The residue is dissolved in 20 ml of dichloromethane and 1.5 g of SOCl 2 are added dropwise at RT. After 30 min. will i.Vak. concentrated, the residue taken up in 20 ml of THF and added dropwise under nitrogen to a suspension of 0.5 g of lithium aluminum hydride in 20 ml of terahydrofuran. The mixture is then heated to 50 ° C for 2 h, cooled, 1, 5mL 4N NaOH was added dropwise and stirred for 30 min. The precipitate is filtered off with suction and the mother liquor i.Vak. concentrated. The residue is filtered through a short silica gel column (about 30 mL silica gel, about 250 mL ethyl acetate). ). The appropriate fractions are evaporated down iV, crystallized from acetone + eth. HCl. Yield 1.1 g (56%), mp: 212 ° C, [α] D 20 = - 71, 6 ° (c = 1, methanol).
Beispiel 6: (2R.2"S)-N-[2-Allyloxy-propyn-1 ,2,3,4,5.6-hexahvdro-6,9,11.11- tetramethyl-2,6-methano-3-benzazocin-10-ol-hydrochloridExample 6: (2R.2 "S) -N- [2-Allyloxy-propyn-1, 2,3,4,5,6-hexahydro-6,9,11,1'-tetramethyl-2,6-methano-3-benzazocine 10-ol hydrochloride
Die Darstellung erfolgt analog zur Durchführung nach Beispiel 5 ausgehend von Beispiel 2. Ausbeute 60%, Schmp.: 215 °C; [ ]D 20_ - -29,3 ° (c = 1 ; Methanol) Die erfindungsgemäßen Verbindungen können oral, transdermal, inhalativ oder parenteral verabreicht werden. Die erfindungsgemäßen Verbindungen liegen hierbei als aktive Bestandteile in üblichen Darreichungsformen vor, beispielsweise in Zusammensetzungen, die im wesentlichen aus einem inerten pharmazeutischen Träger und einer effektiven Dosis des Wirkstoffs bestehen, wie beispielsweise Tabletten, Dragees, Kapseln, Oblaten, Pulver, Lösungen, Suspensionen, Emulsionen, Sirupe, Suppositorien, transdermale Systeme etc.. Eine wirksame Dosis der erfindungsgemäßen Verbindungen liegt bei einer oralen Anwendung zwischen 1 und 1000, vorzugsweise zwischen 1 und 500, besonders bevorzugt zwischen 5-300 mg/Dosis, bei intravenöser, subcutaner oder intramuskulärer Anwendung zwischen 0,001 und 50, vorzugsweise zwischen 0,1 und 10 mg/Dosis. Für die Inhalation sind erfindungsgemäß Lösungen geeignet, die 0,01 bis 1 ,0, vorzugsweise 0,1 bis 0,5 % Wirkstoff enthalten. Für die inhalative Applikation ist die Verwendung von Pulvern bevorzugt. Aufgrund ihrer besonderen physicochemischen Eigenschaften ist es ferner möglich, die erfindungsgemäßen Verbindungen als Infusionslösung, vorzugsweise in einer physiologischen Kochsalzlösung oder Nährsalzlösung einzusetzen. Bei einer Infusion könnte 10-100 mg/h bevorzugt 25-60 mg/h zur Anwendung kommen . Die letztgenannte Applikationsform ist erfindungsgemäß von herausragender Bedeutung.The preparation is analogous to the procedure of Example 5 starting from Example 2. Yield 60%, mp. 215 ° C; [] D 20_ - -29.3 ° (c = 1, methanol) The compounds according to the invention can be administered orally, transdermally, by inhalation or parenterally. The compounds of the invention are present as active ingredients in conventional dosage forms, for example in compositions consisting essentially of an inert pharmaceutical carrier and an effective dose of the active ingredient, such as tablets, dragees, capsules, wafers, powders, solutions, suspensions, emulsions , Syrups, suppositories, transdermal systems etc. An effective dose of the compounds according to the invention is between 1 and 1000, preferably between 1 and 500, more preferably between 5-300 mg / dose when administered orally, when administered intravenously, subcutaneously or intramuscularly 0.001 and 50, preferably between 0.1 and 10 mg / dose. For inhalation solutions are suitable according to the invention containing 0.01 to 1, 0, preferably 0.1 to 0.5% active ingredient. For the inhalation application, the use of powders is preferred. Because of their particular physicochemical properties, it is also possible to use the compounds according to the invention as infusion solution, preferably in a physiological saline solution or nutrient salt solution. For an infusion, 10-100 mg / h, preferably 25-60 mg / h, could be used. The latter application form is of outstanding importance according to the invention.
