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WO2002046163A2 - Quinoline derivatives and their use as anti-epileptics - Google Patents

Quinoline derivatives and their use as anti-epileptics Download PDF

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Publication number
WO2002046163A2
WO2002046163A2 PCT/DE2001/004452 DE0104452W WO0246163A2 WO 2002046163 A2 WO2002046163 A2 WO 2002046163A2 DE 0104452 W DE0104452 W DE 0104452W WO 0246163 A2 WO0246163 A2 WO 0246163A2
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Prior art keywords
quinoline
hydroxy
methylquinoline
radical
methyl
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German (de)
French (fr)
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WO2002046163A3 (en
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Michael Wackernagel
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Priority to AU2002216939A priority patent/AU2002216939A1/en
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Publication of WO2002046163A3 publication Critical patent/WO2002046163A3/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • 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

Definitions

  • the present invention relates to quinoline derivatives of the general formula (I) or physiologically compatible derivatives or analogs thereof, processes for their preparation, pharmaceutical compositions containing these compounds, the use of these compounds for the preparation of medicaments for the prophylaxis and therapy of sodium channel-dependent diseases such as in particular epilepsy and methods for the prophylaxis and control of sodium channel-dependent diseases such as, in particular, epileptic seizures.
  • Epilepsy is a disease that is characterized as paroxysmal, self-sustaining or self-limiting excessive neuronal discharges of the brain, genetically determined, physiologically acquired or as a result of an organic change. Based on clinical and electroencephalographic observations, the four general subtypes of epilepsy are as follows:
  • anti-epileptics Medications to treat epilepsy are called anti-epileptics.
  • the known anti-epileptics have one or more of the following mechanisms of action A :
  • Tegretal ® active ingredient: carbamazepine
  • Carbamazepine is a sodium channel blocker that reduces repetitive discharges of neuronal membranes (sodium channels) 5 .
  • Phenhydan ® active ingredient: phenytoin
  • Phenytoin is a sodium channel blocker that reduces repetitive discharges of neuronal membranes (sodium channels) 0 .
  • Antiepileptic drugs are believed to prevent or control seizures by acting on the focus of the attack. These seizures represent either a cluster of pathophysiologically altered neurons, normal cells with reduced vascular supply or an injured area in which the nerve fibers have not yet been destroyed.
  • the known drugs for epilepsy treatment can only be used for the prophylaxis of epileptic symptoms such as. B. the reduction and control of epileptic seizures, but not used to cure epilepsy. Only about 50% of epileptic patients can be adequately treated with the currently available anti-epileptic drugs H. Therefore, there is still an urgent need for more selective, effective and less toxic antiepileptics.
  • the present invention is therefore based on the object of eliminating the disadvantages of the prior art.
  • new pharmaceutically active compounds are to be provided which have a better action, fewer side effects and fewer interactions with other medicaments.
  • Another goal is to provide compounds that ensure easier use compared to the drugs available hitherto in the therapy of epilepsy and other sodium channel-dependent diseases.
  • the quinoline derivatives according to the invention are more effective than the prior art for the treatment of epilepsy and other sodium channel-dependent diseases.
  • the present invention also provides new quinoline derivatives compared to the prior art.
  • the present invention provides pharmaceutical preparations or compositions comprising the quinoline derivatives according to the invention.
  • the present invention further relates to the use of the quinoline derivatives according to the invention.
  • the quinoline derivatives according to the invention are particularly suitable for the treatment of epilepsy patients with simple partial seizures, complex partial seizures, grand attacks and mixed forms of epilepsy.
  • the quinoline derivatives according to the invention are also provided for the manufacture of medicaments for the prophylaxis and therapy of epilepsy, in particular simple partial seizures, complex partial seizures, grand mal seizures and mixed forms of epilepsy, as well as other sodium channel-dependent diseases.
  • quinoline derivatives provided by the present invention and in particular the quinoline derivatives which are new compared to the prior art and which can be used for the prophylaxis and control of epilepsy and other sodium channel-dependent diseases have the following advantages over known medicaments for these indications Properties: They are relatively non-toxic, have a high degree of effectiveness and enable a therapeutic response over a relatively long period of time.
  • R 1 is a straight-chain or branched, cyclic and / or acyclic alkyl radical with 1 to 15 C atoms without or with 1 to three hydroxyl groups; a straight-chain or branched, cyclic and / or acyclic alkenyl or alkynyl radical and oxyalkynyl radical (-O-CC-) having 1 to 15 C atoms, and 1 to 3 unsaturated CC- Bonds with or without substituents, such as. B.
  • hydroxy groups (1 to 3 pieces), ether groups, unsubstituted or substituted aryl groups, such as p-tolyl or phenyl groups, substituted carbonyl, oxycarbonyl groups or silyl groups; a straight-chain or branched, cyclic and / or acyclic alkoxy radical; a hydrogen atom or a hydroxyl group.
  • alkoxy groups with 1 to 5 carbon atoms a straight-chain or branched cyclic and / or acyclic alkenyl or alkynyl radical with 1 to 15 C atoms, and 1 to 3 unsaturated C-C bonds with or without substituents such as.
  • Phenyl groups substituted carbonyl or oxycarbonyl groups, silyl groups, substituted or unsubstituted cyclohexyl groups. The following may be mentioned as specific substituents:
  • R 3 is a hydrogen atom, a hydroxyl group, a straight-chain or branched alkoxy radical having 1 to 5 carbon atoms, a straight-chain or branched alkyl radical 1 to 5 carbon atoms without or with 1 to 3 hydroxyl groups or a substituted carbonyl group.
  • R, R, R and R represent a hydrogen atom; a straight-chain or branched, cyclic and / or acyclic alkyl radical with 1 to 4 carbon atoms, such as cycloexyl, alkylcyclohexyl radical with 1 to 4 carbon atoms in the alkyl part, cycloheptyl, cyclooctyl; a substituted or unsubstituted aryl radical, such as phenyl radical, which may be mono- or disubstituted by halogen, such as fluorine, chlorine or bromine, a straight-chain or branched alkyl radical having 1 to 4 carbon atoms and a straight-chain or branched alkoxy radical having 1 to 3 carbon atoms can; a straight-chain or branched, cyclic and / or acyclic alkoxy radical having 1 to 3 carbon atoms; a substituted or unsubstituted aryl
  • R is a straight-chain or branched cyclic and / or acyclic alkyl radical having 1 to 15 carbon atoms, with or without substituents such as, for.
  • substituents such as, for.
  • hydroxyl groups (1 to 3 pieces), ether groups, alkoxy groups with 1 to 5 carbon atoms, substituted or unsubstituted aryl groups, such as p-tolyl or phenyl groups, substituted carbonyl or oxycarbonyl groups, silyl groups, substituted or unsubstituted cyclohexyl groups, are not only particularly well suited for the purposes of the present invention (ie for the prophylaxis and therapy of sodium channel-dependent diseases such as in particular epilepsy) and therefore particularly preferred, but also new compared to the prior art.
  • quinoline compounds according to the invention are particularly suitable for the therapy and prophylaxis of sodium channel-dependent diseases, for example epilepsy.
  • the following may be mentioned as preferred compounds (the new, alkynyl- or oxy-alkynyl-substituted derivatives compared to the prior art have the numbers 1.1.1 to 1.16.3):
  • the invention also includes their salts with pharmaceutically acceptable acids such as. B. with hydrohalic acids, especially hydrochloric acid, acetic acid, malic acid, tartaric acid, maleic acid, fumaric acid, methanesulfonic acids and the like.
  • pharmaceutically acceptable derivatives and analogs of the quinoline derivatives presented are also suitable for the purposes of the present invention.
  • Preferred quinoline derivatives according to the present invention are compounds according to the general formula (I) above, where:
  • R 1 is a hydrogen atom, a hydroxyl group, the group -OR 2 , an alkyl, such as a methyl or an alkoxy, such as a methoxy radical;
  • R 3 is a hydrogen atom, a hydroxyl group, an alkyl, such as a methyl or an alkoxy, such as a methoxy radical and
  • R 4 , R 5 , R 6 and R 7 are each the same or different and independently a hydrogen atom, a halogen, such as. B. are a chlorine atom, an alkoxy, such as a methoxy or an ethoxy radical, and physiologically acceptable derivatives or analogues thereof.
  • quinoline derivatives of the general formula (I) are particularly well suited for the treatment of sodium channel-dependent diseases according to the present invention
  • R is a hydroxyl group or the group -OR
  • R is a methyl radical
  • R 4 , R 5 , R 6 and R 7 are all hydrogen atoms, as well as physiologically compatible derivatives and analogues thereof.
  • R 1 is a hydroxyl group or -OR 2
  • R 3 is a methyl radical
  • R 4 , R 5
  • R and R are a hydrogen atom and R is an alkynyl group as indicated above.
  • R 2 -CC- (CH 2 ) 4 -CH 3
  • the invention further relates to the use of the quinoline derivatives of the general formula (I) according to the invention including the preferred compounds indicated above and their physiologically tolerable derivatives or analogs for the manufacture of a medicament for the prophylaxis and therapy of sodium channel-dependent diseases, in particular epilepsy.
  • the quinoline derivatives according to the invention which are suitable for the prophylaxis and therapy of sodium channel-dependent diseases, in particular epilepsy, or physiologically tolerable derivatives or analogs thereof are expediently processed in the customary manner into pharmaceutical preparations.
  • the quinoline derivatives according to the invention or physiologically compatible derivatives and analogues thereof can be processed into tablets, dragees or capsules, for rectal use into suppositories, which may contain conventional pharmaceutical carriers, diluents and / or auxiliaries in addition to the active ingredients.
  • the active ingredient content is 1 to 95% by weight, preferably 10 to 80% by weight, based on the total weight of the composition.
  • carriers, diluents and auxiliaries come, for.
  • calcium carbonate calcium phosphate, sodium phosphate, milk sugar, corn starch, alginates, gelatin, aluminum or magnesium stearate, talc or silicone oil.
  • Such a medicament can expediently be prepared in dosage units which are tailored to the desired therapy.
  • the quinoline derivative according to the invention or a physiologically compatible derivative or analogue thereof should be administered in an amount which is effective for the prophylaxis and therapy of a sodium channel-dependent disease, in particular epilepsy.
  • the determination of a therapeutically effective amount falls under the skill of a person skilled in the art and can be carried out in the usual way.
  • Medicaments according to the invention can contain 0.1 to 1000 mg, advantageously 1 to 600 mg, of a quinoline derivative according to the invention or a physiologically tolerable derivative or analogs thereof as active ingredient per single dose.
  • the active substances can be used in the form of injectable aqueous or oily suspensions, which additionally contain suspending agents, such as. B. sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium alginate or polyvinyl pyrrolidone, dispersants such as polyoxyethylene stearate and preservatives may contain; the oily suspensions can be in peanut, olive, coconut, sesame or paraffin oil.
  • Preferred forms of administration are oral administration as a capsule, dragee or tablet and parenteral administration as an injection or infusion.
  • the compounds on which this invention is based can, in particular, due to its sodium channel blocking effect, it can be used as a drug for the treatment of epilepsy and other sodium channel-dependent diseases.
  • Preferred forms of epilepsy are:
  • Grand mal especially focal genesis (e.g. sleep grand mal, diffuse grand mal) 4.
  • focal genesis e.g. sleep grand mal, diffuse grand mal
  • treatment The therapy and / or prophylaxis (hereinafter referred to as treatment) of neurological diseases, in particular for the prophylaxis of manic-depressive phases (bipolar disorders) 2. Preventing seizures during alcohol withdrawal L
  • the palladium-catalyzed alkyne coupling of organic halogen compounds is a method for the formation of carbon-carbon bonds 2 and therefore for Attaching alkynyl substituents.
  • Compounds such as 2-hydroxy-3- (l-hydroxy-l-methyl-3-butynyl) -4-methoxyquinoline have already been synthesized by this method *. This method is very suitable for the preparation of the new quinoline derivatives according to the invention.
  • the 4-methylquinoline derivative is reacted with the acetylene derivative at 40 ° C. for 6.5 hours and worked up analogously to method A.
  • test object was intact myelinated nerve fibers of the clawed frog Xenopus l ⁇ evis.
  • the Ranvier lacing ring examined in each case was spread out in compartment A of a multi-chambered plexiglass block.
  • the compartment A was continuously flowed through with different bath solutions.
  • the normal bath medium of the examined lacing ring was Ringer's solution.
  • test temperature was uniformly 10 ( ⁇ 0.5) ° C.
  • test substances examined were dissolved in DMSO and then diluted to the desired concentration with Ringer's solution.
  • the DMSO concentrations in the test solutions were always constant at 0.7 mol / 1.
  • the potassium currents were examined with stimulus strengths of 130 mV (100 ms duration) and the sodium currents with stimulus strengths of 70 mV (2 ms duration). evaluation
  • the percentage blockages B of the potassium currents and sodium currents by the corresponding test substances were determined from the difference between the currents in Ringer's solution and test solution and standardized to the corresponding current values in Ringer's solution.
  • the quinoline derivatives according to the invention as well as physiologically compatible derivatives and analogues thereof are highly effective in voltage clamp tests.
  • the most effective of the quinoline derivatives according to the invention have EC 50 values ⁇ 100 nmol / l and thus exceed both in their sodium channel blocking action
  • crayfish eggs 50 mg were incubated in 80 ml of fresh sea water at 23 ° C under normal light and with the addition of air from a commercially available aquarium pump within 48 hours. 10 crabs were counted in a snap-lid jar and 3 ml of sea water and a drop of yeast suspension (3 mg of baker's yeast in 5 ml of sea water) were added as an additional food source.
  • Stock solutions of the substances tested were prepared in methanol (LiChrosolv Merck 1.06018) and diluted according to the desired test concentration. 60 ⁇ l portions of the test solution were poured into the snap-lid jars. The blank value was determined using 60 ⁇ l methanol instead of the test substance. The samples were then kept in a water bath at 23 ° C. for 24 hours.
  • the new quinoline derivatives of the present invention have an extraordinarily strong activity with a lack of toxicity compared to the compounds of the prior art.
  • Rhone Poulenc Rorer patent: EP 0674520 A1, WO 94/13298
  • Rhone Poulenc Rorer patent: EP 0687179 A1, WO 94/20110 v Rhone Poulenc Rorer, patent: EP 0678026 B1 w
  • Kienast H.W., Boshes L.D . Clinical trials of carbamazepine in suppressing pain. Headache [1968] 8 (1) pp. 1-5
  • Rhone-Poulenc Rorer S.A Use of carbamazepine and oxcarbazepine for the treatment of traumatic neurological pests. [1993] EP
  • Rhone-Poulenc Rorer S.A Administration of anticonvulsants, such as carbamazepine and oxcarbazepine, for the treatment of euro-aids. [1994] EP 0687179 AI; [1994 C] WO 94/20110
  • Rhone-Poulenc Rorer S.A Use of carbamazepine and oxcarbazepine for the treatment of Parkinson's and Parkinson's syndromes. [1994] EP 0678026 Bl
  • Wackernagel M Structure dependence of the potassium channel blocking effect of quinolines and furoquinolines - synthesis and investigation of the influence on the membrane currents of myelinated nerve fibers. Dissertation. [1998]
  • Zlotkin E The insect voltage-gated sodium Channel as target of insecticides. Annu Rev Entomol [1999] 44 pp. 429-455

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Abstract

The invention relates to novel quinoline derivatives, which are suitable for the prophylaxis and treatment of sodium channel-dependent disorders, in particular epilepsy. The invention also relates to pharmaceutical preparations containing said quinoline derivatives and to a method for treating sodium channel-dependent disorders, in particular epilepsy. The inventive quinoline derivatives are highly effective and have an extremely low toxicity in comparison with compounds disclosed in prior art.

Description

CHINOLIN-DERIVATE UND IHRE VERWENDUNG CHINOLINE DERIVATIVES AND THEIR USE

Die vorliegende Erfindung betrifft Chinolin-Derivate der allgemeinen Formel (I) oder physiologisch verträgliche Derivate oder Analoga davon, Verfahren zu deren Herstellung, diese Verbindungen enthaltende pharmazeutische Zusammensetzungen, die Verwendung dieser Verbindungen zur Herstellung von Arzneimitteln zur Prophylaxe und Therapie von Natriumkanal-abhängigen Erkrankungen wie insbesondere der Epilepsie sowie Verfahren zur Prophylaxe und Kontrolle von Natriumkanal-abhängigen Erkrankungen wie insbesondere epileptischen Anfällen.The present invention relates to quinoline derivatives of the general formula (I) or physiologically compatible derivatives or analogs thereof, processes for their preparation, pharmaceutical compositions containing these compounds, the use of these compounds for the preparation of medicaments for the prophylaxis and therapy of sodium channel-dependent diseases such as in particular epilepsy and methods for the prophylaxis and control of sodium channel-dependent diseases such as, in particular, epileptic seizures.

Figure imgf000002_0001
Figure imgf000002_0001

Epilepsie ist eine Erkrankung, die charakterisiert ist als paroxysmale, selbst erhaltende oder selbst limitierende exzessive neuronale Entladungen des Gehirns, genetisch bedingt, physiologisch erworben oder infolge einer organischen Veränderung. Basierend auf klinischen und elektroenzephalografischen Beobachtungen sind die vier generellen Subtypen der Epilepsie folgende:Epilepsy is a disease that is characterized as paroxysmal, self-sustaining or self-limiting excessive neuronal discharges of the brain, genetically determined, physiologically acquired or as a result of an organic change. Based on clinical and electroencephalographic observations, the four general subtypes of epilepsy are as follows:

1. Grand mal1. Grand times

2. Petit mal 3. Psyc omotorisch2. Petit times 3. Psyc motorized

4. Autonom. Die von der Epilepsie betroffenen Patienten weisen entweder eine oder mehrere der vorangegangenen Formen dieser Erkrankung auf.4. Autonomous. Patients affected by epilepsy have either one or more of the previous forms of the disease.

Medikamente zur Therapie der Epilepsie werden als Antiepileptika bezeichnet. Im allgemeinen weisen die bekannten Antiepileptika einen oder mehrere der folgenden WirkungsmechanismenAauf:Medications to treat epilepsy are called anti-epileptics. In general, the known anti-epileptics have one or more of the following mechanisms of action A :

1. Blockade der spannungsabhängigen NatriumionenströmeB.1. Blockage of the voltage-dependent sodium ion currents B.

2. Potenzierung des körpereigenen hemmenden Neurotransmitters GABA.2. Potentiation of the body's inhibitory neurotransmitter GABA.

3. Hemmung der pathologischen Aktivität des exzitatorischen Neurotransmitters Glutamat.3. Inhibition of the pathological activity of the excitatory neurotransmitter glutamate.

4. Hemmung des T-Kalziumeinstroms.4. Inhibition of T calcium influx.

In der Fachinformation0 von Tegretal® (Wirkstoff: Carbamazepin) sowie in weiteren klinischen Studien0 wird beschrieben, dass Carbamazepin als Arzneistoff zur Anwendung bei Epilepsie geeignet ist. Carbamazepin ist ein Natriumkanalblocker, der eine Verringerung repetitiver Entladungen neuronaler Membranen (Natriumkanäle) bewirkt5.The technical information 0 of Tegretal ® (active ingredient: carbamazepine) and other clinical studies 0 describe that carbamazepine is suitable as a drug for use in epilepsy. Carbamazepine is a sodium channel blocker that reduces repetitive discharges of neuronal membranes (sodium channels) 5 .

In der FachinformationF von Phenhydan® (Wirkstoff: Phenytoin) sowie in weiteren klinischen Studien wird beschrieben, dass Phenytoin als Arzneistoff zur Anwendung bei Epilepsie geeignet ist. Phenytoin ist ein Natriumkanalblocker, der eine Verringerung repetitiver Entladungen neuronaler Membranen (Natriumkanäle) bewirkt0.The technical information F of Phenhydan ® (active ingredient: phenytoin) and other clinical studies describe that phenytoin is suitable as a drug for use in epilepsy. Phenytoin is a sodium channel blocker that reduces repetitive discharges of neuronal membranes (sodium channels) 0 .

Es wird angenommen, dass antiepileptisch wirkende Medikamente Anfälle verhindern oder kontrollieren, indem sie auf die Anfallsherde einwirken. Diese Anfallsherde stellen entweder eine Ansammlung von pathophysiologisch veränderten Neuronen, normale Zellen mit verminderter Gefäßversorgung oder ein verletztes Areal, in dem die Nervenfasern noch nicht zerstört worden sind, dar.Antiepileptic drugs are believed to prevent or control seizures by acting on the focus of the attack. These seizures represent either a cluster of pathophysiologically altered neurons, normal cells with reduced vascular supply or an injured area in which the nerve fibers have not yet been destroyed.