Die erfindungsgemäßen Verbindungen können allein oder in Kombination mit anderen erfindungsgemäßen Wirkstoffen, gegebenenfalls auch in Kombination mit weiteren pharmakologisch aktiven Wirkstoffen, zur Anwendung gelangen. Geeignete Anwendungsformen sind beispielsweise Tabletten, Kapseln, Zäpfchen, Lösungen, Säfte, Emulsionen oder dispersible Pulver. Entsprechende Tabletten können beispielsweise durch Mischen des oder der Wirkstoffe mit bekannten Hilfsstoffen, beispielsweise inerten Verdünnungsmitteln, wie Calciumcarbonat, Calciumphosphat oder Milchzucker, Sprengmitteln, wie Maisstärke oder Alginsäure, Bindemitteln, wie Stärke oder Gelatine, Schmiermitteln, wie Magnesiumstearat oder Talk, und/oder Mitteln zur Erzielung des Depoteffektes, wie Carboxymethylcellulose,The compounds according to the invention can be used alone or in combination with other active compounds according to the invention, if appropriate also in combination with other pharmacologically active substances. Suitable application forms are, for example, tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders. Corresponding tablets can be prepared, for example, by mixing the active substance (s) with known excipients, 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 carboxymethylcellulose,
Celluloseacetatphthalat, oder Polyvinylacetat erhalten werden. Die Tabletten können auch aus mehreren Schichten bestehen.Cellulose acetate phthalate, or polyvinyl acetate. The tablets can also consist of several layers.
Entsprechend können Dragees durch Überziehen von analog den Tabletten hergestellten Kernen mit üblicherweise in Drageeüberzügen verwendeten Mitteln, beispielsweise Kollidon oder Schellack, Gummi arabicum, Talk, Titandioxid oder Zucker, hergestellt werden. Zur Erzielung eines Depoteffektes oder zur Vermeidung von Inkompatibilitäten kann der Kern auch aus mehreren Schichten bestehen. Desgleichen kann auch die Drageehülle zur Erzielung eines Depoteffektes aus mehreren Schichten bestehen wobei die oben bei den Tabletten erwähnten Hilfsstoffe verwendet werden können.Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a depot effect or to avoid incompatibilities, the core can also consist of several layers. Similarly, the dragee cover to achieve a depot effect from several layers can be used wherein the above mentioned in the tablets excipients can be used.
Säfte der erfindungsgemäßen Wirkstoffe beziehungsweise Wirkstoffkombinationen können zusätzlich noch ein Süßungsmittel, wie Saccharin, Cyciamat, Glycerin oder Zucker sowie ein geschmacksverbesserndes Mittel, z.B. Aromastoffe, wie Vanillin oder Orangenextrakt, enthalten. Sie können außerdem Suspendierhilfsstoffe oder Dickungsmittel, wie Natriumcarboxymethylcellulose, Netzmittel, beispielsweise Kondensationsprodukte von Fettalkoholen mit Ethylenoxid, oder Schutzstoffe, wie p- Hydroxybenzoate, enthalten.Juices of the active compounds or active compound combinations according to the invention may additionally contain a sweetener, such as saccharin, cycamate, glycerol or sugar, as well as a taste-improving agent, e.g. Flavorings such as vanillin or orange extract. They may also contain suspending aids or thickening agents, such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
Injektionslösungen werden in üblicher weise, z.B. unter Zusatz von Konservierungsmitteln, wie p-Hydroxybenzoaten, oder Stabilisatoren, wie Alkalisalzen der Ethylendiamintetraessigsäure hergestellt und in Injektionsflaschen oder Ampullen abgefüllt.Injection solutions are prepared in the usual manner, e.g. prepared 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.
Die eine oder mehrere Wirkstoffe beziehungsweise Wirkstoffkombinationen enthaltenden Kapseln können beispielsweise hergestellt werden, indem man die Wirkstoffe mit inerten Trägern, wie Milchzucker oder Sorbit, mischt und in Gelatinekapseln einkapselt.The capsules containing one or more active ingredients or combinations of active substances can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatine capsules.
Geeignete Zäpfchen lassen sich beispielsweise durch Vermischen mit dafür vorgesehenen Trägermitteln, wie Neutralfetten oder Polyäthylenglykol beziehungsweise dessen Derivaten, herstellen.Suitable suppositories can be prepared, for example, by mixing with suitable carriers, such as neutral fats or polyethylene glycol or its derivatives.
Eine therapeutisch wirksame Tagesdosis beträgt zwischen 1 und 2500 mg, bevorzugt 100 - 1000 mg pro Erwachsener. A therapeutically effective daily dose is between 1 and 2500 mg, preferably 100-1000 mg per adult.
Die nachfolgenden Beispiele illustrieren die vorliegende Erfindung ohne sie jedoch in ihrem Umfang zu beschränken:The following examples illustrate the present invention without, however, limiting its scope:
Pharmazeutische FormulierungsbeispielePharmaceutical Formulation Examples
A) Tabletten pro TabletteA) Tablets per tablet
Wirkstoff 100 mg Milchzucker 140 mg Maisstärke 240 mgActive ingredient 100 mg lactose 140 mg corn starch 240 mg
Polyvinylpyrrolidon 15 mg Magnesiumstearat 5 mqPolyvinylpyrrolidone 15 mg magnesium stearate 5 mq
500 mg500 mg
Der feingemahlene Wirkstoff, Milchzucker und ein Teil der Maisstärke werden miteinander vermischt. Die Mischung wird gesiebt, worauf man sie mit einer Lösung von Polyvinylpyrrolidon in Wasser befeuchtet, knetet, feuchtgranuliert und trocknet. Das Granulat, der Rest der Maisstärke und das Magnesiumstearat werden gesiebt und miteinander vermischt. Das Gemisch wird zu Tabletten geeigneter Form und Größe verpreßt.The finely ground active substance, lactose and part of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet granulated and dried. The granules, the remainder of the corn starch and the magnesium stearate are sieved and mixed together. The mixture is compressed into tablets of suitable shape and size.
B) Tabletten pro TabletteB) Tablets per tablet
Wirkstoff 80 mg Maisstärke 190 mgActive ingredient 80 mg corn starch 190 mg
Milchzucker 55 mgLactose 55 mg
Mikrokristalline Cellulose 35 mgMicrocrystalline cellulose 35 mg
Polyvinylpyrrolidon 15 mgPolyvinylpyrrolidone 15 mg
Natrium-carboxymethylstärke 23 mg Magnesiumstearat 2 mqSodium carboxymethyl starch 23 mg Magnesium stearate 2 mq
400 mg400 mg
Der feingemahlene Wirkstoff, ein Teil der Maisstärke, Milchzucker, mikrokristalline Cellulose und Polyvinylpyrrolidon werden miteinander vermischt, die Mischung gesiebt und mit dem Rest der Maisstärke und Wasser zu einem Granulat verarbeitet, welches getrocknet und gesiebt wird. Dazu gibt man die Natrium- carboxymethylstärke und das Magnesiumstearat, vermischt und verpreßt das Gemisch zu Tabletten geeigneter Größe. C) Dragees pro DrageeThe finely ground active ingredient, a portion of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and processed with the remainder of the corn starch and water to a granulate which is dried and sieved. To this is added the sodium carboxymethyl starch and the magnesium stearate, mixed and pressed the mixture into tablets of suitable size. C) dragées per dragee