Die bekannten Medikamente zur Epilepsiebehandlung können nur zur Prophylaxe der epileptischen Symptome wie z. B. der Reduktion und Kontrolle der epileptischen Anfälle, nicht aber zur Heilung der Epilepsie eingesetzt werden. Es können nur etwa 50 % der epileptischen Patienten mit den zur Zeit zur Verfügung stehenden antiepileptisch wirkenden Medikamenten ausreichend behandelt werdenH. Daher besteht immer noch der dringende Bedarf an selektiveren, wirksameren und weniger toxischen Antiepileptika.The known drugs for epilepsy treatment can only be used for the prophylaxis of epileptic symptoms such as. B. the reduction and control of epileptic seizures, but not used to cure epilepsy. Only about 50% of epileptic patients can be adequately treated with the currently available anti-epileptic drugs H. Therefore, there is still an urgent need for more selective, effective and less toxic antiepileptics.

Bis heute erfüllt kein Antiepileptikum alle an ein ideales Antiepileptikum gestellten Anforderungen, wie z. B.: hohe Wirksamkeit, gute Selektivität, gute Verträgliclikeit, optimale Pharmakokinetik (kurze Dosistitration, lineare Pharmakokinetik, keine Metabolisierung über die Leber, lange Halbwertszeit) sowie eine kostengünstige Herstellung.To date, no antiepileptic meets all requirements for an ideal antiepileptic, such as. E.g .: high efficacy, good selectivity, good tolerability, optimal pharmacokinetics (short dose titration, linear pharmacokinetics, no metabolism via the liver, long half-life) as well as cost-effective production.

Die Wirkstoffe Carbamazepin und Phenytoin werden derzeit immer noch bei der Behandlung von generalisierten tonisch-klonischen (grand mal) und partiellen Anfällen angewendet, obwohl sie zahlreiche Schwächen in der Epilepsiebehandlung aufweisen.The active ingredients carbamazepine and phenytoin are currently still used in the treatment of generalized tonic-clonic (grand mal) and partial seizures, although they have numerous weaknesses in the treatment of epilepsy.

Sowohl Carbamazepin als auch Phenytoin zeigen jeweils mehrere der im Folgenden aufgeführten Schwächen:Both carbamazepine and phenytoin each show several of the weaknesses listed below:

1. Langsame einschleichende Dosistitration über mehrere Wochen 2. Schwere Blutbildstörungen (Agranulozytose, aplastische Anämie) mit letalem Ausgang, Blutbildkontrollen erforderlich1. Slow, creeping dose titration over several weeks. 2. Serious blood disorders (agranulocytosis, aplastic anemia) with fatal outcome, blood counts required

3. Viele (72,5% ) Nebenwirkungen zu Behandlungsbeginn, die in ca. 10% der Fälle zum TherapieabbruchJ führen3. Many (72.5%) side effects at the start of treatment, which lead to therapy termination J in approx. 10% of cases

4. Toleranzentwicklung durch Autoinduktion, deshalb Dosisüberwachung erforderlich4. Development of tolerance through autoinduction, therefore dose monitoring is necessary

5. Enzyminduktion, zahlreiche Arzneimittelinteraktionen5. Enzyme induction, numerous drug interactions

6. Enge therapeutische Breite6. Narrow therapeutic breadth

7. Höhere Inzidenz kognitiver Beeinträchtigungen7. Higher incidence of cognitive impairment

8. Schwere kosmetische Nebenwirkungen (Zahlfleischwucherungen (Inzidenz ca. 50%), verstärkte Körperbehaarung, Vergröberung der8. Severe cosmetic side effects (growth of number flesh (incidence approx. 50%), increased body hair, coarsening of the

Gesichtszüge) 9. Plasmaspiegelkontrolle erforderlich (enger therapeutischer Bereich)Facial features) 9. Plasma level control required (narrow therapeutic range)

10. Kleinhirnatrophie durch toxische Spiegel mit Gangartstörungen, (Sättigungskinetik)10. Cerebellar atrophy due to toxic levels with gait disorders (satiety kinetics)

Der vorliegenden Erfindung liegt daher die Aufgabe zugrunde, die Nachteile nach dem Stand der Technik zu beseitigen. Insbesondere sollen gegenüber dem Stand der Technik neue pharmazeutisch wirksame Verbindungen bereit gestellt werden, die eine bessere Wirkung, geringere Nebenwirkungen und weniger Wechselwirkungen mit anderen Arzneimitteln aufweisen. Weiters Ziel ist die Bereitstellung von Verbindungen, die eine einfachere Anwendung gegenüber den bisher verfügbaren Arzneimitteln in der Therapie der Epilepsie und anderer Natriumkanal-abhängiger Erkrankungen gewährleisten.The present invention is therefore based on the object of eliminating the disadvantages of the prior art. In particular, compared to the prior art, new pharmaceutically active compounds are to be provided which have a better action, fewer side effects and fewer interactions with other medicaments. Another goal is to provide compounds that ensure easier use compared to the drugs available hitherto in the therapy of epilepsy and other sodium channel-dependent diseases.

Diese Aufgabe wird durch die Merkmale der Ansprüche 1, 6, 11, 18 und 28 gelöst. Zweckmäßige Ausgestaltungen ergeben sich aus den Ansprüchen 2 bis 5, 7 bis 10 und 18 bis 27.This object is solved by the features of claims 1, 6, 11, 18 and 28. Appropriate configurations result from claims 2 to 5, 7 to 10 and 18 to 27.

Überraschenderweise stellte sich heraus, dass die Chinolin-Derivate gemäß der vorliegenden Erfindung eine außergewöhnlich starke Wirkung bei der Natriumkanal- Blockierung bei einer gleichzeitig fehlenden Toxizität zeigen.Surprisingly, it was found that the quinoline derivatives according to the present invention show an exceptionally strong action in sodium channel blocking with a simultaneous lack of toxicity.

Die erfindungsgemäßen Chinolin-Derivate sind gegenüber dem Stand der Technik effektiver für die Behandlung der Epilepsie und anderer Natriumkanal-abhängiger Erkrankungen. Die vorliegende Erfindung stellt in diesem Zusammenhang auch gegenüber dem Stand der Technik neue Chinolin-Derivate bereit. Weiterhin stellt die vorliegende Erfindung pharmazeutische Präparate bzw. Zusammensetzungen, umfassend die erfindungsgemäßen Chinolin-Derivate bereit.The quinoline derivatives according to the invention are more effective than the prior art for the treatment of epilepsy and other sodium channel-dependent diseases. In this connection, the present invention also provides new quinoline derivatives compared to the prior art. Furthermore, the present invention provides pharmaceutical preparations or compositions comprising the quinoline derivatives according to the invention.

Die vorliegende Erfindung betrifft ferner die Verwendung der erfindungsgemäßen Chinolin-Derivate. Insbesondere eignen sich die erfindungsgemäßen Chinolin-Derivate zur Behandlung von Epilepsie-Patienten mit einfachen partiellen Anfällen, komplexen partiellen Anfällen, grand mal Anfallen und gemischten Epilepsieformen.The present invention further relates to the use of the quinoline derivatives according to the invention. The quinoline derivatives according to the invention are particularly suitable for the treatment of epilepsy patients with simple partial seizures, complex partial seizures, grand attacks and mixed forms of epilepsy.

Gemäß der vorliegenden Erfindung werden außerdem die erfindungsgemäßen Chinolin- Derivate zur Herstellung von Arzneimitteln zur Prophylaxe und Therapie von Epilepsien, insbesondere einfachen partiellen Anfällen, komplexen partiellen Anfällen, grand mal Anfällen und gemischte Epilepsieformen, sowie weiteren Natriumkanal- abhängigen Erkrankungen bereitgestellt.According to the present invention, the quinoline derivatives according to the invention are also provided for the manufacture of medicaments for the prophylaxis and therapy of epilepsy, in particular simple partial seizures, complex partial seizures, grand mal seizures and mixed forms of epilepsy, as well as other sodium channel-dependent diseases.

Die von der vorliegende Erfindung bereitgestellten Chinolin-Derivate und insbesondere die gegenüber dem Stand der Technik neuen Chinolin-Derivate, die zur Prophylaxe und Kontrolle von Epilepsien und anderen Natriumkanal-abhängigen Erkrankungen verwendet werden können, besitzen die folgenden, gegenüber bekannten Arzneimitteln für diese Indikationen vorteilhaften Eigenschaften: Sie sind relativ untoxisch, besitzen einen hohen Wirkungsgrad und ermöglichen ein therapeutisches Ansprechen über einen relativ langen Zeitraum.The quinoline derivatives provided by the present invention and in particular the quinoline derivatives which are new compared to the prior art and which can be used for the prophylaxis and control of epilepsy and other sodium channel-dependent diseases have the following advantages over known medicaments for these indications Properties: They are relatively non-toxic, have a high degree of effectiveness and enable a therapeutic response over a relatively long period of time.

Erfϊndungsgemäß werden Chinolin-Verbindungen der allgemeinen Formel (I) beansprucht:According to the invention, quinoline compounds of the general formula (I) are claimed:

Figure imgf000006_0001
Figure imgf000006_0001

In der allgemeinen Formel (I) bedeuten:In the general formula (I):

R1 ein geradkettiger oder verzweigter, cyclischer und/oder acyclischer Alkylrest mit 1 bis 15 C-Atomen ohne oder mit 1 bis drei Hydroxylgruppen; ein geradkettiger oder verzweigter, cyclischer und/oder acyclischer Alkenyl- oder Alkinylrest sowie Oxy- Alkinylrest (-O-CC-) mit 1 bis 15 C-Atomen, sowie 1 bis 3 ungesättigten C-C- Bindungen mit oder ohne Substituenten, wie z. B. Hydroxygruppen (1 bis 3 Stück), Ethergruppen, unsubstituierten oder substituierten Arylgruppen, wie p-Tolyl- oder Phenylgruppen, substituierten Carbonyl-, Oxycarbonylgruppen oder Silylgruppen; ein geradkettiger oder verzweigter, cyclischer und/oder acyclischer Alkoxyrest; ein Wasserstoffatom oder eine Hydroxylgruppe.R 1 is a straight-chain or branched, cyclic and / or acyclic alkyl radical with 1 to 15 C atoms without or with 1 to three hydroxyl groups; a straight-chain or branched, cyclic and / or acyclic alkenyl or alkynyl radical and oxyalkynyl radical (-O-CC-) having 1 to 15 C atoms, and 1 to 3 unsaturated CC- Bonds with or without substituents, such as. B. hydroxy groups (1 to 3 pieces), ether groups, unsubstituted or substituted aryl groups, such as p-tolyl or phenyl groups, substituted carbonyl, oxycarbonyl groups or silyl groups; a straight-chain or branched, cyclic and / or acyclic alkoxy radical; a hydrogen atom or a hydroxyl group.

Als spezifische Substituenten seien genannt:The following may be mentioned as specific substituents:

-OCC-(CH2)7-CH3 -OCC-(CH2)3-OH-OCC- (CH 2 ) 7 -CH 3 -OCC- (CH 2 ) 3 -OH

-OCC-(CH2)6-CH3 -OCC-(CH2)3-OCH3 -OCC-(CH2)5-CH3 -OCC-(CH2)3-OC2H5 -OCC- (CH 2 ) 6 -CH 3 -OCC- (CH 2 ) 3 -OCH 3 -OCC- (CH 2 ) 5 -CH 3 -OCC- (CH 2 ) 3 -OC 2 H 5

-OCC-(CH2)4-CH3 -OCC-(CH2)3-O(CH2)2-CH3 -OCC- (CH 2 ) 4 -CH 3 -OCC- (CH 2 ) 3 -O (CH 2 ) 2 -CH 3

-OCC-(CH2)3-CH3 -OCC-(CH-OH)-(CH2)4-CH3 -OCC- (CH 2 ) 3 -CH 3 -OCC- (CH-OH) - (CH 2 ) 4 -CH 3

-OCC-(CH2)2-CH3 -OCC-(CH-OCH3)-(CH2)4-CH3 -OCC- (CH 2 ) 2 -CH 3 -OCC- (CH-OCH 3 ) - (CH 2 ) 4 -CH 3

-OCC-(CH2)-CH3 -OCC-(CH-OC2H5)-(CH2)4-CH3 -OCC- (CH 2) -CH 3 -OCC- (CH-OC 2 H 5) - (CH 2) 4 -CH 3

-OCC-(CH2)-OH -OCC-O-C2H5 -OCC-(CH2)-OCH3 -OCC-(CO)-OCH3 -OCC- (CH 2 ) -OH -OCC-OC 2 H 5 -OCC- (CH 2 ) -OCH 3 -OCC- (CO) -OCH 3

-OCC-(CH2)2-OCH3 -OCC-(CO)-OC2H5 -OCC- (CH 2 ) 2 -OCH 3 -OCC- (CO) -OC 2 H 5

-OCC-(CH2)-O-C2H5 -OCC-C(CH3)2-OH-OCC- (CH 2 ) -OC 2 H 5 -OCC-C (CH 3 ) 2 -OH

-OCC-(CH2)-O-(CH2)2-CH3 -OCC-C(CH3)(C2H5)-OH-OCC- (CH 2 ) -O- (CH 2 ) 2 -CH 3 -OCC-C (CH 3 ) (C 2 H 5 ) -OH

-OCC-(CH2)-O-(CH2)3-CH3 -OCC-Si-(CH3)3 -OCC- (CH 2) -O- (CH 2) 3 -CH 3 -OCC-Si- (CH 3) 3

-OCC-(CH2)-O-(CH2)4-CH3 -OCC-(Phenyl) -OCC-(p-Tolyl)-OCC- (CH 2 ) -O- (CH 2 ) 4 -CH 3 -OCC- (phenyl) -OCC- (p-tolyl)

-OCC-(CH-(cyclohexyl)(OH))-OCC- (CH- (cyclohexyl) (OH))

-H; OH, OCH3, OC2H5, CH3, C2H5, CH2OH-H; OH, OCH 3 , OC 2 H 5 , CH 3 , C2H 5 , CH 2 OH

ein geradkettiger oder verzweigter cyclischer und/oder acyclischer Alkylrest mit 1 bis 15 C-Atomen, mit oder ohne Substituenten wie z. B. Hydroxylgruppen (1 bis 3a straight-chain or branched cyclic and / or acyclic alkyl radical having 1 to 15 carbon atoms, with or without substituents such as. B. hydroxyl groups (1 to 3

Stück), Alkoxygruppen mit 1 bis 5 C-Atomen ; ein geradkettiger oder verzweigter cyclischer und/oder acyclischer Alkenyl- oder Alkinylrest mit 1 bis 15 C-Atomen, sowie 1 bis 3 ungesättigten C-C-Bindungen mit oder ohne Substituenten wie z. B. Hydroxyylgruppen (1 bis 3 Stück), Ethergruppen, Alkoxyresten mit 1 bis 5 C- Atomen, substituierten oder unsubstituierten Arylresten, wie p-Tolyl- oderPiece), alkoxy groups with 1 to 5 carbon atoms; a straight-chain or branched cyclic and / or acyclic alkenyl or alkynyl radical with 1 to 15 C atoms, and 1 to 3 unsaturated C-C bonds with or without substituents such as. B. hydroxyyl groups (1 to 3 pieces), ether groups, alkoxy radicals having 1 to 5 carbon atoms, substituted or unsubstituted aryl radicals, such as p-tolyl or

Phenylgruppen, substituierten Carbonyl- oder Oxycarbonylgruppen, Silylgruppen, substituierten oder unsubstituierten Cyclohexylgruppen. Als spezifische Substituenten seien genannt:Phenyl groups, substituted carbonyl or oxycarbonyl groups, silyl groups, substituted or unsubstituted cyclohexyl groups. The following may be mentioned as specific substituents:

CC-(CH2)rCH3 -C2H2-(CH2) -CH3 -(CH2)g-CH3 CC- (CH 2 ) rCH 3 -C2H 2 - (CH2) -CH 3 - (CH2) g-CH 3

-CC-(CH2)6"CH3 -C2H2-(CH2)6-CH3 -(CH2)8-CH3 -CC- (CH 2 ) 6 "CH 3 -C2H 2 - (CH 2 ) 6 -CH 3 - (CH 2 ) 8 -CH 3

CC-(CH2)5-CH3 -C2H2-(CH2)5-CH3 -(CH2) -CH3 CC- (CH 2 ) 5 -CH 3 -C 2 H 2 - (CH2) 5-CH 3 - (CH2) -CH 3

CC-(CH2) -CH3 -C2H2-(CH2)4-CH3 "(CH2)6~CH3 CC- (CH 2 ) -CH 3 -C2H2- (CH2) 4-CH 3 "(CH 2 ) 6 ~ CH 3

CC-(Cri2)3-CH3 -C2H2-(CH2)3-CH3 -(CH2)5-CH3 CC- (Cri2) 3 -CH 3 -C2H2- (CH2) 3 -CH 3 - (CH 2 ) 5-CH 3

CC-(Cπ2)2-Cπ3 -C2H2-(CH2)2-CH3 _(CH2) -CH3 CC (Cπ2) 2-Cπ 3 -C2H 2 - (CH 2) 2 CH 3 _ (CH 2) -CH 3

CC-(CH2)-CH3 -C2H2-C2H5 -(C )2)3-CH3 CC- (CH 2 ) -CH 3 -C2H2-C 2 H 5 - (C) 2 ) 3 -CH 3

CC-(CH2)-OH -C2H2-(CH2)-OH -(CH2)3-OHCC- (CH 2 ) -OH -C 2 H 2 - (CH 2 ) -OH - (CH 2 ) 3 -OH

CC-(CH2)-OCH3 -C2H2-(CH2)-OCH3 -(CH2)3-OCH3 CC- (CH 2 ) -OCH 3 -C 2 H 2 - (CH 2 ) -OCH 3 - (CH 2 ) 3 -OCH 3

CC-(CH2)2-OCH3 -C2π2-(C H2)2-OC π3 -(CH2)4-OCH3 CC- (CH 2 ) 2 -OCH 3 -C 2 π 2 - (CH 2 ) 2 -OC π 3 - (CH 2 ) 4 -OCH 3

-CC-(CH2)-0-C2H5 -C2H2-(CH2)-0-C2H5 -(CH2)3"0-C2H5 -CC- (CH 2 ) -0-C 2 H 5 -C2H 2 - (CH 2 ) -0-C2H5 - (CH 2 ) 3 "0-C2H 5

CC-(CH2)-0-(CH2)2-CH3 -C2H2-(CH2)-0-(CH2)2-CH3 -(CH2)3-0-(CH2)2-CH3 CC- (CH 2 ) -0- (CH 2 ) 2 -CH 3 -C 2 H2- (CH 2 ) -0- (CH 2 ) 2 -CH 3 - (CH 2 ) 3 -0- (CH 2 ) 2 -CH 3

CC-(CH2)-0-(CH2)3-CH3 -C2H2-(CH2)-0-(CH2)3-CH3 -(CH2)3-0-(CH2)3-CH3 CC- (CH 2 ) -0- (CH 2 ) 3 -CH 3 -C 2 H2- (CH2) -0- (CH 2 ) 3 -CH 3 - (CH 2 ) 3 -0- (CH 2 ) 3 -CH 3rd

CC-(CH2)-0-(CH2)4-CH3 -C2H2-(CH2)-0-(CH2)4-CH3 -(CH2)3-0-(CH2)4-CH3 CC- (CH 2 ) -0- (CH 2 ) 4 -CH 3 -C 2 H 2 - (CH 2 ) -0- (CH 2 ) 4 -CH 3 - (CH 2 ) 3 -0- (CH 2 ) 4 -CH 3

-CC-(CH2)3-OH -C2H2-(CH2)3-OH -(CH2)5-OH-CC- (CH 2) 3 -OH -C 2 H 2 - (CH 2) 3 -OH - (CH 2) 5 -OH

CC-(CH2)3-OCH3 -C2H2-(C H2)3-OC H3 -(CH2)5-OCH3 CC- (CH 2 ) 3 -OCH 3 -C 2 H 2 - (CH 2 ) 3 -OC H 3 - (CH 2 ) 5 -OCH 3

CC-(CH2)3-OC2H5 -C2H2-(CH2)3-0(CH2)-CH3 -(CH2)5-OC2H5CC- (CH 2 ) 3 -OC 2 H 5 -C 2 H 2 - (CH 2 ) 3 -0 (CH 2 ) -CH 3 - (CH 2 ) 5-OC 2 H5

CC-(CH2)3-0(CH2)2-CH3 -C2ri2-(CH2)3-0(CH2)2-CH3 -(CH2)5-0(CH2)2-CH3 CC- (CH2) 3 -0 (CH 2 ) 2 -CH 3 -C 2 ri2- (CH 2 ) 3 -0 (CH 2 ) 2 -CH 3 - (CH 2 ) 5 -0 (CH 2 ) 2 - CH 3

CC-(CH-OH)-(CH2)4-CH3 -C2H2-(CH-OH)-(CH2)4-CH3 -(CH2)2-(CH-OH)-(CH2)4-CH3 CC- (CH-OH) - (CH 2 ) 4 -CH 3 -C 2 H 2 - (CH-OH) - (CH 2 ) 4 -CH 3 - (CH 2 ) 2 - (CH-OH) - ( CH 2 ) 4 -CH 3

CC-(CH-OCH3)-(CH2)4-CH3 -C2H2-(CH-OCH3)-(CH2)4-CH3 -(CH2)2-(CH-OCH3)-(CH2)4-CH3CC- (CH-OCH 3 ) - (CH 2 ) 4-CH 3 -C 2 H 2 - (CH-OCH 3 ) - (CH 2 ) 4-CH3 - (CH 2 ) 2- (CH-OCH 3 ) - (CH2) 4 -CH3

CC-(CH-OC2H5)-(CH2)4-CH3 -C2H2-(CH-OC2H5)-(CH2)4-CH3 -(CH2)2-(CH-OC2H5)-(CH2)4-CH3CC- (CH-OC 2 H 5 ) - (CH 2 ) 4-CH3 -C2H2- (CH-OC2H 5 ) - (CH 2 ) 4-CH 3 - (CH 2 ) 2- (CH-OC2H 5 ) - (CH 2 ) 4-CH3

CC-O-C2H5 -C2H2-0-C2H5 -(CH2)2-0-C2H5CC-OC 2 H5 -C 2 H 2 -0-C 2 H5 - (CH2) 2-0-C 2 H5

CC-(CO)-OCH3 CC- (CO) -OCH 3

CC-(CO)-OC2H5 CC- (CO) -OC 2 H 5

CC-C(CH3)2-OH

Figure imgf000008_0001
CC-C (CH 3 ) 2 -OH
Figure imgf000008_0001

CC-Si-(CH3)3 CC-Si (CH 3 ) 3

CC-(Phenyl)C-C (phenyl)

CC-(p-Tolyl)CC (p-tolyl)

CC-(CH-(cyclohexyl)(OH))CC (CH (cyclohexyl) (OH))

R3 ein Wasserstoffatom, eine Hydroxylgruppe, ein geradkettiger oder verzweigter Alkoxyrest mit 1 bis 5 C-Atomen, ein geradkettiger oder verzweigter Alkylrest mit 1 bis 5 C-Atomen ohne oder mitl bis 3 Hydroxylgruppen oder eine substituierte Carbonylgruppe.R 3 is a hydrogen atom, a hydroxyl group, a straight-chain or branched alkoxy radical having 1 to 5 carbon atoms, a straight-chain or branched alkyl radical 1 to 5 carbon atoms without or with 1 to 3 hydroxyl groups or a substituted carbonyl group.