Wirkstoff 5 mgActive ingredient 5 mg
Maisstärke 41 ,5 mgCornstarch 41, 5 mg
Milchzucker 30 mgLactose 30 mg
Polyvinylpyrrolidon 3 mgPolyvinylpyrrolidone 3 mg
Magnesiumstearat 0.5 mqMagnesium stearate 0.5 mq
80 mg80 mg
Der Wirkstoff, Maisstärke, Milchzucker und Polyvinylpyrrolidon werden gut gemischt und mit Wasser befeuchtet. Die feuchte Masse drückt man durch ein Sieb mit 1 mm-Maschenweite, trocknet bei ca. 45°C und schlägt das Granulat anschließend durch dasselbe Sieb. Nach dem Zumischen von Magnesiumstearat werden auf einer Tablettiermaschine gewölbte Drageekerne mit einem Durchmesser von 6 mm gepreßt. Die so hergestellten Drageekerne werden auf bekannte Weise mit einer Schicht überzogen, die im wesentlichten aus Zucker und Talkum besteht. Die fertigen Dragees werden mit Wachs poliert.The active ingredient, corn starch, lactose and polyvinylpyrrolidone are mixed well and moistened with water. The moist mass is forced through a sieve with 1 mm mesh size, dried at about 45 ° C and then strikes the granules through the same sieve. After admixing magnesium stearate, curved tablet cores having a diameter of 6 mm are pressed on a tableting machine. The coated dragee cores are coated in a known manner with a layer which consists essentially of sugar and talc. The finished dragees are polished with wax.
D) Kapseln pro KapselD) Capsules per capsule
Wirkstoff 50 mgActive ingredient 50 mg
Maisstärke 268,5 mgCorn starch 268.5 mg
Magnesiumstearat 1 ,5 mgMagnesium stearate 1, 5 mg
320 mg320 mg
Substanz und Maisstärke werden gemischt und mit Wasser befeuchtet. Die feuchte Masse wird gesiebt und getrocknet. Das trockene Granulat wird gesiebt und mit Magensiumstearat gemischt. Die Endmischung wird in Hartgelatinekapseln Größe 1 abgefüllt.Substance and cornstarch are mixed and moistened with water. The moist mass is sieved and dried. The dry granules are sieved and mixed with magnesium stearate. The final mixture is filled into hard gelatine capsules size 1.
E) AmpullenlösungE) Ampoule solution
Wirkstoff 50 mgActive ingredient 50 mg
Natriumchlorid 50 mg Aqua pro inj. 5 mlSodium chloride 50 mg Aqua per inj. 5 ml
Der Wirkstoff wird bei Eigen-pH oder gegebenenfalls bei pH 5,5 bis 6,5 in Wasser gelöst und mit Natriumchlorid als Isotonans versetzt, die erhaltene Lösung wird pyrogenfrei filtriert und das Filtrat unter aseptischen Bedingungen in Ampullen abgefüllt, die anschließend sterilisiert und zugeschmolzen werden. Die Ampullen enthalten 5 mg, 25 mg und 50 mg Wirkstoff.The active ingredient is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and treated with sodium chloride as isotonic, the resulting solution is filtered pyrogen-free and the filtrate under aseptic conditions in ampoules bottled, which are then sterilized and sealed. The vials contain 5 mg, 25 mg and 50 mg active ingredient.
F) SuppositorienF) Suppositories
Wirkstoff 50 mgActive ingredient 50 mg
Adeps solidus 1650 mgAdeps solidus 1650 mg
1700 mg1700 mg
Das Hartfett wird geschmolzen. Bei 40°C wird die gemahlene Wirksubstanz homogen dispergiert. Es wird auf 38°C abgekühlt und in schwach vorgekühlte Suppositorienformen ausgegossen. The hard fat is melted. At 40 ° C., the ground active substance is dispersed homogeneously. It is cooled to 38 ° C and poured into slightly pre-cooled suppository molds.

Claims

Patentansprücheclaims
1 ) Verbindungen der allgemeinen Formel 11) Compounds of general formula 1
worin wherein
R"! , R2 und R3 gleich oder verschieden, Wasserstoff, Methyl oder Ethyl; R4 Wasserstoff, Methyl oder Ethyl;R ", R 2 and R 3 are identical or different, are hydrogen, methyl or ethyl;! R4 is hydrogen, methyl or ethyl;
R5, R6 und R7 gleich oder verschieden, Wasserstoff, Methyl oder Ethyl; R3 und R9 gleich oder verschieden Wasserstoff, Fluor, Chlor, Brom, Methyl,R5, R6 and R7 are the same or different, are hydrogen, methyl or ethyl; R 3 and R 9 are identical or different and are hydrogen, fluorine, chlorine, bromine, methyl,
Ethyl, Hydroxy oder Methoxy bedeuten können, gegebenenfalls in Form ihrer Racemate, ihrer Enantiomere, ihrer Diastereomere und ihrer Gemische, sowie gegebenenfalls ihrer pharmakologisch unbedenklichen Säureadditionssalze.Ethyl, hydroxy or methoxy, optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their pharmacologically acceptable acid addition salts.
2) Verbindungen der allgemeinen Formel 1 nach Anspruch 1 , worin2) Compounds of general formula 1 according to claim 1, wherein
R1 , R2 und R3 gleich oder verschieden, Wasserstoff oder Methyl;R1, R 2 and R 3 are identical or different, are hydrogen or methyl;
R4 Wasserstoff oder Methyl;R4 is hydrogen or methyl;
R5, R6 und R7 gleich oder verschieden, Wasserstoff oder Methyl; vorzugsweiseR 5 , R 6 and R 7 are identical or different, hydrogen or methyl; preferably
Methyl;Methyl;
R3 Wasserstoff, Methyl, Hydroxy oder Methoxy, bevorzugtR 3 is hydrogen, methyl, hydroxy or methoxy, preferred
Wasserstoff oder Methyl bedeuten können,Can mean hydrogen or methyl,
R9 Wasserstoff oder Methyl bedeuten können, gegebenenfalls in Form ihrer Racemate, ihrer Enantiomere, ihrer Diastereomere und ihrer Gemische, sowie gegebenenfalls ihrer pharmakologisch unbedenklichen Säureadditionssalze. 3) Verbindungen der allgemeinen Formel nach Anspruch 1 oder 2, worinR 9 may be hydrogen or methyl, optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their pharmacologically acceptable acid addition salts. 3) Compounds of the general formula according to claim 1 or 2, wherein
R1 , R2 und R3 gleich oder verschieden, Wasserstoff oder Methyl; R4 Wasserstoff oder Methyl; R5, R6 und R7 Methyl;R1, R 2 and R 3 are identical or different, are hydrogen or methyl; R 4 is hydrogen or methyl; R 5 , R 6 and R 7 are methyl;
R3 Wasserstoff oder Methyl, bevorzugt Wasserstoff;R 3 is hydrogen or methyl, preferably hydrogen;
R9 Wasserstoff oder Methyl bedeuten können, gegebenenfalls in Form ihrer Racemate, ihrer Enantiomere, ihrer Diastereomere und ihrer Gemische, sowie gegebenenfalls ihrer pharmakologisch unbedenklichen Säureadditionssalze.R 9 may be hydrogen or methyl, optionally in the form of their racemates, their enantiomers, their diastereomers and their mixtures, and optionally their pharmacologically acceptable acid addition salts.
4) Verbindungen der allgemeinen Formel i nach Anspruch 1 , 2 oder 3, dadurch gekennzeichnet, daß sie in der 1 R und, sofern R4 nicht Wasserstoff bedeutet, ferner in der 2"S-Konfiguration vorliegen.4) Compounds of general formula i according to claim 1, 2 or 3, characterized in that they are in the 1 R and, unless R4 is hydrogen, also in the 2 "S configuration.
5) Pharmazeutische Zubereitung gekennzeichnet durch einen Gehalt an einer der Verbindungen der Formel 1 nach einem der Ansprüche 1 bis 4 neben üblichen Hilfs- und Trägerstoffen.5) A pharmaceutical preparation characterized by a content of one of the compounds of formula 1 according to any one of claims 1 to 4 in addition to conventional excipients and carriers.
6) Verwendung einer der Verbindungen der Formel 1 nach einem der Ansprüche 1 bis 4 als Arzneimittel.6) Use of one of the compounds of formula 1 according to any one of claims 1 to 4 as a medicament.
7) Verwendung einer der Verbindungen der Formel 1 nach einem der Ansprüche 1 bis 4 zur Herstellung eines Arzneimittels zur Vorbeugung oder Behandlung von Erkrankungen oder Störungen, bei denen die Blockade des spannungsabhängigen Natriumkanals einen therapeutischen Nutzen entfalten kann.7) Use of one of the compounds of formula 1 according to any one of claims 1 to 4 for the manufacture of a medicament for the prevention or treatment of diseases or disorders in which the blockage of the voltage-dependent sodium channel can develop a therapeutic benefit.
8) Verwendung einer der Verbindungen der Formel nach einem der Ansprüche 1 bis 4 zur Herstellung eines Arzneimittels zur Vorbeugung oder Behandlung von Arrhythmien, Spasmen, kardialen und Gehirnischämien, Schmerzen sowie neurodegenerative Erkrankungen. 9) Verwendung einer der Verbindungen der Formel nach einem der Ansprüche 1 bis 4 zur Herstellung eines Arzneimittels zur Vorbeugung oder Behandlung von Epilepsie, Hypoglykämie, Hypoxie, Anoxie, Gehirntrauma, Gehirnoedem, Gehirn-Schlaganfall, perinatale Asphyxie, Degenerationen des Cerebellums, amyotrope laterale Sklerose, Morbus Huntington, Morbus Alzheimer, Morbus Parkinson, Zyklophrenie, Hypotonie, Herzinfakt, Herzrhythmusstörungen, Angina pectoris, chronischer Schmerz, neuropathischer Schmerz oder Lokalanaesthesie. 8) Use of one of the compounds of the formula according to any one of claims 1 to 4 for the manufacture of a medicament for the prevention or treatment of arrhythmias, spasms, cardiac and cerebral ischemia, pain and neurodegenerative diseases. 9) Use of one of the compounds of the formula according to one of claims 1 to 4 for the manufacture of a medicament for the prevention or treatment of epilepsy, hypoglycemia, hypoxia, anoxia, brain trauma, brain edema, brain stroke, perinatal asphyxia, degenerations of the cerebellum, amyotrophic lateral sclerosis , Huntington's disease, Alzheimer's disease, Parkinson's disease, cyclophrenia, hypotension, cardiac infarction, cardiac arrhythmias, angina pectoris, chronic pain, neuropathic pain or local anesthesia.
EP03737261A 2002-02-02 2003-01-21 N-allyloxyethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines and the use of the same as pharmaceuticals Withdrawn EP1474398A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10204276A DE10204276A1 (en) 2002-02-02 2002-02-02 N-Allyloxyethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines and their use as pharmaceuticals
DE10204276 2002-02-02
PCT/EP2003/000538 WO2003066599A1 (en) 2002-02-02 2003-01-21 N-allyloxyethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines and the use of the same as pharmaceuticals