Als spezifische Substituenten seien genannt:The following may be mentioned as specific substituents:

-H, -OH-H, -OH

-CH2OH-CH 2 OH

-CH3 -CH 3rd

-C2H5 -(CH2)2-CH3 -C 2 H 5 - (CH 2 ) 2 -CH 3

-(CH2)3-CH3 - (CH 2 ) 3 -CH 3

-OCH3 -OCH 3

-OC2H5 -OC 2 H 5

-O(CH2)2-CH3 -COCH3 -O (CH 2) 2 -CH 3 -COCH 3

R , R , R und R gleich oder verschieden und von einander unabhänging ein Wasserstoffatom; ein geradkettiger oder verzweigter, cyclischer und/oder acyclischer Alkylrest mit 1 bis 4 C-Atomen, wie Cyclo exyl-, Alkylcyclohexylrest mit 1 bis 4 C-Atomen im Alkylteil, Cycloheptyl, Cyclooctyl; ein substituierter oder unsubstituierter Arylrest, wie Phenylrest, der durch Halogen, wie Fluor, Chlor oder Brom, einen geradkettigen oder verzweigten Alkylrest mit 1 bis 4 C-Atomen sowie einen geradkettigen oder verzweigten Alkoxyrest mit 1 bis 3 C-Atomen mono- oder disubstituiert sein kann; ein geradkettiger oder verzweigter, cyclischer und/oder acyclischer Alkoxyrest mit 1 bis 3 C-Atomen; ein substituierter oder unsubstituierter Arylrest, wie Phenylalkylest mit 1 bis 4 C-Atomen im Alkylteil, wobei der Arylkern wie vorstehend bei Phenylrest angegeben substituiert sein kann; Halogen, wie Fluor, Chlor oder Brom; ein Mono- und/oder Dihydroxyalkylrest mit 1 bis 4 C-Atomen; eine primäre, sekundäre oder tertiäreR, R, R and R, the same or different and independent of one another, represent a hydrogen atom; a straight-chain or branched, cyclic and / or acyclic alkyl radical with 1 to 4 carbon atoms, such as cycloexyl, alkylcyclohexyl radical with 1 to 4 carbon atoms in the alkyl part, cycloheptyl, cyclooctyl; a substituted or unsubstituted aryl radical, such as phenyl radical, which may be mono- or disubstituted by halogen, such as fluorine, chlorine or bromine, a straight-chain or branched alkyl radical having 1 to 4 carbon atoms and a straight-chain or branched alkoxy radical having 1 to 3 carbon atoms can; a straight-chain or branched, cyclic and / or acyclic alkoxy radical having 1 to 3 carbon atoms; a substituted or unsubstituted aryl radical, such as phenylalkyl radical having 1 to 4 carbon atoms in the alkyl part, where the aryl nucleus can be substituted as indicated above for the phenyl radical; Halogen such as fluorine, chlorine or bromine; a mono- and / or dihydroxyalkyl radical with 1 to 4 carbon atoms; a primary, secondary or tertiary

Aminogruppe; eine Nitrogruppe; eine Sulfonylgruppe. Als spezifische Substituenten seien genannt:amino group; a nitro group; a sulfonyl group. The following may be mentioned as specific substituents:

-H,-H,

-CH3 -C2H5

Figure imgf000010_0001
-CH 3 -C 2 H 5
Figure imgf000010_0001

-OCH3 -OCH 3

-OC2H5 -OC 2 H 5

-OC3H7 -F, -Cl, -Br-OC 3 H 7 -F, -Cl, -Br

-NH2 -NH 2nd

-NH-CH3 -NH-CH 3

-N-(CH3)2 -N- (CH 3) 2

-NO2 -SO3H-NO 2 -SO 3 H

Derivate, bei denen R ein geradkettiger oder verzweigter cyclischer und/oder acyclischer Alkylrest mit 1 bis 15 C-Atomen, mit oder ohne Substituenten wie z. B. Hydroxylgruppen (1 bis 3 Stück), Alkoxygruppen mit 1 bis 5 C-Atomen ; ein geradkettiger oder verzweigter cyclischer und/oder acyclischer Alkenyl- oder Alkinylrest mit 1 bis 15 C-Atomen, sowie 1 bis 3 ungesättigten C-C-Bindungen mit oder ohne Substituenten wie z. B. Hydroxylgruppen (1 bis 3 Stück), Ethergruppen, Alkoxygruppen mit 1 bis 5 C-Atomen, substituierten oder unsubstituierten Arylgruppen, wie p-Tolyl- oder Phenylgruppen, substituierten Carbonyl- oder Oxycarbonylgruppen, Silylgruppen, substituierten oder unsubstituierten Cyclohexylgruppen, sind nicht nur besonders gut für die Zwecke der vorliegenden Erfindung (d.h. zur Prophylaxe und Therapie Natriumkanal-abhängiger Erkrankungen wie insbesondere Epilepsie) geeignet und daher besonders bevorzugt, sondern zudem auch neu gegenüber dem Stand der Technik.Derivatives in which R is a straight-chain or branched cyclic and / or acyclic alkyl radical having 1 to 15 carbon atoms, with or without substituents such as, for. B. hydroxyl groups (1 to 3 pieces), alkoxy groups with 1 to 5 carbon atoms; a straight-chain or branched cyclic and / or acyclic alkenyl or alkynyl radical with 1 to 15 C atoms, and 1 to 3 unsaturated C-C bonds with or without substituents such as. B. hydroxyl groups (1 to 3 pieces), ether groups, alkoxy groups with 1 to 5 carbon atoms, substituted or unsubstituted aryl groups, such as p-tolyl or phenyl groups, substituted carbonyl or oxycarbonyl groups, silyl groups, substituted or unsubstituted cyclohexyl groups, are not only particularly well suited for the purposes of the present invention (ie for the prophylaxis and therapy of sodium channel-dependent diseases such as in particular epilepsy) and therefore particularly preferred, but also new compared to the prior art.

Die erfindungsgemäßen Chinolin- Verbindungen sind insbesondere zur Therapie und Prophylaxe Natriumkanal-abhängiger Erkrankungen, z.B. der Epilepsie, geeignet. Als bevorzugte Verbindungen seien genannt (die gegenüber dem Stand der Technik neuen, Alkinyl- oder Oxy-Alkinyl-substituierten Derivate tragen die Nummern 1.1.1 bis 1.16.3):The quinoline compounds according to the invention are particularly suitable for the therapy and prophylaxis of sodium channel-dependent diseases, for example epilepsy. The following may be mentioned as preferred compounds (the new, alkynyl- or oxy-alkynyl-substituted derivatives compared to the prior art have the numbers 1.1.1 to 1.16.3):

Tabelle 1Table 1

Nr. NomenklaturNo nomenclature

1.1.1 3 -( 1 -Decinyl)-2-hydroxy-4-methylchinolin1.1.1 3 - (1 -Decynyl) -2-hydroxy-4-methylquinoline

1.2 2-Hydroxy-4-methyl-3-(l-noninyl)-chinolin1.2 2-Hydroxy-4-methyl-3- (1-noninyl) quinoline

1.3 2-Hydroxy-4-methyl-3-(l-octinyl)-chinolin1.3 2-Hydroxy-4-methyl-3- (l-octynyl) quinoline

1.4 3 -( 1 -Heptinyl)-2-hydroxy-4-methylchinolin1.4 3 - (1-Heptinyl) -2-hydroxy-4-methylquinoline

1.5 3 -( 1 -Hexinyl)-2-hydroxy-4-methylchinolin1.5 3 - (1-Hexinyl) -2-hydroxy-4-methylquinoline

1.6 2-Hydroxy-4-methyl-3-(l-pentinyl)-chinolin1.6 2-Hydroxy-4-methyl-3- (l-pentinyl) quinoline

1.7 3-(l-Butinyl)-2-hydroxy-4-methylchinolin1.7 3- (l-Butynyl) -2-hydroxy-4-methylquinoline

1.8 2-Hydroxy-3-(3-hydroxy- 1 -propinyl)-4-methylchinolin1.8 2-Hydroxy-3- (3-hydroxy-1-propynyl) -4-methylquinoline

1.9 2-Hydroxy-3 -(3 -methoxy- 1 -propinyl)-4-methylchinolin1.9 2-Hydroxy-3 - (3-methoxy-1-propynyl) -4-methylquinoline

1.10 2-Hydroxy-3-(4-methoxy- 1 -butinyl)-4-methylchinolin1.10 2-Hydroxy-3- (4-methoxy-1-butynyl) -4-methylquinoline

1.11 3-(3-Ethoxy- 1 -propinyl)-2-hydroxy-4-methylchinolm1.11 3- (3-Ethoxy-1-propynyl) -2-hydroxy-4-methylquinol

1.12 2-Hydroxy-4-methyl-3-(3-propoxy-l-piOpinyl)-chinolin1.12 2-Hydroxy-4-methyl-3- (3-propoxy-l-piOpinyl) quinoline

1.13 3-(3-Butoxy- 1 -propinyl)-2-hydroxy-4-methylchinolm1.13 3- (3-Butoxy-1-propynyl) -2-hydroxy-4-methylquinol

1.14 2-Hydroxy-4-methyl-3 -(3 -pentoxy- 1 -propinyl)-chinolin1.14 2-Hydroxy-4-methyl-3 - (3-pentoxy-1-propynyl) quinoline

1.15 2-Hydroxy-4-methyl-3 -(5 -hydroxy- 1 -pentinyl)-chinolin1.15 2-Hydroxy-4-methyl-3 - (5-hydroxy-1-pentynyl) quinoline

1.16 2-Hydroxy-3-(5-methoxy- 1 -pentinyl)-4-methylchinolin1.16 2-Hydroxy-3- (5-methoxy-1-pentynyl) -4-methylquinoline

1.17 3-(5-Ethoxy-l-ρentinyl)-2-hydroxy-4-methylchinolin1.17 3- (5-Ethoxy-1-pentynyl) -2-hydroxy-4-methylquinoline

1.18 2-Hydroxy-4-methyl-3-(5-propoxy- 1 -pentinyl)-chinolin1.18 2-Hydroxy-4-methyl-3- (5-propoxy-1-pentynyl) quinoline

1.19 2-Hydroxy-3-(3-hydroxy- 1 -octinyl)-4-methylchinolin1.19 2-Hydroxy-3- (3-hydroxy-1-octynyl) -4-methylquinoline

1.20 2-Hydroxy-3 -(3 -methoxy- 1 -octinyl)-4-methylchinolin1.20 2-Hydroxy-3 - (3-methoxy-1-octynyl) -4-methylquinoline

1.21 13 -(3 -Ethoxy- 1 -octinyl)-2-hydroxy-4-methylchinolin1.21 13 - (3-Ethoxy-1-octynyl) -2-hydroxy-4-methylquinoline

1.22 3-(Ethoxyethinyl)-2-hydroxy-4-methylchinolin1.22 3- (Ethoxyethynyl) -2-hydroxy-4-methylquinoline

1.23 2-Hydroxy-4-methyl-3-(methyloxycarbonyl-ethinyl)-chinolin1.23 2-Hydroxy-4-methyl-3- (methyloxycarbonylethynyl) quinoline

1.1.24 3-(Ethyloxycarbonyl-etlιinyl)-2-hydroxy-4-methylchinolin 1.1.24 3- (Ethyloxycarbonyl-ethyl) -2-hydroxy-4-methylquinoline

Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
2.13.1 2,4-Dimethyl-3-(l -heptenyl)-chinolin
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
2.13.1 2,4-Dimethyl-3- (l-heptenyl) quinoline

2.13.2 2,4-Dimethyl-3-(l-hexenyl)-chinolin2.13.2 2,4-Dimethyl-3- (l-hexenyl) quinoline

2.13.3 2,4-Dimethyl-3 -(1 -pentenyl)-chinolin2.13.3 2,4-Dimethyl-3 - (1-pentenyl) quinoline

2.14.1 3 -( 1 -Heptenyl)-4-hydroxy-2-methylchinolin2.14.1 3 - (1-Heptenyl) -4-hydroxy-2-methylquinoline

2.14.2 3 -( 1 -Hexenyl)-4-hydroxy-2-methylchinolin2.14.2 3 - (1-Hexenyl) -4-hydroxy-2-methylquinoline

2.14.3 4-Hydroxy-2-methyl-3 -(1 -pentenyl)-chinolin2.14.3 4-Hydroxy-2-methyl-3 - (1-pentenyl) quinoline

2.15.1 7-Chlor-3 -(1 -heptenyl)-4-methylchinolin2.15.1 7-chloro-3 - (1-heptenyl) -4-methylquinoline

2.15.2 7-Chlor-3 -(1 -hexenyl)-4-methylchinolin2.15.2 7-chloro-3 - (1-hexenyl) -4-methylquinoline

2.15.3 7-Chlor-4-methyl-3-( 1 -pentenyl)-chinolin2.15.3 7-chloro-4-methyl-3- (1-pentenyl) quinoline

3.1.1 3-Decyl-2-hydroxy-4-methylchinolin3.1.1 3-Decyl-2-hydroxy-4-methylquinoline

3.1.2 2-Hydroxy-4-methyl-3-nonylchinolin3.1.2 2-Hydroxy-4-methyl-3-nonylquinoline

3.1.3 2-Hydroxy-4-methyl-3-octylchinolin3.1.3 2-Hydroxy-4-methyl-3-octylquinoline

3.1.4 3 -Heptyl-2-hydroxy-4-methylchinolin3.1.4 3-Heptyl-2-hydroxy-4-methylquinoline

3.1.5 3 -Hexyl-2-hydroxy-4-methylchinolin3.1.5 3-Hexyl-2-hydroxy-4-methylquinoline

3.1.6 2-Hydroxy-4-methyl-3-pentylchinolin3.1.6 2-Hydroxy-4-methyl-3-pentylquinoline

3.1.7 3-Butyl-2-hydroxy-4-methylchinolin3.1.7 3-butyl-2-hydroxy-4-methylquinoline

3.1.8 2-Hydroxy-3-(3-hydroxypropyl)-4-methylchinolin3.1.8 2-Hydroxy-3- (3-hydroxypropyl) -4-methylquinoline

3.1.9 2-Hydroxy-3-(3-methoxypropyl)-4-methylchinolin3.1.9 2-Hydroxy-3- (3-methoxypropyl) -4-methylquinoline

3.1.10 2-Hydroxy-3-(4-methoxybutyl)-4-methylchinolin3.1.10 2-Hydroxy-3- (4-methoxybutyl) -4-methylquinoline

3.1.11 3 -(3 -Ethoxypropyl)-2-hydroxy-4-methylchinolin3.1.11 3 - (3-Ethoxypropyl) -2-hydroxy-4-methylquinoline

3.1.12 2-Hydroxy-4-methyl-3-(3-propoxypropyl)-chinolin3.1.12 2-hydroxy-4-methyl-3- (3-propoxypropyl) quinoline

3.1.13 3 -(3 -Butoxypropyl)-2-hydroxy-4-methylchinolin3.1.13 3 - (3-Butoxypropyl) -2-hydroxy-4-methylquinoline

3.1.14 2-Hydroxy-4-methyl-3-(3-pentoxypropyl)-chinolin3.1.14 2-Hydroxy-4-methyl-3- (3-pentoxypropyl) quinoline

3.1.15 2-Hydroxy-3-(5-hydroxypentyl)-4-methylchinolin3.1.15 2-Hydroxy-3- (5-hydroxypentyl) -4-methylquinoline

3.1.16 2-Hydroxy-3-(5-methoxypentyl)-4-methylchinolin3.1.16 2-Hydroxy-3- (5-methoxypentyl) -4-methylquinoline

3.1.17 3-(5-Ethoxypentyl)-2-hydroxy-4-methylchinolin3.1.17 3- (5-ethoxypentyl) -2-hydroxy-4-methylquinoline

3.1.18 2-Hydroxy-4-methyl-3-(5-propoxypentyl)-chinolin3.1.18 2-Hydroxy-4-methyl-3- (5-propoxypentyl) quinoline

3.1.19 2-Hydroxy-3-(3-hydroxyoctyl)-4-methylchinolin3.1.19 2-Hydroxy-3- (3-hydroxyoctyl) -4-methylquinoline

3.1.20 2-Hydroxy-3-(3-methoxyoctyl)-4-methylchinolin3.1.20 2-Hydroxy-3- (3-methoxyoctyl) -4-methylquinoline

3.1.21 3-(3-Ethoxyoctyl)-2-hydroxy-4-methylchinolin3.1.21 3- (3-Ethoxyoctyl) -2-hydroxy-4-methylquinoline

3.1.22 3-(2-Ethoxyethyl)-2-hydroxy-4-methylchinolin

Figure imgf000020_0001
Figure imgf000021_0001
3.1.22 3- (2-ethoxyethyl) -2-hydroxy-4-methylquinoline
Figure imgf000020_0001
Figure imgf000021_0001

Figure imgf000022_0001
Figure imgf000022_0001

Soweit die erfindungsgemäß anzuwendenden Verbindungen basischen Charakter haben, umfasst die Erfindung auch ihre Salze mit pharmazeutisch verträglichen Säuren wie z. B. mit Halogenwasserstoffsäuren, insbesondere Salzsäure, Essigsäure, Apfelsäure, Weinsäure, Maleinsäure, Fumarsäure, Methansulfonsäuren und ähnlichen. Weitere pharmazeutisch verträgliche Derivate und Analoga der vorgestellten Chinolin-Derivate sind ebenfalls für die Zwecke der vorliegenden Erfindung geeignet. Bevorzugte Chinolin-Derivate gemäß der vorliegenden Erfindung sind Verbindungen gemäß der vorstehenden allgemeinen Formel (I), wobei:Insofar as the compounds to be used according to the invention have a basic character, the invention also includes their salts with pharmaceutically acceptable acids such as. B. with hydrohalic acids, especially hydrochloric acid, acetic acid, malic acid, tartaric acid, maleic acid, fumaric acid, methanesulfonic acids and the like. Further pharmaceutically acceptable derivatives and analogs of the quinoline derivatives presented are also suitable for the purposes of the present invention. Preferred quinoline derivatives according to the present invention are compounds according to the general formula (I) above, where:

R1 ein Wasserstoffatom, eine Hydroxylgruppe, die Gruppe -OR2, ein Alkyl-, wie ein Methyl- oder ein Alkoxy-, wie ein Methoxyrest ist; R2 die vorstehend bei der allgemeinen Formel (I) angegebene Bedeutung hat und insbesondere ein Alkinylrest, wie vorstehend angegeben, ist; R3 ein Wasserstoffatom, eine Hydroxylgruppe, ein Alkyl-, wie ein Methyl- oder ein Alkoxy, wie ein Methoxyrest ist undR 1 is a hydrogen atom, a hydroxyl group, the group -OR 2 , an alkyl, such as a methyl or an alkoxy, such as a methoxy radical; R 2 (I) above in the general formula defined above and in particular an alkynyl group, as indicated above, is; R 3 is a hydrogen atom, a hydroxyl group, an alkyl, such as a methyl or an alkoxy, such as a methoxy radical and

R4, R5, R6 und R7 jeweils gleich oder verschieden und voneinander unabhängig ein Wasserstoffatom, ein Halogen, wie z. B. ein Chloratom, ein Alkoxy-, wie ein Methoxy- oder ein Ethoxyrest sind, sowie physiologisch verträgliche Derivate oder Analoga davon.R 4 , R 5 , R 6 and R 7 are each the same or different and independently a hydrogen atom, a halogen, such as. B. are a chlorine atom, an alkoxy, such as a methoxy or an ethoxy radical, and physiologically acceptable derivatives or analogues thereof.

Außergewöhnlich gut zur Behandlung von Natriumkanal-abhängigen Erkrankungen gemäß der vorliegenden Erfindung geeignet sind insbesondere die Chinolin-Derivate der allgemeinen Formel (I), wobeiThe quinoline derivatives of the general formula (I) are particularly well suited for the treatment of sodium channel-dependent diseases according to the present invention

R eine Hydroxylgruppe oder die Gruppe -OR ist;R is a hydroxyl group or the group -OR;

R2 die vorstehend bei der allgemeinen Formel (I) angegebene Bedeutung hat;R 2 above in the general formula (I) has the meaning given;

R ein Methylrest ist;R is a methyl radical;

R4, R5, R6 und R7 alle Wasserstoffatome sind, sowie physiologisch verträgliche Derivate und Analoga davon.R 4 , R 5 , R 6 and R 7 are all hydrogen atoms, as well as physiologically compatible derivatives and analogues thereof.

Ganz besonders bevorzugt sind jene Chinolin-Derivate gemäß der vorliegendenThose quinoline derivatives according to the present are very particularly preferred

Erfindung, bei denen R1 eine Hydroxylgruppe oder -OR2 ist, R3 ein Methylrest, R4, R5,Invention in which R 1 is a hydroxyl group or -OR 2 , R 3 is a methyl radical, R 4 , R 5 ,

R und R ein Wasserstoffatom und R ein Alkinylrest wie vorstehend angegeben ist.R and R are a hydrogen atom and R is an alkynyl group as indicated above.

Als spezifische, besonders bevorzugte Substituenten für R2 seien genannt: -CC-(CH2)4-CH3 The following may be mentioned as specific, particularly preferred substituents for R 2 : -CC- (CH 2 ) 4 -CH 3

Figure imgf000024_0001
Figure imgf000024_0001

-CC-(CH2)-CH3 -CC- (CH 2 ) -CH 3

-CC-(CH2)-OCH3 -CC- (CH 2) 3 -OCH

-CC-(CH2)2-OCH3 -CC- (CH 2 ) 2 -OCH 3

-CC-(CH2)-O-C2H5 -CC- (CH2) -O-C 2 H 5

-CC-(CH2)-O-(CH2)2-CH3 -CC- (CH 2 ) -O- (CH 2 ) 2 -CH 3

-CC-(CH2)-O-(CH2)3-CH3 -CC- (CH 2 ) -O- (CH 2 ) 3 -CH 3

-CC-(CH2)3-OCH3 -CC- (CH 2 ) 3 -OCH 3

-CC-(CH2)3-OC2H5

Figure imgf000024_0002
-CC- (CH 2 ) 3 -OC 2 H 5
Figure imgf000024_0002

-CC-(CO)-OCH3 -CC- (CO) -OCH 3

-CC-(CO)-OC2H5 -CC- (CO) -OC 2 H 5

Bevorzugt seien neben den in Beispielen aufgeführten, besonders bevorzugten Chinolin-Derivaten folgende Verbindungen genannt:In addition to the particularly preferred quinoline derivatives listed in examples, the following compounds are preferred:

Figure imgf000024_0003
1.1.17 3 -(5-Ethoxy- 1 -pentinyl)-2-hydroxy-4-methylchinolin
Figure imgf000024_0003
1.1.17 3 - (5-ethoxy-1-pentynyl) -2-hydroxy-4-methylquinoline

1.1.22 3-(Ethoxyethinyl)-2-hydroxy-4-methylchinolin1.1.22 3- (Ethoxyethynyl) -2-hydroxy-4-methylquinoline

1.1.23 2-Hydroxy-4-memyl-3-(me yloxycarbonyl-ethinyl)-chinolin1.1.23 2-Hydroxy-4-memyl-3- (methyloxycarbonylethynyl) quinoline

1.1.24 3-(Ethyloxycarbonyl-ethinyl)-2-hydroxy-4-methylchinolin1.1.24 3- (Ethyloxycarbonylethynyl) -2-hydroxy-4-methylquinoline

Die Erfindung betrifft ferner die Verwendung der erfindungsgemäßen Chinolin- Derivate der allgemeinen Formel (I) einschließlich der vorstehend angegebenen bevorzugten Verbindungen sowie deren physiologisch verträgliche Derivate oder Analoga zur Herstellung eines Arzneimittels zur Prophylaxe und Therapie von Natriumkanal-abhängigen Erkrankungen, insbesondere der Epilepsie.The invention further relates to the use of the quinoline derivatives of the general formula (I) according to the invention including the preferred compounds indicated above and their physiologically tolerable derivatives or analogs for the manufacture of a medicament for the prophylaxis and therapy of sodium channel-dependent diseases, in particular epilepsy.

Die für die Prophylaxe und Therapie von Natriumkanal-abhängigen Erkrankungen, insbesondere der Epilepsie, geeigneten erfindungsgemäßen Chinolin-Derivate oder physiologisch verträglichen Derivate oder Analoga davon werden zweckmäßig in üblicher Weise in pharmazeutische Präparate verarbeitet. Für die perorale Anwendung können die erfindungsgemäßen Chinolin-Derivate oder physiologisch verträglichen Derivate und Analoga davon zu Tabletten, Dragees oder Kapseln, für die rektale Anwendung zu Suppositorien verarbeitet werden, die gegebenenfalls neben den Wirkstoffen übliche pharmazeutische Trägerstoffe, Verdünnungsmittel und/oder Hilfsstoffe enthalten. Der Wirkstoffgehalt beträgt 1 bis 95 Gewichts-%, vorzugsweise 10 bis 80 Gewichts-%, bezogen auf das Gesamtgewicht der Zusammensetzung. Als Trägerstoffe, Verdümiungsmittel und Hilfsstoffe kommen z. B. Calciumcarbonat, Calciumphosphat, Natriumphosphat, Milchzucker, Maisstärke, Alginate, Gelatine, Aluminium oder Magnesiumstearat, Talkum oder Silikonöl in Betracht.The quinoline derivatives according to the invention which are suitable for the prophylaxis and therapy of sodium channel-dependent diseases, in particular epilepsy, or physiologically tolerable derivatives or analogs thereof are expediently processed in the customary manner into pharmaceutical preparations. For oral use, the quinoline derivatives according to the invention or physiologically compatible derivatives and analogues thereof can be processed into tablets, dragees or capsules, for rectal use into suppositories, which may contain conventional pharmaceutical carriers, diluents and / or auxiliaries in addition to the active ingredients. The active ingredient content is 1 to 95% by weight, preferably 10 to 80% by weight, based on the total weight of the composition. As carriers, diluents and auxiliaries come, for. As calcium carbonate, calcium phosphate, sodium phosphate, milk sugar, corn starch, alginates, gelatin, aluminum or magnesium stearate, talc or silicone oil.

Zweckmäßig kann ein solches Arzneimittel in Dosierungseinheiten zubereitet werden, die auf die gewünschte Therapie abgestimmt sind. Das erfindungsgemäße Chinolin- Derivat oder ein physiologisch verträgliches Derivat oder Analogon davon sollten in einer Menge verabreicht werden, die wirksam ist zur Prophylaxe und Therapie einer Natriumkanal-abhängigen Erkrankung, insbesondere der Epilepsie. Die Bestimmung einer therapeutisch wirksamen Menge fallt unter die Fähigkeiten eines Fachmanns und kann auf übliche Art und Weise durchgeführt werden. Erfindungsgemäße Arzneimittel können pro Einzeldosis 0,1 bis 1000 mg, vorteilhaft 1 bis 600 mg eines erfindungsgemäßen Chinolin-Derivats oder eines physiologisch verträglichen Derivats oder Analogons davon als Wirkstoff enthalten.Such a medicament can expediently be prepared in dosage units which are tailored to the desired therapy. The quinoline derivative according to the invention or a physiologically compatible derivative or analogue thereof should be administered in an amount which is effective for the prophylaxis and therapy of a sodium channel-dependent disease, in particular epilepsy. The determination of a therapeutically effective amount falls under the skill of a person skilled in the art and can be carried out in the usual way. Medicaments according to the invention can contain 0.1 to 1000 mg, advantageously 1 to 600 mg, of a quinoline derivative according to the invention or a physiologically tolerable derivative or analogs thereof as active ingredient per single dose.

Für die parenterale Verabreichung kommt die Anwendung der Wirkstoffe in Form von injizierbaren wässrigen oder öligen Suspension in Betracht, die zusätzlich noch Suspendiermittel, wie z. B. Natriumcarboxymethylcellulose, Methylcellulose, Hy- droxypropylcellulose, Natriumalginat oder Polyvinylpyrrolidon, Dispergiermittel wie Polyoxyethylenstearat und Konservierungsmittel enthalten können; die öligen Suspensionen können in Erdnuss-, Oliven-, Kokos-, Sesam-, oder Paraffinöl vorliegen.For parenteral administration, the active substances can be used in the form of injectable aqueous or oily suspensions, which additionally contain suspending agents, such as. B. sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, sodium alginate or polyvinyl pyrrolidone, dispersants such as polyoxyethylene stearate and preservatives may contain; the oily suspensions can be in peanut, olive, coconut, sesame or paraffin oil.

Bevorzugte Applikationsformen sind die perorale Gabe als Kapsel, Dragee oder Tablette sowie die parenterale Verbreichung als Injektion oder Infusion.Preferred forms of administration are oral administration as a capsule, dragee or tablet and parenteral administration as an injection or infusion.

Die dieser Erfindung zugrundeliegenden Verbindungen können v.a. aufgrund ilirer natriumkanalblockierenden Wirkung als Arzneimittel zur Therapie der Epilepsie und anderer Natriumkanal-abhängiger Erkrankungen eingesetzt werden. Bevorzugte Epilepsieformen sind:The compounds on which this invention is based can, in particular, due to its sodium channel blocking effect, it can be used as a drug for the treatment of epilepsy and other sodium channel-dependent diseases. Preferred forms of epilepsy are:

1. Einfache partielle Anfälle (fokale Anfälle)1. Simple partial seizures (focal seizures)

2. Komplexe partielle Anfalle (psychomotorische Anfalle)2. Complex partial attacks (psychomotor attacks)

3. Grand mal, insbesondere fokaler Genese (z. B. Schlaf-Grand mal, diffuses Grand mal) 4. Gemischte Epilepsieformen3. Grand mal, especially focal genesis (e.g. sleep grand mal, diffuse grand mal) 4. Mixed forms of epilepsy

Weitere Natriumkanal-abhängige Erkrankungen, die mit den erfindungsgemäßen Verbindungen behandelt werden können, sind insbesondere:Other sodium channel-dependent diseases that can be treated with the compounds according to the invention are in particular:

1. Die Therapie und/oder Prophylaxe (im Folgenden Behandlung genannt) neurologischer Erkrankungen, insbesondere zur Prophylaxe manischdepressiver Phasen (bipolare Störungen) 2. Die Anfallsverhütung beim AlkoholentzugL 1. The therapy and / or prophylaxis (hereinafter referred to as treatment) of neurological diseases, in particular for the prophylaxis of manic-depressive phases (bipolar disorders) 2. Preventing seizures during alcohol withdrawal L

3. Die Behandlung von akuten und/oder chronischen Schmerzen, z. B. Trigeminusneuralgie3. Treatment of acute and / or chronic pain, e.g. B. Trigeminal neuralgia

4. Die Behandlung der MigräneN 5. Die lokale Behandlung zur Juckreizstillung und/oder Schmerzstillung4. Treatment of migraines N 5. Local treatment for itching and / or pain relief

(Lokalanästhetika)(Local anesthetics)

6. Die Behandlung der cystischen Fibröse0 6. Treatment of cystic fibrosis 0

7. Die Behandlung nichtepileptischer Anfälle, z. B. bei Multipler Sklerosep 7. Treatment of non-epileptic seizures, e.g. B. in multiple sclerosis p

8. Die Behandlung von HerzrhythmusstörungenQ 9. Die NeuroprotektionR und neurodegenerative Erkrankungen wie z. B.8. Treatment of cardiac arrhythmias Q 9. Neuroprotection R and neurodegenerative diseases such as. B.

Perinataler Asphyxia, Alzheimer Erkrankung, Huntington Erkrankung, Morbus Parkinson oder amyotrophe LateralsklerosePerinatal asphyxia, Alzheimer's disease, Huntington's disease, Parkinson's disease or amyotrophic lateral sclerosis

10. Die Behandlung traumatischer neurologischer Schädigungen10. Treatment of traumatic neurological damage

9. Die Behandlung von Neuro Aidsu 10. Die Behandlung von Parkinson und Parkinson-Syndromenv 9. The treatment of neuro-AIDS and 10. The treatment of Parkinson's disease and parkinsonian syndromes v

11. Die Behandlung schmerzhafter diabetischer Neuropathienw 11. Treatment of Painful Diabetic Neuropathies w

12. Die Behandlung der Hypertoniex 12. Treatment of hypertension x

Des weiteren können die erfindungsgemäßen Chinolin-Derivate der allgemeinenFurthermore, the quinoline derivatives of the general

1 71 7

Formel (I) mit den Substituenten R bis R in ihrer allgemeinsten sowie bevorzugten Bedeutung wie vorstehend angegeben, insbesondere die genannten, gegenüber dem Stand der Technik neuen, erfindungsgemäßen Chinolin-Derivate, aufgrund ihrer Natriumkanal-blockierenden Eigenschaften auch in der Landwirtschaft als Insektizide γ Verwendung finden. Auch hierbei ist die geringe Toxizität der erfindungsgemäßen Verbindungen für den Menschen von besonderem Vorteil.Formula (I) with the substituents R to R in their most general and preferred meaning as indicated above, in particular the quinoline derivatives according to the invention which are new compared to the prior art and, owing to their sodium channel-blocking properties, are also used as insecticides γ in agriculture Find. Here too, the low toxicity of the compounds according to the invention is of particular advantage for humans.

Die vorliegende Erfindung soll anhand nachstehender Beispiele näher erläutert werden. Die Beispiele sind nicht beschränkend aufzufassen.The present invention will be explained in more detail using the following examples. The examples are not to be interpreted as restrictive.

Synthese der erfindungsgemäßen, neuen Chinolin-Derivate und BeispieleSynthesis of the new quinoline derivatives according to the invention and examples

Die palladiumkatalysierte Alkin-Kupplung von organischen Halogenverbindungen ist eine Methode zur Ausbildung von Kohlenstoff-Kohlenstoff-Bindungen2 und daher zum Anbringen von Alkinyl-Substituenten. Nach dieser Methode wurden schon Verbindungen wie zum Beispiel 2-Hydroxy-3-(l-hydroxy-l-metlιyl-3-butinyl)-4- methoxychinolin synthetisiert*. Diese Methode eignet sich sehr gut zur Darstellung der erfindungsgemäßen, neuen Chinolin-Derivate.The palladium-catalyzed alkyne coupling of organic halogen compounds is a method for the formation of carbon-carbon bonds 2 and therefore for Attaching alkynyl substituents. Compounds such as 2-hydroxy-3- (l-hydroxy-l-methyl-3-butynyl) -4-methoxyquinoline have already been synthesized by this method *. This method is very suitable for the preparation of the new quinoline derivatives according to the invention.

Das zur Herstellung anderer, von den nachstehend aufgeführten Beispielen verschiedener, erfindungsgemäßer und gegenüber dem Stand der Technik neuer Cliinolin-Derivate gemäß der allgemeinen Formel (I) (z. B. Derivate gemäß der Tabelle 1) notwendige Anbringen weiterer, unterschiedlicher Substituenten an den Aromatenkem kami gemäß Aromatensubstitutionsverfahren, die dem Fachmann bekannt sind, erreicht werden.The attachment of further, different substituents to the aromatic nucleus necessary for the preparation of other, according to the invention, novel cliinoline derivatives according to the general formula (I) which are different from the examples listed below (e.g. derivatives according to Table 1) kami according to aromatic substitution methods known to those skilled in the art can be achieved.

Zur Herstellung der beispielhaft aufgeführten Verbindungen ist die jeweils aufgeführte der nachstehenden Methoden gewählt worden.To prepare the compounds listed by way of example, the methods listed below have been selected.

Methode AMethod A

3-Iod-4-methylchinolin-2(lH)on (1 Mol-Äquivalent) wird zusammen mit dem Acetylenderivat (2 Mol-Äquivalente), Bis-(triphenylphosphin)-palladium-(II)-chlorid, und Kupferiodid 20 Stunden bei 65-70 °C in 40 ml Triethylamin unter Lichtschutz und Stickstoffatmosphäre erhitzt. Der Reaktionsverlauf wird mittels Dünnschicht- Chromatographie (DC) verfolgt. Nach Reaktionsende wird der Ansatz mit Ethylacetat verdünnt und der Katalysator abfiltriert. Das Lösungsmittel wird im Vakuum entfernt. Der zurückbleibende Niederschlag wird in einem geeigneten Lösungsmittel gelöst. Die synthetisierten Produkte werden mittels Mitteldruckflüssigkeits-Chromatographie (MPLC) isoliert.3-Iodo-4-methylquinolin-2 (1H) one (1 mole equivalent) together with the acetylene derivative (2 mole equivalents), bis (triphenylphosphine) palladium (II) chloride, and copper iodide are added for 20 hours Heated 65-70 ° C in 40 ml triethylamine under light protection and nitrogen atmosphere. The course of the reaction is monitored by means of thin layer chromatography (TLC). After the end of the reaction, the mixture is diluted with ethyl acetate and the catalyst is filtered off. The solvent is removed in vacuo. The remaining precipitate is dissolved in a suitable solvent. The synthesized products are isolated using medium pressure liquid chromatography (MPLC).

Methode BMethod B

1 Mol-Äquivalent des 3-Iod-4-methylchinolin-2(lH)ons wird mit 10 Mol-Äquivalenten des Acetylenderivates gemäß zu Methode A umgesetzt. Methode C1 mol equivalent of 3-iodo-4-methylquinolin-2 (1H) ons is reacted with 10 mol equivalents of the acetylene derivative according to method A. Method C

Das 3-Iod-4-methylchinolin-2(lH)on (1 Moläquivalent) wird zusammen mit dem Acetylenderivat (2 Moläquivalente) 10 Stunden bei 65-70 °C und anscliließend 10 Stunden bei 100 °C erhitzt. Die Aufarbeitung erfogt wie in Methode A beschrieben.The 3-iodo-4-methylquinolin-2 (1H) one (1 mol equivalent) is heated together with the acetylene derivative (2 mol equivalents) for 10 hours at 65-70 ° C and then for 10 hours at 100 ° C. The processing takes place as described in method A.