Publications (1)

Publication Number Publication Date
EP1474398A1 true EP1474398A1 (en) 2004-11-10

Family

ID=7713598

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03737261A Withdrawn EP1474398A1 (en) 2002-02-02 2003-01-21 N-allyloxyethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines and the use of the same as pharmaceuticals

Country Status (10)

Country Link
EP (1) EP1474398A1 (en)
JP (1) JP2005517013A (en)
AR (1) AR038381A1 (en)
AU (1) AU2003215540A1 (en)
CA (1) CA2474687A1 (en)
DE (1) DE10204276A1 (en)
PE (1) PE20030991A1 (en)
TW (1) TW200303203A (en)
UY (1) UY27637A1 (en)
WO (1) WO2003066599A1 (en)

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL7804509A (en) * 1978-04-26 1979-10-30 Acf Chemiefarma Nv Novel 6,7-benzomorphan derivatives and their acid addition salts.
DE4121821A1 (en) * 1991-07-02 1993-01-14 Boehringer Ingelheim Kg NEW BENZOMORPHANE AND ITS USE AS A MEDICAMENT
DE4122141C2 (en) * 1991-07-04 1999-05-27 Porsche Ag Exhaust pipe of an internal combustion engine
DE19740110A1 (en) * 1997-09-12 1999-03-18 Boehringer Ingelheim Pharma New hydroxy substituted benzomorphan derivatives
US6245777B1 (en) * 1999-02-23 2001-06-12 Boehringer Ingelheim Pharma Kg N-(5-phenyl-tetrahydrofuranyl)methyl- and N-(6-phenyl-tetrahydropyranyl)methyl-substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-10-ols
DE19907874A1 (en) * 1999-02-23 2000-08-24 Boehringer Ingelheim Pharma New N-substituted hexahydro-2,6-methano-3-benzazocin-10-ol derivatives, as tension-dependent sodium channel blockers useful for treating e.g. arrhythmia, spasms, pain or neurodegenerative diseases
DE19957156A1 (en) * 1999-11-27 2001-05-31 Boehringer Ingelheim Pharma New amino and fluoro substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine derivatives useful in treatment of e.g. arrythmias, spasms, ischaemia, pain and neurodegenerative disorders