Methode DMethod D

Das 4-Methylchinolinderivat wird mit dem Acetylenderivat bei 40 °C 6,5 Stunden umgesetzt und analog zu Methode A aufgearbeitet.The 4-methylquinoline derivative is reacted with the acetylene derivative at 40 ° C. for 6.5 hours and worked up analogously to method A.

Beispiel 1:Example 1:

2-Hydroxy-3 -(3 -hydroxy- 1 -propinylV 4-methylchinolin (Nr. : 1.1.8)2-Hydroxy-3 - (3-hydroxy-1-propynylV 4-methylquinoline (No.: 1.1.8)

Figure imgf000029_0001
Figure imgf000029_0001

C13H11NO2 Molmasse: 213,23C13H11NO2 molar mass: 213.23

Darstellung nach Methode C aus 2-Hydroxy-3-Iod-4-methylchinolin und 2-Propin-l- ol.Preparation according to method C from 2-hydroxy-3-iodo-4-methylquinoline and 2-propyn-1-ol.

Ansatzgröße: 285,1 mg 2-Hydroxy-3-Iod-4-methylchinolin (lmmol)Batch size: 285.1 mg 2-hydroxy-3-iodo-4-methylquinoline (lmmol)

112,1 mg 2-Propin-l-ol (2 mmol)112.1 mg 2-propyn-l-ol (2 mmol)

35.1 mg Bis-(triphenylphosphin)-palladium-(II)-chlorid (0,05 mmol)35.1 mg bis (triphenylphosphine) palladium (II) chloride (0.05 mmol)

70.2 mg Kupferiodid (0,37 mmol)70.2 mg copper iodide (0.37 mmol)

Ausbeute: 27 mg (12,7 % d.Th.)Yield: 27 mg (12.7% of theory)

Schmelzpunkt: > 320 °C (Cyclohexan 2, Ethylacetat 3, hellbraunesMelting point:> 320 ° C (cyclohexane 2, ethyl acetate 3, light brown

Pulver)Powder)

Rf (Lösungsmittel): 0,14 (Cyclohexan 2, Ethylacetat 3) IR(KBr) [cπT1] 3374 (br, OH), 3082 (CH aromat), 2959, 2906, 2856 (CH aliphat.), 2188 (CC Dreifachbindung), 1653 (C=O), 1555, 1498 (C=C), 891, 820, 754Rf (solvent): 0.14 (cyclohexane 2, ethyl acetate 3) IR (KBr) [cπT 1 ] 3374 (br, OH), 3082 (CH aromat), 2959, 2906, 2856 (CH aliphatic), 2188 (CC triple bond), 1653 (C = O), 1555, 1498 (C = C), 891, 820, 754

1H-NMR (δ [ppm]): 2,42 (s, 3H, 4-CH3), 4,31 (d, 3J - 5,5 Hz, 2H, 3'-CH2), 5,28 300 MHz (DMSO-d6) (t, 3J = 5,5 Hz, 1H, 4'-OH, austauschbar), 6,43 (s, 1H, H-5), 7,28 (d, 3J = 8,4 Hz, 1H, H-6), 7,53 (d, 3J - 8,4 Hz, 1H, H- 7), 7,74 (s, 1H, H-8), 11,72 (s, 1H, 1-NH, austauschbar) 13C-NMR (δ [ppm]): 18,8 (+) 4-CH3, 49,9 (-) CI 2 OH, 116,4 (+), 122,0 (+), 75,5 MHz (DMSO-d6) 128,3 (+), 133,4 (+) (4 CH aromatisch), 83,9, 89,6, 116,0, 120,1, 138,9, 148,0, 161,9 (7 C quartär)1H NMR (δ [ppm]): 2.42 (s, 3H, 4-CH 3 ), 4.31 (d, 3 J - 5.5 Hz, 2H, 3'-CH 2 ), 5.28 300 MHz (DMSO-d 6 ) (t, 3 J = 5.5 Hz, 1H, 4'-OH, exchangeable), 6.43 (s, 1H, H-5), 7.28 (d, 3 J = 8.4 Hz, 1H, H-6), 7.53 (d, 3 J - 8.4 Hz, 1H, H-7), 7.74 (s, 1H, H-8), 11.72 (s, 1H, 1-NH, exchangeable) 13 C-NMR (δ [ppm]): 18.8 (+) 4-CH 3 , 49.9 (-) CI 2 OH, 116.4 (+), 122.0 (+), 75.5 MHz (DMSO-d 6 ) 128.3 (+), 133.4 (+) (4 CH aromatic), 83.9, 89.6, 116.0, 120, 1, 138.9, 148.0, 161.9 (7 C quaternary)

MS (70 eV), m/z (%): 214 (12) [MLAI], 213 (63) [M*], 196 (16) [M -OH], 184 (28), 156 (36), 130 (28), 77 (26), 55 (31) [C3H2OH], 43MS (70 eV), m / z (%): 214 (12) [MLAI], 213 (63) [M *], 196 (16) [M -OH], 184 (28), 156 (36), 130 (28), 77 (26), 55 (31) [C 3 H 2 OH], 43

(100). Molmasse (Hochauflösung): [ / ] [TViAl] berechnet: 213,0789 214,0823 gefunden: 213,0788 214,0823 Beispiel 2:(100). Molar mass (high resolution): [/] [TViAl] calculated: 213.0789 214.0823 found: 213.0788 214.0823 Example 2:

3-(3-Hydroxy-l -propinyl)- 2-r3-hvdroxy-l-propinyloxy -4-methyl-chinolin (Nr.: 1.2.8)3- (3-hydroxy-l-propynyl) - 2-r3-hvdroxy-l-propynyloxy -4-methyl-quinoline (No .: 1.2.8)

C16Hι3NO3 Molmasse: 267,28 C 16 Hι 3 NO 3 molar mass: 267.28

Darstellung nach Methode C aus 2-Hydroxy-3-Iod-4-methylchinolin und 2-Propin-l-ol. Ansatzgröße: 285,1 mg 2-Hydroxy-3-Iod-4-methylchinolin (lmmol) 112,1 mg 2-Propin-l-ol (2 mmol)Preparation according to method C from 2-hydroxy-3-iodo-4-methylquinoline and 2-propyn-l-ol. Batch size: 285.1 mg 2-hydroxy-3-iodo-4-methylquinoline (mmol) 112.1 mg 2-propyn-l-ol (2 mmol)

35.1 mg Bis-(triphenylphosphin)-palladium-(II)-chlorid (0,05 mmol)35.1 mg bis (triphenylphosphine) palladium (II) chloride (0.05 mmol)

70.2 mg Kupferiodid (0,37 mmol70.2 mg copper iodide (0.37 mmol

Ausbeute: 12mg (4,5 % d.Th.)Yield: 12mg (4.5% of theory)

Schmelzpunkt: 214 °C (Cyclohexan 2, Ethylacetat 3, hellbraunes Pulver)Melting point: 214 ° C (cyclohexane 2, ethyl acetate 3, light brown powder)

Rf (Lösungsmittel): 0,20 (Cyclohexan 2, Ethylacetat 3)Rf (solvent): 0.20 (cyclohexane 2, ethyl acetate 3)

IR(KBr) [cm-1]: 3368 (br, OH), 3108 (CH aroma), 2919, 2856 (CH aliphat), 2212 (CC Dreifachbindung), 1595, 1506 (C=C), 879, 836, 746IR (KBr) [cm -1 ]: 3368 (br, OH), 3108 (CH aroma), 2919, 2856 (CH aliphatic), 2212 (CC triple bond), 1595, 1506 (C = C), 879, 836, 746

1H-NMR (δ [ppm]): 2,86 (s, 3H, 4-CH3), 4,38 (d, 3J = 5,7 Hz, 2H, 3"-CH2), 300 MHz (DMSO-d6) 4,65 (d, 3J = 5,6 Hz, 2H, 4'-CH2), 5,38 (t, 3J = 5,7 Hz, IH, 4"-OH, austauschbar), 5,67 (t, 3J = 5,6 Hz, IH, 5'-OH, austauschbar), 7, 10 (s, IH, H-5), 7,69 (d, 3J = 8,7 Hz, IH, H- 6), 7,95 (d, 3J = 8,7 Hz, IH, H-7), 8,24 (s, IH, H-8)1H-NMR (δ [ppm]): 2.86 (s, 3H, 4-CH 3 ), 4.38 (d, 3 J = 5.7 Hz, 2H, 3 "-CH 2 ), 300 MHz ( DMSO-d 6 ) 4.65 (d, 3 J = 5.6 Hz, 2H, 4'-CH 2 ), 5.38 (t, 3 J = 5.7 Hz, IH, 4 "-OH, interchangeable ), 5.67 (t, 3 J = 5.6 Hz, IH, 5'-OH, exchangeable), 7, 10 (s, IH, H-5), 7.69 (d, 3 J = 8, 7 Hz, IH, H- 6), 7.95 (d, 3 J = 8.7 Hz, IH, H-7), 8.24 (s, IH, H-8)

MS (70 eV), m/z (%): 268 (18) [MAl], 267 (100) [M1"], 250 (17) [M^-OH], 238 (31), 222(12), 210 (17), 208 (9), 191 (9) [208-OH]MS (70 eV), m / z (%): 268 (18) [MAl], 267 (100) [M 1 " ], 250 (17) [M ^ -OH], 238 (31), 222 (12 ), 210 (17), 208 (9), 191 (9) [208-OH]

Molmasse (Hochauflösung): [M1-] [M*"+l] berechnet: 267,0895 268,0929 gefunden: 267,0895 268,0928 Beispiel 3:Molar mass (high resolution): [M 1 -] [M * " + l] calculated: 267.0895 268.0929 found: 267.0895 268.0928 Example 3:

2-Hydroxy-3-(3-hvdroxy-3-methyl- 1 -butinyl)-4-methylchinolin (Nr. : 1.1.25)2-Hydroxy-3- (3-hvdroxy-3-methyl-1-butinyl) -4-methylquinoline (No.: 1.1.25)

Figure imgf000032_0001
Figure imgf000032_0001

Cι5H15NO2 Molmasse: 241,29Cι 5 H 15 NO 2 molar mass: 241.29

Darstellung nach Methode A aus 2-Hydroxy-3-Iod-4-methylchinolin und 2-Methyl-3- butin-2-ol.Preparation according to method A from 2-hydroxy-3-iodo-4-methylquinoline and 2-methyl-3-butyn-2-ol.

Ansatzgröße: 285.1 mg 32-Hydroxy-3-Iod-4-methylchinolin (lmmol)Batch size: 285.1 mg 32-hydroxy-3-iodo-4-methylquinoline (lmmol)

168.2 mg 2-Methyl-3-butin-2-ol (2 mmol)168.2 mg of 2-methyl-3-butyn-2-ol (2 mmol)

35.1 mg Bis-(triphenylphosphin)-palladium-(II)-chlorid (0,05 mmol)35.1 mg bis (triphenylphosphine) palladium (II) chloride (0.05 mmol)

70.2 mg Kupferiodid (0,37 mmol)70.2 mg copper iodide (0.37 mmol)

Ausbeute: 41 mg (17,0 % d.Th.)Yield: 41 mg (17.0% of theory)

Schmelzpunkt: 244 °C (Cyclohexan 2, Ethylacetat 3, weißes Pulver)Melting point: 244 ° C (cyclohexane 2, ethyl acetate 3, white powder)

Rf (Lösungsmittel): 0,4 (Cyclohexan 2, Ethylacetat 3)Rf (solvent): 0.4 (cyclohexane 2, ethyl acetate 3)

IR (KBr) [cm-1 ]: 3342 (br., OH), 3087 (CH aromtisch), 2976, 2899, 2864 (CH aliphat.), 2211 (CC Dreifachbindung), 1650 (C=O), 1602, 1556, 1497 (C=C), 888, 845, 828, 752IR (KBr) [cm -1 ]: 3342 (br., OH), 3087 (CH aromatic), 2976, 2899, 2864 (CH aliphatic), 2211 (CC triple bond), 1650 (C = O), 1602, 1556, 1497 (C = C), 888, 845, 828, 752

1H-NMR (δ [ppm]): 1,46 (s, 6H, 4'-, 5'-CH3 ), 2,41 (s, 3H, 4-CH3), 5,43 300 MHz (DMSO-d6) (s, IH, 3'-OH, austauschbar), 6,42 (s, IH, H-5), 7,26 (d, 3J = 8,5 Hz, IH, H-6), 7,48 (d, 3J = 8,5 Hz, IH, H-7), 7,66 (s, IH, H-8), 11,71 (s, IH, 1-NH, austauschbar)1H NMR (δ [ppm]): 1.46 (s, 6H, 4'-, 5'-CH 3 ), 2.41 (s, 3H, 4-CH 3 ), 5.43 300 MHz (DMSO-d 6 ) (s, IH, 3'-OH, replaceable), 6.42 (s, IH, H-5), 7.26 (d, 3 J = 8.5 Hz, IH, H-6), 7.48 (d, 3 J = 8.5 Hz, IH, H-7), 7.66 (s, IH, H-8), 11.71 (s, IH, 1-NH , interchangeable)

13C-NMR (δ [ppm]): 18,3 (+) (4-CH3), 31,6 (+) (X-, 5'-CH3), 115,8 (+), 121,5 75,5 MHz (DMSO-d6) (+), 127,5 (+), 132,9 (+) (4 CH aromatisch), 63,6, 80,1, 95,2, 115,6, 119,5, 138,3, 147,5, 161,4 (6 C quartär) 13 C-NMR (δ [ppm]): 18.3 (+) (4-CH 3 ), 31.6 (+) (X-, 5'-CH 3 ), 115.8 (+), 121, 5 75.5 MHz (DMSO-d 6 ) (+), 127.5 (+), 132.9 (+) (4 CH aromatic), 63.6, 80.1, 95.2, 115.6, 119.5, 138.3, 147.5, 161.4 (6 C quaternary)

MS (70 eV), m/z (%): 242 (13) [M^l], 241 (68) [M1"], 226 (100) [M+-CH3], 224MS (70 eV), m / z (%): 242 (13) [M ^ l], 241 (68) [M 1 " ], 226 (100) [M + -CH 3 ], 224

(5), 184 (42), 166 (10), 154 (12), 99 (17)(5), 184 (42), 166 (10), 154 (12), 99 (17)

Molmasse (Hochauflösung): [M [M^l] berechnet: 241,1103 242,1136 gefunden: 241,1108 242,1139Molar mass (high resolution): [M [M ^ l] calculated: 241.1103 242.1136 found: 241.1108 242.1139

Beispiel 4:Example 4:

3-(3-Hydroxy-3-methyl-l-butinyl -2-(3-hydroxy-3-methyl-l-butinyloxy)-4-methyl- chinolin f r.: 1.2.19)3- (3-Hydroxy-3-methyl-l-butynyl -2- (3-hydroxy-3-methyl-l-butynyloxy) -4-methyl-quinoline for: 1.2.19)

Figure imgf000033_0001
Figure imgf000033_0001

C20H21NO3 Molmasse: 323,39C 20 H 21 NO 3 molar mass: 323.39

Darstellung nach Methode C aus 2-Hydroxy-3-Iod-4-methylchinolin und 2-Methyl-3- butin-2-ol.Preparation according to method C from 2-hydroxy-3-iodo-4-methylquinoline and 2-methyl-3-butyn-2-ol.

Ansatzgröße: 285,1 mg 2-Hydroxy-3-Iod-4-methylchinolin (lmmol) 168,2 mg 2-Methyl-3-butin-2-ol (2 mmol)Batch size: 285.1 mg 2-hydroxy-3-iodo-4-methylquinoline (lmmol) 168.2 mg of 2-methyl-3-butyn-2-ol (2 mmol)

35.1 mg Bis-(triphenylphosphin)-palladium (U)-chlorid (0,05 mmol)35.1 mg bis (triphenylphosphine) palladium (U) chloride (0.05 mmol)

70.2 mg Kupferiodid (0,37 mmol)70.2 mg copper iodide (0.37 mmol)

Ausbeute: 64 mg (19,8 % d.Th.)Yield: 64 mg (19.8% of theory)

Schmelzpunkt: 242 °C (Cyclohexan 2, Ethylacetat 3, weißes Pulver)Melting point: 242 ° C (cyclohexane 2, ethyl acetate 3, white powder)

Rf (Lösungsmittel): 0,39 (Cyclohexan 2, Ethylacetat 3)Rf (solvent): 0.39 (cyclohexane 2, ethyl acetate 3)

IR (KBr) [cm-1 ] 3380 (br, OH), 3058 (CH aromat), 2975, 2929 (CH aliphat.), 2205 (CC Dreifachbindung), 1597, 1507 (C=C), 890, 825, 802, 776IR (KBr) [cm -1 ] 3380 (br, OH), 3058 (CH aromat), 2975, 2929 (CH aliphatic), 2205 (CC triple bond), 1597, 1507 (C = C), 890, 825, 802, 776

1H-NMR (δ [ppm]): 1,52 (s, 6H, 4"-, 5"-CH3), 1,57 (s, 6H, 5'-, 6'-CH3), 300 MHz (DMSO-d6) 2,86 (s, 3H, 4-CH3), 5,51 (s, IH, 3"-OH, austauschbar), 5,59 (s, IH, 4'-OH, austauschbar), 7,03 (s, IH, H-5), 7,65 (d, 3J = 8,6 Hz, IH, H-6), 7,92 (d, 3J = 8,6 Hz, IH, H-7), 8,18 (s, lH, H-8)1H-NMR (δ [ppm]): 1.52 (s, 6H, 4 "-, 5" -CH 3 ), 1.57 (s, 6H, 5'-, 6'-CH 3 ), 300 MHz (DMSO-d 6 ) 2.86 (s, 3H, 4-CH 3 ), 5.51 (s, IH, 3 "-OH, interchangeable), 5.59 (s, IH, 4'-OH, interchangeable ), 7.03 (s, IH, H-5), 7.65 (d, 3 J = 8.6 Hz, IH, H-6), 7.92 (d, 3 J = 8.6 Hz, IH, H-7), 8.18 (s, lH, H-8)

1 "3C-NMR (δ [ppm]): 14,8 (+) (4-CH3), 28,6 (+) (2 mal CH3), 31,6 (+) (2 mal 75,5 MHz (DMSO-d6) CH3), 63,7, 67,8, 80,6, 96,5, 118,5, 121,6, 125,2, 137,4, 143,2, 161,0, 166,2 (11 C quartär), 98,3 (+), 127,3 (+), 128,8 (+), 130,6 (+) (4 CH aromatisch)1 "3C-NMR (δ [ppm]): 14.8 (+) (4-CH 3 ), 28.6 (+) (2 times CH 3 ), 31.6 (+) (2 times 75.5 MHz (DMSO-d 6 ) CH 3 ), 63.7, 67.8, 80.6, 96.5, 118.5, 121.6, 125.2, 137.4, 143.2, 161.0 , 166.2 (11 C quaternary), 98.3 (+), 127.3 (+), 128.8 (+), 130.6 (+) (4 CH aromatic)

MS (70 eV), m/z (%): 324 (13) [M'+l], 323 (54) pv ], 308 (100) [M'-CHa], 280 (16) [308-CO], 266 (19), 250 (11), 208 (11), 146 (16)MS (70 eV), m / z (%): 324 (13) [M '+ 1], 323 (54) pv], 308 (100) [M'-CHa], 280 (16) [308-CO ], 266 (19), 250 (11), 208 (11), 146 (16)

Molmasse (Hochauflösung): [M [M'+l] berechnet: 323,1521 324,1554 gefunden: 323,1520 324,1555 Beispiel 5:Molar mass (high resolution): [M [M '+ 1] calculated: 323.1521 324.1554 found: 323.1520 324.1555 Example 5:

2-Hvdroxy-4-me yl-3-(l-octinyl)-chinolin (Nr.: 1.1.3)2-Hvdroxy-4-me yl-3- (l-octynyl) quinoline (No .: 1.1.3)

Figure imgf000035_0001
Figure imgf000035_0001

Cj8H21NO Molmasse: 267,37Cj 8 H 21 NO molar mass: 267.37

Darstellung nach Methode B aus 2-Hydroxy-3-Iod-4-methylchinolin und 1-Octin.Preparation according to method B from 2-hydroxy-3-iodo-4-methylquinoline and 1-octyne.

Ansatzgröße: 285,1 mg 2-Hydroxy-3-Iod-4-methylchinolin (lmmol) l,l g l-Octin (10 mmol)Batch size: 285.1 mg 2-hydroxy-3-iodo-4-methylquinoline (lmmol) l, l g l-octyne (10 mmol)

35.1 mg Bis-(triphenylphosphin)-palladium-(II)-chlorid (0,05 mmol)35.1 mg bis (triphenylphosphine) palladium (II) chloride (0.05 mmol)

70.2 mg Kupferiodid (0,37 mmol)70.2 mg copper iodide (0.37 mmol)

Ausbeute: 26 mg (9,7 % d.Th.)Yield: 26 mg (9.7% of theory)

Schmelzpunkt: 167 °C (Cyclohexan 2, Ethylacetat 3, beiges Pulver)Melting point: 167 ° C (cyclohexane 2, ethyl acetate 3, beige powder)

Rf (Lösungsmittel) : 0,2 (Cyclohexan 2, Ethylacetat 3)Rf (solvent): 0.2 (cyclohexane 2, ethyl acetate 3)

IR(KBr) [cm-1]: 3082 (CH aromat.), 2956, 2933, 2864 (CH aliphat.), 1655 (C=O), 1561, 1496 (C=C), 925, 889, 865, 831IR (KBr) [cm -1 ]: 3082 (CH aromat.), 2956, 2933, 2864 (CH aliphatic.), 1655 (C = O), 1561, 1496 (C = C), 925, 889, 865, 831

1H-NMR (δ [ppm]): 0,92 (t, 3J = 6,8 Hz, 3H, 6'-CH3), 1,21-1,36 (m, 4H, 4'-, 300 MHz (CDC13) 5'-CH2), 1,46 (quin, 3J = 6,8 Hz, 2H, 3'-CH2), 1,63 (quin, 3J = 6,8 Hz, 2H, 2'-CH2), 2,43 (t, 3J = 6,8 Hz, 2H, l '-CH2), 2,49 (s, 3H, 4-CH3), 6,57 (s, IH, H-5), 7,32 (d, 3J = 8,5 Hz, IH, H-6), 7,52 (d, 3J = 8,5 Hz, IH, H-7), 7,71 (s, IH, H-8), 12,25 (s, IH, 1-NH, austauschbar)1H-NMR (δ [ppm]): 0.92 (t, 3 J = 6.8 Hz, 3H, 6'-CH 3 ), 1.21-1.36 (m, 4H, 4'-, 300 MHz (CDC1 3 ) 5'-CH 2 ), 1.46 (quin, 3 J = 6.8 Hz, 2H, 3'-CH 2 ), 1.63 (quin, 3 J = 6.8 Hz, 2H , 2'-CH 2 ), 2.43 (t, 3 J = 6.8 Hz, 2H, l '-CH 2 ), 2.49 (s, 3H, 4-CH 3 ), 6.57 (s , IH, H-5), 7.32 (d, 3 J = 8.5 Hz, IH, H-6), 7.52 (d, 3 J = 8.5 Hz, IH, H-7), 7.71 (s, IH, H-8), 12.25 (s, IH, 1-NH, replaceable)

MS (70 eV), m/z (%):), 268 (15) ^+1], 267 (65) [Iv ], 252 (3) [M'-CHg], 238 (21) [252-CH2], 224 (44) [238-CH2, 210 (45) [224-CH2], 196 (100) [210-CH2], 180 (32), 167 (60), 154 (18), 139 (23), 115 (15), 77 (149, 55 (14)MS (70 eV), m / z (%) :), 268 (15) ^ + 1], 267 (65) [Iv], 252 (3) [M'-CHg], 238 (21) [252- CH 2 ], 224 (44) [238-CH 2 , 210 (45) [224-CH 2 ], 196 (100) [210-CH 2 ], 180 (32), 167 (60), 154 (18) , 139 (23), 115 (15), 77 (149, 55 (14)

Molmasse (Hochauflösung): [MT] [MΓ+1] berechnet: 267,1623 268,1656 gefunden: 267,1621 268,1655Molar mass (high resolution): [MT] [MΓ + 1] calculated: 267.1623 268.1656 found: 267.1621 268.1655

Beispiel 6:Example 6:

3-(l-Hexinyl)-2-hvdroχy-4-methylchinolin (Nr.: 1.1.5)3- (l-Hexinyl) -2-hvdroχy-4-methylquinoline (No .: 1.1.5)

Figure imgf000036_0001
Figure imgf000036_0001

C16H17NO Molmasse: 239,32C 16 H 17 NO molar mass: 239.32

Darstellung nach Methode B aus 2-Hydroxy-3-Iod-4-methylchinolin und 1 -Hexin.Preparation according to method B from 2-hydroxy-3-iodo-4-methylquinoline and 1-hexin.

Ansatzgröße: 285,1 mg 2-Hydroxy-3-Iod-4-methylchinolin (lmmol) 822 mg 1 -Hexin (10 mmol)Batch size: 285.1 mg 2-hydroxy-3-iodo-4-methylquinoline (lmmol) 822 mg 1-hexin (10 mmol)

35.1 mg Bis-(triphenylphosphin)-palladium-(II)-chlorid (0,05 mmol)35.1 mg bis (triphenylphosphine) palladium (II) chloride (0.05 mmol)

70.2 mg Kupferiodid (0,37 mmol)70.2 mg copper iodide (0.37 mmol)

Ausbeute: 54 mg (22,6 % d.Th.)Yield: 54 mg (22.6% of theory)

Schmelzpunkt: 169,5 °C (Cyclohexan 2, Ethylacetat 3, weiße Kristalle) Rf (Lösungsmittel) : 0,53 (Cyclohexan 2, Ethylacetat 3)Melting point: 169.5 ° C (cyclohexane 2, ethyl acetate 3, white crystals) Rf (solvent): 0.53 (cyclohexane 2, ethyl acetate 3)

IR(KBr) [cm"1]: 3082, 3035 (CH aromat.), 2947, 2924, 2865 (CH aliphat.), 1656 (C=O), 1600, 1562, 1494 (C=C), 894, 861, 823, 744IR (KBr) [cm "1 ]: 3082, 3035 (CH aromat.), 2947, 2924, 2865 (CH aliphatic.), 1656 (C = O), 1600, 1562, 1494 (C = C), 894, 861, 823, 744

1H-NMR (δ [ppm]): 0,97 (t, 3J = 7,2 Hz, 3H, 4'-CH3), 1,49 (quin. 3J = 6,9 Hz, 300 MHz (CDC13) 3'-CH2), 1,61 (quin, 3J = 6,9 Hz, 2H, 2'-CH2), 2,43 (t, 3J = 6,9 Hz, 2H, r-CH2), 2,49 (s, 3H, 4-CH3), 6,57 (s, IH, H-5), 7,39 (d, 3J = 8,5 Hz, IH, H-6), 7,52 (d, 3J = 8,4 Hz, IH, H- 7), 7,72 (s, IH, H-8), 11,77 (s, IH, 1-NH, austauschbar)1H-NMR (δ [ppm]): 0.97 (t, 3 J = 7.2 Hz, 3H, 4'-CH 3 ), 1.49 (quin. 3 J = 6.9 Hz, 300 MHz ( CDC1 3 ) 3'-CH 2 ), 1.61 (quin, 3 J = 6.9 Hz, 2H, 2'-CH 2 ), 2.43 (t, 3 J = 6.9 Hz, 2H, r -CH 2 ), 2.49 (s, 3H, 4-CH 3 ), 6.57 (s, IH, H-5), 7.39 (d, 3 J = 8.5 Hz, IH, H- 6), 7.52 (d, 3 J = 8.4 Hz, IH, H-7), 7.72 (s, IH, H-8), 11.77 (s, IH, 1-NH, interchangeable )

13C-NMR (δ [ppm]): 14,3 (+) (4-CH3), 19,8 (-), 22,8 (-), 31,5 (-) (T-, 3'-, 4'- 75,5 MHz (CDCI3) CH2), 80,6, 90,9, 119,1, 212,1, 138,0, 149,5, 164,5 (7 C quartär), 117,0 (+), 121,7 (+), 128,4 (+), 134,3 (+) (4 CH aromatisch) 13 C-NMR (δ [ppm]): 14.3 (+) (4-CH 3 ), 19.8 (-), 22.8 (-), 31.5 (-) (T-, 3 ' -, 4'- 75.5 MHz (CDCI3) CH 2 ), 80.6, 90.9, 119.1, 212.1, 138.0, 149.5, 164.5 (7 C quaternary), 117 , 0 (+), 121.7 (+), 128.4 (+), 134.3 (+) (4 CH aromatic)

MS (70 eV), m/z (%): 240 (19) [M l], 239 (100) [M1], 224 (51) [M^-CHs], 210 (50) [224-CH2], 196 (98) [210-CH2], 180 (14), 176 (44), 54 (11), 139 (17), 115 (11), 77 (10), 63 (11)MS (70 eV), m / z (%): 240 (19) [M 1], 239 (100) [M 1 ], 224 (51) [M ^ -CHs], 210 (50) [224-CH 2 ], 196 (98) [210-CH 2 ], 180 (14), 176 (44), 54 (11), 139 (17), 115 (11), 77 (10), 63 (11)

Molmasse (Hochauflösung): [Ml [M^+l] berechnet: 239,1310 240,1343 gefunden: 239,1308 240,1342Molar mass (high resolution): [Ml [M ^ + l] calculated: 239.1310 240.1343 found: 239.1308 240.1342

Beispiel 7:Example 7:

3-(l-Heptinyl)-2-hvdroxy-4-methylchinolin (Nr.: 1.1.4)3- (l-heptinyl) -2-hvdroxy-4-methylquinoline (No .: 1.1.4)

Figure imgf000037_0001
C H19NO Molmasse: 253,34
Figure imgf000037_0001
CH 19 NO molar mass: 253.34

Darstellung nach Methode B aus 2-Hydroxy-3-Iod-4-methylchinolin und 1-Heptin.Preparation according to method B from 2-hydroxy-3-iodo-4-methylquinoline and 1-heptin.

Ansatzgröße: 285,1 mg 2-Hydroxy-3-Iod-4-methylchinolin (lmmol) 962 mg 1-Heptin (10 mmol)Batch size: 285.1 mg 2-hydroxy-3-iodo-4-methylquinoline (lmmol) 962 mg 1-heptin (10 mmol)

35.1 mg Bis-(triphenylphosphü )-palladium-(lI)-chlorid (0,05 mmol)35.1 mg bis (triphenylphosphine) palladium (III) chloride (0.05 mmol)

70.2 mg Kupferiodid (0,37 mmol) Ausbeute: 112,3 mg (48,3 % d.Th.)70.2 mg copper iodide (0.37 mmol) yield: 112.3 mg (48.3% of theory)

Schmelzpunkt: 171 °C (Cyclohexan 2, Ethylacetat 3, weißes Pulver)Melting point: 171 ° C (cyclohexane 2, ethyl acetate 3, white powder)

Rf (Lösungsmittel) : 0,32 (Cyclohexan 2, Ethylacetat 3)Rf (solvent): 0.32 (cyclohexane 2, ethyl acetate 3)

IR (KBr) [cm-1]: 3141 (CH aromat), 2952, 2928, 2867 (CH aliphat.), 1678 (C=O), 2357 (CC Dreifachbindung), 1602, 1564, 1496 (C=C), 966, 886, 821IR (KBr) [cm -1 ]: 3141 (CH aromat), 2952, 2928, 2867 (CH aliphatic), 1678 (C = O), 2357 (CC triple bond), 1602, 1564, 1496 (C = C) , 966, 886, 821

1H-NMR (δ [ppm]): 0,93 (t, 3J = 7,1 Hz, 3H, 7'-CH3), 1,25-1,50 (m, 4H, 6'-, 5'-300 MHz (CDCl3) CH2), 1,63 (quint, 3J = 7,1 Hz, 2H, 4'-CH2), 2,42 (t, 3J = 7,1 Hz, 2H, 3'-CH2), 2,49 (s, 3H, 4-CH3), 6,57 (s, IH, H-5), 7,32 (d, 3J = 8,4 Hz, IH, H-6), 7,52 (d, 3J = 8,4 Hz,1H-NMR (δ [ppm]): 0.93 (t, 3 J = 7.1 Hz, 3H, 7'-CH 3 ), 1.25-1.50 (m, 4H, 6'-, 5 '-300 MHz (CDCl 3 ) CH 2 ), 1.63 (quint, 3 J = 7.1 Hz, 2H, 4'-CH 2 ), 2.42 (t, 3 J = 7.1 Hz, 2H , 3'-CH 2 ), 2.49 (s, 3H, 4-CH 3 ), 6.57 (s, IH, H-5), 7.32 (d, 3 J = 8.4 Hz, IH , H-6), 7.52 (d, 3 J = 8.4 Hz,

IH, H-7), 7,71 (s, IH, H-8) 12,25 (s, IH, 1-NH, austauschbar)IH, H-7), 7.71 (s, IH, H-8) 12.25 (s, IH, 1-NH, interchangeable)

13C-NMR (δ [ppm]): 14,0 (+) (7'-CH3), 19,0 (+) (4-CH3), 19,4 (-) (6'-CH2), 22,2 75,5 MHz (CDC13) (-) (5'-CH2), 28,5 (-) (4'-CH2), 31,2 (-) (3'-CH2), 79,9, 90,3, 118,3, 120,4, 137,4, 148,7, 164,9 (7 C quartär), 116,5 (+), 120,9 (+), 127,6 (+), 133,6 (+) (4 CH aromatisch) 13 C-NMR (δ [ppm]): 14.0 (+) (7'-CH 3), 19.0 (+) (4-CH 3), 19.4 (-) (6'-CH 2 ), 22.2 75.5 MHz (CDC1 3 ) (-) (5'-CH 2 ), 28.5 (-) (4'-CH 2 ), 31.2 (-) (3'-CH 2 ), 79.9, 90.3, 118.3, 120.4, 137.4, 148.7, 164.9 (7 C quaternary), 116.5 (+), 120.9 (+), 127 , 6 (+), 133.6 (+) (4 CH aromatic)

MS (70 eV), m/z (%): 254 (15) [MLAI], 253 (73) [M1"], 238 (17) [M"-CH3), 224 (53) [238-CH2], 210 (55), 196 (100), 180 (27), 167 (42), 154 (11), 139 (13), 127 (7), 115 (9)MS (70 eV), m / z (%): 254 (15) [MLAI], 253 (73) [M 1 " ], 238 (17) [M" -CH 3 ), 224 (53) [238-CH 2 ], 210 (55), 196 (100), 180 (27), 167 (42), 154 (11), 139 (13), 127 (7), 115 (9)

Molmasse (Hochauflösung): [ pv +i] berechnet: 253,1467 254,1500 gefunden: 253,1465 254,1500Molar mass (high resolution): [pv + i] calculated: 253.1467 254.1500 found: 253.1465 254.1500

Beispiel 8:Example 8:

2-Hydroxy-4-methyl-3-(l-pentinyl)-chinolin (Nr.: 1.1.6)2-hydroxy-4-methyl-3- (l-pentinyl) quinoline (No .: 1.1.6)

Figure imgf000039_0001
Figure imgf000039_0001

Cι5H15NO Molmasse: 225,29Cι 5 H 15 NO molar mass: 225.29

Darstellung nach Methode D aus 2-Hydroxy-3-Iod-4-methylchinolin und 1-Pentin.Preparation according to method D from 2-hydroxy-3-iodo-4-methylquinoline and 1-pentine.

Ansatzgröße: 285,1 mg 2-Hydroxy-3-Iod-4-methylchinolin (lmmol) 681 mg 1-Heptin (10 mmol)Batch size: 285.1 mg 2-hydroxy-3-iodo-4-methylquinoline (lmmol) 681 mg 1-heptin (10 mmol)

35.1 mg Bis-(triphenylphosphin)-palladium-(II)-chlorid (0,05 mmol)35.1 mg bis (triphenylphosphine) palladium (II) chloride (0.05 mmol)

70.2 mg Kupferiodid (0,37 mmol)70.2 mg copper iodide (0.37 mmol)

Ausbeute: 35,1 mg (15,6 % d.Th.)Yield: 35.1 mg (15.6% of theory)

Schmelzpunkt: 204,5 °C (Cyclohexan 2, Ethylacetat 3, weißes Pulver)Melting point: 204.5 ° C (cyclohexane 2, ethyl acetate 3, white powder)

Rf (Lösungsmittel) : 0,22 (Cyclohexan 2, Ethylacetat 3) IR(KBr) [cm-1]: 3142 (CH aromat.), 2957, 2929, 2868 (CH aliphat.), 1676 (C=O), 2360 (CC Dreifachbindung), 1600, 1564, 1496 (C=C), 966, 886, 821Rf (solvent): 0.22 (cyclohexane 2, ethyl acetate 3) IR (KBr) [cm -1]: 3142 (CH aromat.), 2957, 2929, 2868 (CH aliphatic.), 1676 (C = O), 2360 (CC triple bond), 1600, 1564, 1496 (C = C ), 966, 886, 821

1H-NMR (δ [ppm]): 1,06 (t, 3J = 7,2 Hz, 3H, 5'-CH3), 1,67 (sext, 3J = 7,2 Hz, 300 MHz (CDC13) 2H, 4'-CH2), 2,41 (t, 3J = 7,2 Hz, 2H, 3'-CH2), 2,49 (s, 3H, 4-CH3), 6,57, (s, IH, H-5), 7,29 (d, 3J = 8,5 Hz, IH, H-6), 7,52 (d, 3J = 8,5 Hz, IH, H-7), 7,72 (s, IH, H-8), 11,8 (s, IH, 1-NH, austauschbar) 13C-NMR (δ [ppm]): 13,6 (+) (5'-CH3), 19,0 (+) (4-CH3), 21,4 (-) (4'-CH2), 22,2 75,5 MHz (CDC13) (-) (3'-CH2), 80,0, 90,1, 118,3, 120,4, 137,3, 148,7, 163,8 (7 C quartär), 116,3 (+), 121,0 (+), 127,6 (+), 133,6 (+) (4 CH aromatisch)1H-NMR (δ [ppm]): 1.06 (t, 3 J = 7.2 Hz, 3H, 5'-CH 3 ), 1.67 (sext, 3 J = 7.2 Hz, 300 MHz ( CDC1 3 ) 2H, 4'-CH 2 ), 2.41 (t, 3 J = 7.2 Hz, 2H, 3'-CH 2 ), 2.49 (s, 3H, 4-CH3), 6, 57, (s, IH, H-5), 7.29 (d, 3 J = 8.5 Hz, IH, H-6), 7.52 (d, 3 J = 8.5 Hz, IH, H -7), 7.72 (s, IH, H-8), 11.8 (s, IH, 1-NH, exchangeable) 13 C-NMR (δ [ppm]): 13.6 (+) (5th '-CH 3 ), 19.0 (+) (4-CH 3 ), 21.4 (-) (4'-CH 2 ), 22.2 75.5 MHz (CDC1 3 ) (-) (3' -CH 2 ), 80.0, 90.1, 118.3, 120.4, 137.3, 148.7, 163.8 (7 C quaternary), 116.3 (+), 121.0 (+ ), 127.6 (+), 133.6 (+) (4 CH aromatic)

MS (70 eV), m/z (%): 226 (15) [M^+l], 225 (85) [M1"], 210 (17) [MT -CH3], 196 (100), 180 (5), 167 (23), 154 (4), 139 (8)MS (70 eV), m / z (%): 226 (15) [M ^ + l], 225 (85) [M 1 " ], 210 (17) [MT -CH 3 ], 196 (100), 180 (5), 167 (23), 154 (4), 139 (8)

Molmasse (Hochauflösung): [M [M l] berechnet: 225,1154 226,1187 gefunden: 225,1152 226,1186Molar mass (high resolution): [M [M l] calculated: 225.1154 226.1187 found: 225.1152 226.1186

Die pharmakologischen und die toxikologischen Wirkungen der Chinolin-Derivate wurden in verschiedenen Testmodellen geprüft.The pharmacological and toxicological effects of the quinoline derivatives were tested in different test models.