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO03066599A1 *

Also Published As

Publication number Publication date
TW200303203A (en) 2003-09-01
DE10204276A1 (en) 2003-08-07
AR038381A1 (en) 2005-01-12
AU2003215540A1 (en) 2003-09-02
WO2003066599A1 (en) 2003-08-14
CA2474687A1 (en) 2003-08-14
UY27637A1 (en) 2003-08-29
PE20030991A1 (en) 2004-01-27
JP2005517013A (en) 2005-06-09

Similar Documents

Publication Publication Date Title
DE69829286T2 (en) NEW METHOD FOR PRODUCING PAROXETINE-CONTAINING SOLID DISPERSIONS
EP1622612B1 (en) Pharmaceutical formulation of the sodium salt of telmisartan
DD293493A5 (en) USE OF ADAMANTAN DERIVATIVES FOR THE PREVENTION AND TREATMENT OF CEREBRAL ISCHAEMY
EP1418915B1 (en) Neuroprotective drug
EP1442023B1 (en) Crystalline sodium salt of telmisartan and the use of the same as an angiotensin antagonist
DE60125981T2 (en) AMLODIPIN IN THE FORM OF THE FREE BASE
DE69612753T2 (en) (R) -5-BROMO-N- (1-ETHYL-4-METHYLHEXAHYDRO-1H-1,4-DIAZEPIN-6-YL) -2-METHOXY-6-METHYLAMINO-3-PYRIDINE-CARBOXAMIDE, METHOD FOR THE PRODUCTION THEREOF AND THE CONTAINER THEREOF MEDICAL PREPARATION
EP1485057B9 (en) Derivatives of azaspiro compounds for the treatment of pain
EP0002672B1 (en) Substituted pyrrolidines, process for their preparation and medicaments containing them
EP1157020B1 (en) Substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-10-ols, method for producing them and their use as medicaments
DE2749584A1 (en) Bridged geminal di:phenyl-piperidine(s) - used as CNS stimulants, spasmolytic agents and esp. for treating Parkinsonism
WO2003066599A1 (en) N-allyloxyethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines and the use of the same as pharmaceuticals
DE10203104A1 (en) Ambroxol for the treatment of chronic pain
EP1100780B1 (en) 2,3,3a,4,9,9a-HEXAHYDRO-8-HYDROXY-1H-BENZ[F]INDOLES, A METHOD FOR THE PRODUCTION THEREOF, AND THEIR USE AS MEDICAMENTS
DE1695785C3 (en) 2-aminomethyl-beitzofurans, processes for their production and preparations containing these compounds
US6683089B2 (en) N-allyoxyethyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine-10-ols
DE19957156A1 (en) New amino and fluoro substituted 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine derivatives useful in treatment of e.g. arrythmias, spasms, ischaemia, pain and neurodegenerative disorders
DE3316155C2 (en)
DE1967186C3 (en) Medicinal products containing 4,4-diarylpiperidines
DE2843328A1 (en) PHENYLACETAMIDE COMPOUNDS AND THE COMPOSITION CONTAINING THEM
DE1620407C (en) 3 Hydroxy 6 oxo-N phenylethyl morphinan (ice) compounds and their salts and processes for their production
DE3712385A1 (en) 2-(Phenylimino)imidazolidines
DE19948428A1 (en) New LTB¶4¶ antagonist, process for its preparation and its use as a medicament
CH637626A5 (en) Process for the preparation of peptides
DE2226702A1 (en) Hypoglycaemic tetrahydrocarbazoles - for treating diabetes mellitus

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: 20040902

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO

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: 20100803