Testung auf Natrium- und KaliumkanalblockadeTesting for sodium and potassium channel blockade

Prinzip Zur Prüfung der natrium- und kaliumkanalblockierenden Eigenschaften der Verbindungen wurden lonenstrommessungen an intakten myelinisierten Nervenfasern von Xenopus laevis durchgeführt. Hier wurde das von Dodge und Frankenhäusereingeführte voltage-clamp-\ erfahren^ verwendet. Mit Hilfe des voltage-clamp-Verfahrens können Substanzen auf ihre natriumkanalblockierende Wirkung hin untersucht werden. Dieses Verfahren eignet sich somit nicht nur zur Bestimmung von Substanzen zur Behandlung der Epilepsie, sondern auch für die Bestimmung von Substanzen zur Behandlung von neurologischen Erkrankungen, der Migräne, von akuten und/oder chronischen Schmerzen, der Anfallsverhütung beim Alkoholentzug, der lokalen Behandlung zur Juckreizstillung und/oder Schmerzstillung, Behandlung der cystischen Fibröse, Behandlung nichtepileptischer Anfälle, z. B. bei Multipler Sklerose, Behandlung traumatischer neurologischer Schädigungen, Behandlung von Neuro Aids, schmerzhafter diabetischer Neuropathien sowie zur Behandlung von Parkinson und Parkinson-Syndromen.Principle To test the sodium and potassium channel blocking properties of the compounds, ion current measurements were carried out on intact myelinated nerve fibers from Xenopus laevis. Here was Dodge and Frankenhäuse introduced voltage clamp \ experienced ^ used. With the help of the voltage clamp method, substances can be examined for their sodium channel blocking effect. This method is therefore not only suitable for the determination of substances for the treatment of epilepsy, but also for the determination of substances for the treatment of neurological diseases, migraines, acute and / or chronic pain, seizure prevention during alcohol withdrawal, local treatment for itching relief and / or pain relief, treatment of cystic fibrosis, treatment of non-epileptic seizures, e.g. B. in multiple sclerosis, treatment of traumatic neurological damage, treatment of neuroids, painful diabetic neuropathies and for the treatment of Parkinson's and Parkinson's syndromes.

Versuchsdurchführung Testobjekt waren intakte myelinisierte Nervenfasern des Krallenfrosches Xenopus lαevis. Der jeweils untersuchte Ranviersche Schnürring wurde im Abteil A eines mehrfach gekammerten Plexiglasblocks ausgebreitet. Das Abteil A wurde kontinuierlich mit verschiedenen Badlösungen durchströmt. Das normale Badmedium des untersuchten Schnürrings war Ringerlösung.Test implementation The test object was intact myelinated nerve fibers of the clawed frog Xenopus lαevis. The Ranvier lacing ring examined in each case was spread out in compartment A of a multi-chambered plexiglass block. The compartment A was continuously flowed through with different bath solutions. The normal bath medium of the examined lacing ring was Ringer's solution.

Alle verwendeten Badlösungen wurden mit N,N-Bis-(2-hydroxyethyl)-2-aminoethan- sulfonsäure (BES) gepuffert und mit Natronlauge auf einen pH- Wert von 7,2 (± 0,1) eingestellt.All bath solutions used were buffered with N, N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid (BES) and adjusted to a pH of 7.2 (± 0.1) with sodium hydroxide solution.

Die Versuchstemperatur betrug einheitlich 10 (± 0,5) °C. Die untersuchten Testsubstanzen wurden in DMSO gelöst und anschließend mit Ringer-Lösung auf die gewünschte Konzentration verdünnt. Die DMSO-Konzentrationen waren in den Testlösungen mit 0,7 mol/1 immer konstant. Die Kaliumströme wurden mit Reizstärken von 130 mV (100 ms Dauer) und die Natriumströme mit Reizstärken von 70 mV (2 ms Dauer) untersucht. AuswertungThe test temperature was uniformly 10 (± 0.5) ° C. The test substances examined were dissolved in DMSO and then diluted to the desired concentration with Ringer's solution. The DMSO concentrations in the test solutions were always constant at 0.7 mol / 1. The potassium currents were examined with stimulus strengths of 130 mV (100 ms duration) and the sodium currents with stimulus strengths of 70 mV (2 ms duration). evaluation

Die prozentualen Blockaden B der Kaliumströme und Natriumströme durch die entsprechenden Testsubstanzen wurden aus der Differenz der Ströme in Ringerlösung und Testlösung ermittelt und auf die entsprechenden Stromwerte in Ringerlösung normiert.The percentage blockages B of the potassium currents and sodium currents by the corresponding test substances were determined from the difference between the currents in Ringer's solution and test solution and standardized to the corresponding current values in Ringer's solution.

ErgebnisseResults

Nachfolgend sind die durch die getesteten Verbindungen verursachten Blockaden BNE in Prozent vom Noπnalwert bei den angegebenen Testkonzentrationen in nmol/1 angegeben. Die Kaliumströme wurden nicht blockiert und sind deshalb nicht aufgeführt.Subsequently, the blocks B NE caused by the tested compounds are given in percent of Noπnalwert at the indicated test concentrations in nmol /. 1 The potassium currents were not blocked and are therefore not listed.

Tabelle 3Table 3

Figure imgf000042_0001
Figure imgf000042_0001

Die erfindungsgemäßen Chinolin-Derivate sowie physiologisch verträgliche Derivate und Analoga davon sind hochwirksam in voltage-clamp-Tests. Die am stärksten wirksamen der erfindungsgemäßen Chinolin-Derivate haben EC50- Werte <100 nmol/l und übertreffen damit in ihrer natriumkanalblockierenden Wirkung sowohlThe quinoline derivatives according to the invention as well as physiologically compatible derivatives and analogues thereof are highly effective in voltage clamp tests. The most effective of the quinoline derivatives according to the invention have EC 50 values <100 nmol / l and thus exceed both in their sodium channel blocking action

Carbamazepin als auch Phenytoin um den Faktor 1000 . . Insbesondere die Chinolin- Derivate Nr. 1.1.4 (3 -( 1 -Heptinyl)-2-hydiOxy-4-methylchinolin), 1.1.5 (3 -( 1 -Hexinyl)- 2-hydroxy-4-methylchinolin) und 1.1.6 (2-Hydroxy-4-methyl-3-(l-pentinyl)-chinolin) zeigen schon bei einer Konzentration von nur 100 nmol/l eine außergewöhnlich hohe Aktivität. Für die Chinolin-Derivate wird eine entsprechend starke antiepileptische Wirkung am Menschen oder anderen Säugern erwartet, die jene der bisher im Handel befindlichen Antiepileptika deutlich übertreffen wird.Carbamazepine and phenytoin by a factor of 1000. , In particular the quinoline Derivatives No. 1.1.4 (3 - (1-heptinyl) -2-hydiOxy-4-methylquinoline), 1.1.5 (3 - (1-hexynyl) - 2-hydroxy-4-methylquinoline) and 1.1.6 (2nd -Hydroxy-4-methyl-3- (l-pentinyl) -quinoline) show an extraordinarily high activity even at a concentration of only 100 nmol / l. A correspondingly strong anti-epileptic effect on humans or other mammals is expected for the quinoline derivatives, which will significantly exceed that of the anti-epileptics previously available.

Testung auf ToxikologieTesting for toxicology

Prinzipprinciple

Zur Erhebung erster toxikologischer Daten wurde der als Bioassay für Xenobiotika entwickelte Shrimpstest verwendet. Dieser Test wird heute von der OECD als ein Standardtest (Artoxkit M) für ökotoxikologische Untersuchungen empfohlen. Als Testorganismen dienen Nauplien des Salinenkrebses Artemia salina.The shrimp test developed as a bioassay for xenobiotics was used to collect the first toxicological data. This test is recommended by the OECD today as a standard test (Artoxkit M) for ecotoxicological studies. Nauplii of the saline cancer Artemia salina serve as test organisms.

VersuchsdurchführungExperimental Procedure

50 mg Krebseier (Zoohandlung Knudsen, Kiel) wurden in 80 ml frischem Meerwasser bei 23 °C unter Normallicht und unter Zuführung von Luft aus einer handelsüblichen Aquarienpumpe innerhalb von 48 Stunden ausgebrütet. Jeweils 10 Krebse wurden in ein Schnappdeckelglas gezählt und mit 3 ml Meerwasser sowie einem Tropfen Hefesuspension (3 mg Backhefe in 5 ml Meerwasser) als zusätzlicher Nahrungsquelle versetzt. Von den getesteten Substanzen wurden Stammlösungen in Methanol (LiChrosolv Merck 1.06018) hergestellt und entsprechend der gewünschten Testkonzentration verdünnt. Jeweils 60 μl der Testlösung wurden in die Schnappdeckelgläser eingefüllt. Der Leerwert wurde mit 60 μl Methanol anstelle der Testsubstanz ermittelt. Anschließend wurden die Proben im Wasserbad 24 Stunden bei 23 °C aufbewahrt.50 mg of crayfish eggs (Knudsen pet shop, Kiel) were incubated in 80 ml of fresh sea water at 23 ° C under normal light and with the addition of air from a commercially available aquarium pump within 48 hours. 10 crabs were counted in a snap-lid jar and 3 ml of sea water and a drop of yeast suspension (3 mg of baker's yeast in 5 ml of sea water) were added as an additional food source. Stock solutions of the substances tested were prepared in methanol (LiChrosolv Merck 1.06018) and diluted according to the desired test concentration. 60 μl portions of the test solution were poured into the snap-lid jars. The blank value was determined using 60 μl methanol instead of the test substance. The samples were then kept in a water bath at 23 ° C. for 24 hours.

Auswertung Die toten Krebse wurden ausgezählt und die Absterberaten A [%] der Krebse in unterschiedlichen Konzentrationen C der Testsubstanzen berechnet. Die Substanzen wurden in verschiedenen Konzentrationen getestet, wobei für jede Konzentration drei Proben angesetzt wurden.Evaluation The dead crayfish were counted and the mortality rates A [%] of the crayfish in different concentrations C of the test substances were calculated. The substances were tested in different concentrations, with three samples being prepared for each concentration.

ErgebnisResult

Tabelle 4Table 4

Figure imgf000044_0001
Figure imgf000044_0001

h diesem Test haben sich die Substanzen bis in die höchste Testkonzentration von 25 μmol/1 als nicht toxisch erwiesen. Damit weisen die neuen Chinolin-Derivate der vorliegenden Erfindung gegenüber den Verbindungen des Stands der Technik eine außergewöhnlich starke Wirkung bei einer gleichzeitig fehlenden Toxizität auf.In this test, the substances proved to be non-toxic up to the highest test concentration of 25 μmol / 1. Thus, the new quinoline derivatives of the present invention have an extraordinarily strong activity with a lack of toxicity compared to the compounds of the prior art.

Löscher (1994, 1998); Schmidt (1999)Löscher (1994, 1998); Schmidt (1999)

Ragsdale (1998)Ragsdale (1998)

Novartis Pharma, Fachinformation Tegretal® Novartis Pharma, technical information Tegretal ®

Donner (1965)Thunder (1965)

Schmidt (1999); Stefan (1999)Schmidt (1999); Stefan (1999)

Desitin, Fachinformation Phenhydan® Desitin, technical information Phenhydan ®

Turnbull (1983), Treimann (1998)Turnbull (1983), Treimann (1998)

Schmidt (1999)Schmidt (1999)

Pollock (1984)Pollock (1984)

Schmidt (1984)Schmidt (1984)

Novartis Pharma, Fachinformation Tegretal®; Okuma (1981); Placidi (1986)Novartis Pharma, specialist information Tegretal ® ; Okuma (1981); Placidi (1986)

Novartis Pharma, Fachinformation Tegretal® Novartis Pharma, technical information Tegretal ®

Novartis Pharma, Fachinformation Tegretal®; Hunter (1999); Tanelian (1991); HansenNovartis Pharma, specialist information Tegretal ® ; Hunter (1999); Tanelian (1991); Hansen

(1999); Produktmonographie Mydocalm®(2000); Rockliff (1966); Amols (1970); Kienast(1999); Product monograph Mydocalm ® (2000); Rockliff (1966); Amols (1970); Kienast

(1968); Graham (1966)(1968); Graham (1966)

Mathew (1997); Ghose (1998); Hansen (1999); Evans - WO 98/25594 (1998); RompelMathew (1997); Ghose (1998); Hansen (1999); Evans - WO 98/25594 (1998); Rompel

(1970)(1970)

Rodgers (1999)Rodgers (1999)

Sakurai (1999); Espir (1970); Kuroiwa (1968)Sakurai (1999); Espir (1970); Kuroiwa (1968)

Hondeghem (1977); Carmeliet (1998)Hondeghem (1977); Carmeliet (1998)

Urenjak (1996); Carter (1998); Taylor (1995); Rataud (1994)Urenjak (1996); Carter (1998); Taylor (1995); Rataud (1994)

Warner-Lambert Company, Patent: WO 94/18972Warner-Lambert Company, patent: WO 94/18972

Rhone Poulenc Rorer, Patent: EP 0674520 A1 , WO 94/13298Rhone Poulenc Rorer, patent: EP 0674520 A1, WO 94/13298

Rhone Poulenc Rorer, Patent: EP 0687179 A1, WO 94/20110 v Rhone Poulenc Rorer, Patent: EP 0678026 B1 wRhone Poulenc Rorer, patent: EP 0687179 A1, WO 94/20110 v Rhone Poulenc Rorer, patent: EP 0678026 B1 w

Wright (1994); Rull (1969)Wright (1994); Rull (1969)

X Pamnani (1988) Y Zlotkin (1999) z Grundon (1988); Reisch (1991); Wackernagel (1998)X Pamnani (1988) Y Zlotkin (1999) z Grundon (1988); Reisch (1991); Wackernagel (1998)

AA Dodge und Frankenhäuser (1958, 1959); Bohuslavizki (1994)AA Dodge and Frankenhäuser (1958, 1959); Bohuslavizki (1994)

BB Rogawski (1990) BB Rogawski (1990)

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Claims

PATENTANSPRÜCHE Chinolin-Derivat der allgemeinen FormelQuinoline derivative of the general formula
Figure imgf000052_0001
wobei
Figure imgf000052_0001
in which R1 ein geradkettiger oder verzweigter, acyclischer und/oder cyclischer Alkylrest mit 1 bis 15 C-Atomen ohne oder mit 1 bis drei Hydroxylgruppen; ein geradkettiger oder verzweigter, acyclischer und/oder cyclischer Alkenyl- oder Alkinyl- sowie Oxy- Alkinylrest (-O-CC-) mit 1 bis 15 C-Atomen, sowie 1 bis 3 ungesättigten C-C- Bindungen mit oder ohne Substituenten, wie z. B. Hydroxylgruppen (1 bis 3 Stück), Ethergruppen, substituierten oder unsubstituierten Arylresten, wie p-Tolyl- oder Phenylgruppen, substituierten Carbonyl- oder Oxycarbonylgruppen oder Silylgruppen; ein geradkettiger oder verzweigter, cyclischer und/oder acyclischer Alkoxyrest; ein Wasserstoffatom; oder eine Hydroxylgruppe ist;R 1 is a straight-chain or branched, acyclic and / or cyclic alkyl radical with 1 to 15 C atoms without or with 1 to three hydroxyl groups; a straight-chain or branched, acyclic and / or cyclic alkenyl or alkynyl and oxyalkynyl radical (-O-CC-) having 1 to 15 carbon atoms, and 1 to 3 unsaturated CC bonds with or without substituents, such as. B. hydroxyl groups (1 to 3 pieces), ether groups, substituted or unsubstituted aryl radicals, such as p-tolyl or phenyl groups, substituted carbonyl or oxycarbonyl groups or silyl groups; a straight-chain or branched, cyclic and / or acyclic alkoxy radical; a hydrogen atom; or is a hydroxyl group; R2 ein geradkettiger oder verzweigter, acyclischer und/oder cyclischer Alkinylrest mit 1 bis 15 C-Atomen, sowie 1 bis 3 ungesättigten C-C-Bindungen mit oder ohneR 2 is a straight-chain or branched, acyclic and / or cyclic alkynyl radical having 1 to 15 carbon atoms, and 1 to 3 unsaturated CC bonds with or without Substituenten, wie Hydroxylgruppen (1 bis 3 Stück), Ethergruppen, Alkoxyresten mit 1 bis 5 C-Atomen, substituierten oder unsubstituierten Arylresten, wie p-Tolyl- oder Phenylgruppen, substituierten Carbonyl- oder Oxycarbonylgruppen, Silylgruppen, substituierten oder unsubstituierten Cyclohexylgruppen ist; R3 ein Wasserstoffatom, eine Hydroxylgruppe, ein geradkettiger oder verzweigter Alkoxyrest mit 1 bis 5 C-Atomen, ein geradkettiger oder verzweigter Alkylrest mit 1 bis 5 C-Atomen ohne oder mit 1 bis 3 Hydroxylgruppen oder eine substituierte Carbonylgruppe ist;Is substituents, such as hydroxyl groups (1 to 3 pieces), ether groups, alkoxy radicals having 1 to 5 carbon atoms, substituted or unsubstituted aryl radicals, such as p-tolyl or phenyl groups, substituted carbonyl or oxycarbonyl groups, silyl groups, substituted or unsubstituted cyclohexyl groups; R 3 is a hydrogen atom, a hydroxyl group, a straight-chain or branched alkoxy radical with 1 to 5 C atoms, a straight-chain or branched alkyl radical with 1 to 5 C atoms without or with 1 to 3 hydroxyl groups or a substituted carbonyl group; R4, R5, R6 und R7 jeweils gleich oder verschieden und von einander unabhänging ein Wasserstoffatom; ein geradkettiger oder verzweigter, cyclischer und/oder acyclischer Alkylrest mit 1 bis 4 C-Atomen, wie ein Cyclohexyl-, Alkylcyclohexylrest mit 1 bis 4 C-Atomen im Alkylteil, ein Cycloheptyl- oder Cyclooctylrest; ein substituierter oder unsubstituierter Arylrest, wie ein Phenylrest, der durch Halogen, wie Fluor, Chlor oderR 4 , R 5 , R 6 and R 7 are each the same or different and independently of one another a hydrogen atom; a straight-chain or branched, cyclic and / or acyclic alkyl radical with 1 to 4 carbon atoms, such as a cyclohexyl, alkylcyclohexyl radical with 1 to 4 carbon atoms in the alkyl part, a cycloheptyl or cyclooctyl radical; a substituted or unsubstituted aryl radical, such as a phenyl radical, which is substituted by halogen, such as fluorine, chlorine or Brom, einen geradkettigen oder verzweigten Alkylrest mit 1 bis 4 C-Atomen sowie einen geradkettigen oder verzweigten Alkoxyrest mit 1 bis 3 C-Atomen mono- oder disubstituiert sein kann; ein geradkettiger oder verzweigter, cyclischer und/oder acyclischer Alkoxyrest mit 1 bis 3 C-Atomen; ein substituierter oder unsubstituierter Arylrest, wie ein Phenylalkylrest mit 1 bis 4 C-Atomen im Alkylteil, wobei derBromine, a straight-chain or branched alkyl radical having 1 to 4 carbon atoms and a straight-chain or branched alkoxy radical having 1 to 3 carbon atoms can be mono- or disubstituted; a straight-chain or branched, cyclic and / or acyclic alkoxy radical having 1 to 3 carbon atoms; a substituted or unsubstituted aryl radical, such as a phenylalkyl radical having 1 to 4 carbon atoms in the alkyl part, the Arylkern wie vorstehend beim Phenylrest angegeben substituiert sein kami; ein Halogenatom, wie Fluor, Chlor oder Brom; ein Mono- und/oder Dihydroxyalkylrest mit 1 bis 4 C-Atomen; eine primäre, sekundäre oder tertiäre Aminogruppe; eine Nitrogruppe; oder eine Sulfonylgruppe sind; sowie ein physiologisch verträgliches Derivat oder Analogon davon.Aryl nucleus may be substituted as indicated above for the phenyl radical kami; a halogen atom such as fluorine, chlorine or bromine; a mono- and / or dihydroxyalkyl radical with 1 to 4 carbon atoms; a primary, secondary or tertiary amino group; a nitro group; or are a sulfonyl group; and a physiologically acceptable derivative or analog thereof. 2. Chinolin-Derivat gemäß Anspruch 1, wobei2. Quinoline derivative according to claim 1, wherein R ein Wasserstoffatom, eine Hydroxylgruppe, die Gruppe -OR , ein Alkyl-, wie ein Methyl- oder ein Alkoxy-, wie ein Methoxyrest ist;R is a hydrogen atom, a hydroxyl group, the group -OR, an alkyl, such as a methyl or an alkoxy, such as a methoxy radical; R die in Anspruch 1 angegebene Bedeutung hat;R has the meaning given in claim 1; R ein Wasserstoffatom, eine Hydroxylgruppe, ein Alkyl-, wie ein Methyl- oder ein Alkoxy-, wie ein Methoxyrest ist und R4, R5, R6 xmd R7 jeweils gleich oder verschieden und voneinander unabhängig ein Wasserstoffatom, ein Halogen-, wie ein Chloratom, ein Alkylrest oder ein Alkoxy-, wie ein Methoxy- oder ein Ethoxyrest sind.R is a hydrogen atom, a hydroxyl group, an alkyl, such as a methyl or an alkoxy, such as a methoxy radical and R 4 , R 5 , R 6 xmd R 7 are each the same or different and independently of one another a hydrogen atom, a halogen, such as a chlorine atom, an alkyl radical or an alkoxy, such as a methoxy or an ethoxy radical. Chinolin-Derivat gemäß Anspruch 2, wobei R eine Hydroxylgruppe oder die Gruppe -OR2 ist, R2 die in Anspruch 1 angegebene Bedeutung hat, R3 ein Methylrest ist und R4, R5, R6 und R7 alle Wasserstoffatome sind.Quinoline derivative according to claim 2, wherein R is a hydroxyl group or the group -OR 2 , R 2 has the meaning given in claim 1, R 3 is a methyl radical and R 4 , R 5 , R 6 and R 7 are all hydrogen atoms. 4. Chinolin-Derivat gemäß einem der vorstehenden Ansprüche, ausgewählt aus der Gruppe bestehend aus4. quinoline derivative according to any one of the preceding claims, selected from the group consisting of 3 -( 1 -Decinyl)-2-hydroxy-4-methylchinolin,3 - (1-decynyl) -2-hydroxy-4-methylquinoline, 2-Hydroxy-4-methyl-3-(l-noninyl)-chinolin,2-hydroxy-4-methyl-3- (l-nonynyl) quinoline, 2-Hydroxy-4-methyl-3 -(1 -octinyl)-chinolin, 3 -( 1 -Heptinyl)-2-hydroxy-4-methylchinolin,2-hydroxy-4-methyl-3 - (1-octynyl) quinoline, 3 - (1-heptinyl) -2-hydroxy-4-methylquinoline, 3-(l-Hexinyl)-2-hydroxy-4-methylchinolin,3- (l-hexynyl) -2-hydroxy-4-methylquinoline 2-Hydroxy-4-methyl-3 -( 1 -pentinyl)-chinolin,2-hydroxy-4-methyl-3 - (1-pentinyl) quinoline, 3-( 1 -Butinyl)-2-hydiOxy-4-methylchinolin,3- (1-butynyl) -2-hydiOxy-4-methylquinoline, 2-Hydroxy-3-(3-hydroxy- 1 -propinyl)-4-methylchinolin, 2-Hydroxy-3-(3-methoxy- 1 -propinyl)-4-methylchinolin,2-hydroxy-3- (3-hydroxy-1-propynyl) -4-methylquinoline, 2-hydroxy-3- (3-methoxy-1-propynyl) -4-methylquinoline, 2-Hydroxy-3-(4-methoxy- 1 -butinyl)-4-methylchinolin,2-hydroxy-3- (4-methoxy-1-butynyl) -4-methylquinoline, 3 -(3 -Ethoxy- 1 -proρinyl)-2-hydroxy-4-methylchinolin,3 - (3-ethoxy-1-propynyl) -2-hydroxy-4-methylquinoline, 2-Hydroxy-4-methyl-3-(3-propoxy- 1 -propinyl)-chinolin,2-hydroxy-4-methyl-3- (3-propoxy-1-propynyl) quinoline, 3 -(3 -Butoxy- 1 -propinyl)-2-hydroxy-4-methylchinolin, 2-Hydroxy-4-methyl-3-(3-pentoxy-l-propinyl)-chinolin,3 - (3-butoxy-1-propynyl) -2-hydroxy-4-methylquinoline, 2-hydroxy-4-methyl-3- (3-pentoxy-1-propynyl) quinoline, 2-Hydroxy-4-methyl-3-(5-hydroxy-l-pentinyl)-chinolin,2-hydroxy-4-methyl-3- (5-hydroxy-l-pentynyl) quinoline, 2-Hydroxy-3-(5-methoxy- 1 -pentinyl)-4-methylchinolin,2-hydroxy-3- (5-methoxy-1-pentynyl) -4-methylquinoline, 3-(5-Ethoxy- 1 -pentinyl)-2-hydroxy-4-methylchinolin,3- (5-ethoxy-1-pentynyl) -2-hydroxy-4-methylquinoline, 2-Hydroxy-4-methyl-3 -(5 -propoxy- 1 -pentinyl)-chinolin, 2-Hydroxy-3-(3-hydroxy- 1 -octinyl)-4-methylchinolin, 2-Hydroxy-3-(3-methoxy-l-octinyl)-4-methyl-chinolin, 3 -(3 -Ethoxy- 1 -octinyl)-2-hydroxy-4-methylchinolin, 3-(Ethoxyethinyl)-2-hydroxy-4-methylchinolin, 2-HydiOxy-4-methyl-3-(methyloxycarbonyl-ethinyl)-chinolin, 5 3 -(Ethyloxycarbonyl-ethinyl)-2-hydroxy-4-methylchinolin,2-hydroxy-4-methyl-3 - (5-propoxy-1-pentynyl) quinoline, 2-hydroxy-3- (3-hydroxy-1-octynyl) -4-methylquinoline, 2-hydroxy-3- (3-methoxy-l-octynyl) -4-methyl-quinoline, 3 - (3-ethoxy-1-octynyl) -2-hydroxy-4-methylquinoline, 3- (ethoxyethynyl) -2- hydroxy-4-methylquinoline, 2-hydoxy-4-methyl-3- (methyloxycarbonylethynyl) quinoline, 5 3 - (ethyloxycarbonylethynyl) -2-hydroxy-4-methylquinoline, 2-Hydroxy-3-(3-hydroxy-3-methyl-l-butinyl)-4-methylchinolin, 2-Hydroxy-3-(3-hydroxy-3-methyl-l-pentinyl)-4-methylchinolin, 2-Hydroxy-4-methyl-3-(trimethylsilylethinyl)-chinolin, 2-Hydroxy-4-methyl-3-(phenylethinyl)-chinolin, l o 2-Hydroxy-4-methyl-3-(p-tolylethinyl)chinolin,2-hydroxy-3- (3-hydroxy-3-methyl-l-butynyl) -4-methylquinoline, 2-hydroxy-3- (3-hydroxy-3-methyl-l-pentynyl) -4-methylquinoline, 2- Hydroxy-4-methyl-3- (trimethylsilylethynyl) quinoline, 2-hydroxy-4-methyl-3- (phenylethynyl) quinoline, lo 2-hydroxy-4-methyl-3- (p-tolylethynyl) quinoline, 2-Hydroxy-3-(3-hydroxy-3-cyclohexyl-l-propinyl)-4-methylchinolin, 3 -( 1 -Decinyl)-2-( 1 -decinyloxy)-4-methylchinolin, 4-Methyl-3-( 1 -noninyl)-2-( 1 -noninyloxy)-chinolin, 4-Methyl-3 -( 1 -octinyl)-2-( 1 -octinyloxy)-chinolin,2-hydroxy-3- (3-hydroxy-3-cyclohexyl-l-propynyl) -4-methylquinoline, 3 - (1-decynyl) -2- (1-decynyloxy) -4-methylquinoline, 4-methyl-3- (1 -noninyl) -2- (1 -noninyloxy) -quinoline, 4-methyl-3 - (1 -octinyl) -2- (1 -octinyloxy) -quinoline, 15 3 -( 1 -HeptinyI)-2-( 1 -heptinyloxy)-4-methylchinolin,15 3 - (1-heptinyI) -2- (1-heptinyloxy) -4-methylquinoline, 3 -( 1 -Hexinyl)-2-( 1 -hexinyloxy)-4-methylchinolin, 4-Methyl-3 -( 1 -pentinyl)-2-( 1 -pentinyloxy)-chinolin, 3 -( 1 -Butinyl)-2-( 1 -butinyloxy)-4-methylchinolin, 3 -(3-Hydroxy- 1 -propinyl)- 2-(3 -hydroxy- 1 -propinyloxy)-4-metlιyl-chinolin,3 - (1-hexynyl) -2- (1-hexynyloxy) -4-methylquinoline, 4-methyl-3 - (1-pentynyl) -2- (1-pentynyloxy) quinoline, 3 - (1-butynyl) - 2- (1-butynyloxy) -4-methylquinoline, 3 - (3-hydroxy-1-propynyl) - 2- (3-hydroxy-1-propynyloxy) -4-methyl-quinoline, 20 3 -(3 -Methoxy- 1 -propinyl)-2-(3 -methoxy- 1 -propinyloxy)-4-methylchinolin,20 3 - (3-methoxy-1-propynyl) -2- (3-methoxy-1-propynyloxy) -4-methylquinoline, 3 -(4-Methoxy- 1 -butinyl)- 2-(4-methoxy- 1 -butinyloxy)-4-methylchinolin, 3 -(3 -Ethoxy- 1 -propinyl)-2-(3 -ethoxy- 1 -propinyloxy)-4-methylchinolin, 3 -(3 -Propoxy- 1 -propinyl)-2-(3-propoxy- 1 -propinyloxy)-4-methylchinolin, 3-(5-Hydroxy- 1 -pentinyl)-2-(5-hydroxy- 1 -pentinyloxy)-4-methylchinolin,3 - (4-methoxy-1-butynyl) - 2- (4-methoxy-1-butynyloxy) -4-methylquinoline, 3 - (3-ethoxy-1-propynyl) -2- (3-ethoxy-1-propynyloxy) ) -4-methylquinoline, 3 - (3-propoxy-1-propynyl) -2- (3-propoxy-1-propynyloxy) -4-methylquinoline, 3- (5-hydroxy-1-pentynyl) -2- (5th -hydroxy-1-pentinyloxy) -4-methylquinoline, 25 3-(5-Methoxy-l-pentinyl)-2-(5-methoxy-l-pentinyloxy)-4-methylchinolin,25 3- (5-methoxy-l-pentynyl) -2- (5-methoxy-l-pentynyloxy) -4-methylquinoline, 3-(5-Ethoxy-l-pentinyl)-2-(5-ethoxy-l-pentinyloxy)-4-methylchinolin, 3-(TEthoxyethinyl)-2-(ethoxyethinyloxy)-4-memylchinolitι, 4-Methyl-3-(methyloxycarbonyl-ethinyl)-2-(methyloxycarbonyl-ethinyloxy)~ chinol n, 3-(Ethyloxycarbonyl-etiιinyl)-2-(ethinyloxycarbonyl-ethinyloxy)-4- methylchinolin,3- (5-ethoxy-l-pentinyl) -2- (5-ethoxy-l-pentinyloxy) -4-methylquinoline, 3- (TEthoxyethinyl) -2- (ethoxyethinyloxy) -4-memylquinolite, 4-methyl-3- (methyloxycarbonyl-ethynyl) -2- (methyloxycarbonyl-ethynyloxy) ~ quinol n, 3- (ethyloxycarbonyl-ethinyl) -2- (ethynyloxycarbonyl-ethynyloxy) -4-methylquinoline, 3 -(3 -Hydroxy-3 -methyl- 1 -butinyl)-2-(3 -hydroxy-3 -methyl- 1 -butinyloxy)-4- methylchinolin,3 - (3-hydroxy-3-methyl-1-butynyl) -2- (3-hydroxy-3-methyl-1-butynyloxy) -4-methylquinoline, 3 -( 1 -Decinyl)-chinolin,3 - (1-decynyl) quinoline, 3 -( 1 -Noninyl)-chinolin,3 - (1 -noninyl) quinoline, 3-( 1 -Octinyl)-chinolin,3- (1-octynyl) quinoline, 3-( 1 -Heptinyl)-chinolin,3- (1-heptinyl) quinoline, 3 -( 1 -Hexinyl)-chinolin,3 - (1-hexynyl) quinoline, 3 -( 1 -Pentinyl)-chinolin,3 - (1-pentinyl) quinoline, 3 -( 1 -Butinyl)-chinolin,3 - (1-butynyl) quinoline, 3-(3-Hydroxy-l-propinyl)-chinolin,3- (3-hydroxy-l-propynyl) quinoline, 3 -(3 -Methoxy- 1 -propinyl)-chinolin,3 - (3-methoxy-1-propynyl) quinoline, 3-(4-Methoxy- 1 -butinyl)-chinolin,3- (4-methoxy-1-butynyl) quinoline, 3 -(3 -Ethoxy- 1 -propinyl)-chinolin,3 - (3-ethoxy-1-propynyl) quinoline, 3 -(3 -Butoxy- 1 -propinyl)-chinolin,3 - (3-butoxy-1-propynyl) quinoline, 3 -(3 -Pentoxy- 1 -propinyl)-chinolin,3 - (3 -pentoxy-1-propynyl) quinoline, 3-(5-Hydroxy-l-pentinyl)-chfnolin,3- (5-hydroxy-l-pentynyl) -chfnolin, 3-(5-Methoxy- 1 -pentinyl)-chinolin,3- (5-methoxy-1-pentynyl) quinoline, 3-(5-Ethoxy- 1 -pentinyl)-chinolin,3- (5-ethoxy-1-pentynyl) quinoline, 3-(5-Propoxy- 1 -pentinyl)-chinolin,3- (5-propoxy-1-pentynyl) quinoline, 3-(3-Hydroxy-l-octinyl)-chinolin,3- (3-hydroxy-l-octynyl) quinoline, 3 -(3 -Methoxy- 1 -octinyl)-chinolin,3 - (3-methoxy-1-octynyl) quinoline, 3 -(3 -Ethoxy- 1 -octinyl)-chinolin,3 - (3-ethoxy-1-octynyl) quinoline, 3 -(Ethoxyethinyl)-chinolin,3 - (ethoxyethynyl) quinoline, 3-(Methyloxycarbonyl-ethinyl)-chinolin,3- (methyloxycarbonyl-ethynyl) quinoline, 3-(Ethyloxycarbonyl-ethinyl)-chinolin, 3-(l-Heptinyl)-2-methylchinolin, 3-( 1 -Hexinyl)-2-methylchinolin, 2-Methyl-3-(l-pentinyl)-chinolin, -(4-Methoxy- 1 -butinyl)-2-methylchinolin, -(3 -Ethoxy- 1 -propinyl)-2-methylchinolin, -Methyl-3-(3-propoxy- 1 -propinyl)-chinolin, -(3-Butoxy- 1 -propinyl)-2-methylchinolin, -(5-Methoxy- 1 -pentinyl)-2-methylchinolin, -(5 -Ethoxy- 1 -pentinyl)-2-methylchinolin, -(Εthoxyethinyl)-2-metl ylchinolin, ,4-Dimethoxy-3-(l-heptinyl)-chinolin, ,4-Dimethoxy-3 -(1 -hexinyl)-chinolin, ,4-Dimethoxy-3-(l-pentinyl)-chinolin, ,4-Dimethoxy-3-(4-methoxy- 1 -butinyl)-chinolin, ,4-Dimethoxy-3-(3-ethoxy-l-propinyl)-chinolin, ,4-Dimethoxy-3 -(3 -propoxy- 1 -propinyl)-chinolin, -(3 -Butoxy- 1 -propinyl)-2,4-dimethoxychinolin, ,4-Dimethoxy-3-(5-methoxy- 1 -pentinyl)-chinolin, ,4-Dimethoxy-3-(5-ethoxy-l-pentinyl)-chinolin, ,4-Dimethoxy-3-(ethoxyethinyl)-chinolin, -Chlor-3-(l-heptinyl)-2,4,7-trimethoxychinolin, -Chlor-3-(l-hexinyl)-2,4,7-trimethoxychinolin, -ChIor-3-(l -pentinyl)-2,4,7-trimethoxychinolin, -Chlor-3-(4-methoxy- 1 -butinyl)-2,4,7-trimethoxychinolin, -Chlor-3-(3-ethoxy-l-propinyl)-2,4,7-trimethoxychinolin, -C or-3-(3-propoxy-l-propmyl)-2,4,7-trimethoxychinolin, -Chlor-3 -(3 -butoxy- 1 -propinyl)-2,4,7-trimethoxychinolin, -Chlor-3-(5-methoxy- 1 -pentinyl)-2,4,7-trimethoxychinolin, -Chlor-3-(5-ethoxy-l-pentmyl)-2,4,7-trimethoxychinolin, -Chlor-3-(ethoxyethiιιyl)-2,4,7-trimethoxychinolin, -( 1 -Heptinyl)-2,4, 7-trimethoxychinolin, -(l-Hexinyl)-2,4,7-trimethoxychinolin, -(l-Pentinyl)-2,4,7-trimethoxychinolin, 3-(4-Methoxy-l-butinyl)-2,4,7-trimethoxychinolin, 3-(3-Ethoxy-l-propinyl)-2,4,7-trimethoxychinolin, 3-(3-Propoxy-l-propinyl)-2,4,7-trimethoxychinolin, 3-(3-Butoxy- 1 -propinyl)-2,4,7-trimethoxychinolin, 5 3-(5-Methoxy-l-pentinyl)-2,4,7-trimethoxychinolin,3- (ethyloxycarbonylethynyl) quinoline, 3- (l-heptinyl) -2-methylquinoline, 3- (1-hexynyl) -2-methylquinoline, 2-methyl-3- (l-pentynyl) quinoline, - (4-methoxy-1-butynyl) -2-methylquinoline, - (3-ethoxy-1-propynyl) -2-methylquinoline, -Methyl-3- (3-propoxy-1-propynyl) quinoline, - (3rd -Butoxy-1-propynyl) -2-methylquinoline, - (5-methoxy-1-pentynyl) -2-methylquinoline, - (5-ethoxy-1-pentynyl) -2-methylquinoline, - (Εthoxyethynyl) -2-metl ylquinoline,, 4-dimethoxy-3- (l-heptinyl) -quinoline,, 4-dimethoxy-3 - (1-hexynyl) -quinoline,, 4-dimethoxy-3- (l-pentinyl) -quinoline,, 4- Dimethoxy-3- (4-methoxy-1-butynyl) quinoline,, 4-dimethoxy-3- (3-ethoxy-1-propynyl) quinoline,, 4-dimethoxy-3 - (3-propoxy-1-propynyl) ) -quinoline, - (3-butoxy-1-propynyl) -2,4-dimethoxyquinoline,, 4-dimethoxy-3- (5-methoxy-1-pentynyl) -quinoline,, 4-dimethoxy-3- (5- ethoxy-l-pentinyl) -quinoline,, 4-dimethoxy-3- (ethoxyethinyl) -quinoline, -chloro-3- (l-heptinyl) -2,4,7-trimethoxy-quinoline, -chloro-3- (l-hexynyl ) -2,4,7-trimethoxyquinoline, -ChIor-3- (l -pentinyl) -2,4,7-trimethoxyquinoline, -Chlor-3- (4-methoxy-1-butinyl) -2,4,7- trimethoxyquinoline, chloro-3- (3-ethoxy-l-propynyl) -2,4,7-trimethoxy quinoline, -C or-3- (3-propoxy-l-propmyl) -2,4,7-trimethoxyquinoline, -Chlor-3 - (3-butoxy-1-propynyl) -2,4,7-trimethoxyquinoline, - Chlorine-3- (5-methoxy-1-pentynyl) -2,4,7-trimethoxyquinoline, chlorine-3- (5-ethoxy-l-pentmyl) -2,4,7-trimethoxyquinoline, chlorine-3- (ethoxyethiιιyl) -2,4,7-trimethoxyquinoline, - (1-heptinyl) -2,4, 7-trimethoxyquinoline, - (l-hexynyl) -2,4,7-trimethoxyquinoline, - (l-pentynyl) -2 , 4,7-trimethoxy, 3- (4-methoxy-l-butynyl) -2,4,7-trimethoxyquinoline, 3- (3-ethoxy-l-propynyl) -2,4,7-trimethoxyquinoline, 3- (3-propoxy-l-propynyl) ) -2,4,7-trimethoxyquinoline, 3- (3-butoxy-1-propynyl) -2,4,7-trimethoxyquinoline, 5 3- (5-methoxy-l-pentynyl) -2,4,7-trimethoxyquinoline . 3-(5-Ethoxy- 1 -pentinyl)-2,4,7-trimethoxychinolin, 3-(Ethoxyethinyl)-2,4,7-trimethoxychinolin, 7-Ethoxy-2,4-dimethoxy-3-(l-heptinyl)-chinolin, 7-Ethoxy-2,4-dimethoxy-3 -(1 -hexinyl)-chinolin, l o 7-Ethoxy-2,4-dimethoxy-3 -(1 -pentinyl)-chinolin,3- (5-ethoxy-1-pentynyl) -2,4,7-trimethoxyquinoline, 3- (ethoxyethynyl) -2,4,7-trimethoxyquinoline, 7-ethoxy-2,4-dimethoxy-3- (l-heptinyl ) -quinoline, 7-ethoxy-2,4-dimethoxy-3 - (1-hexynyl) -quinoline, lo 7-ethoxy-2,4-dimethoxy-3 - (1-pentynyl) -quinoline, 3-(l-Heptinyl)-2,4,6-trimethoxychinolin, 3-(l-Hexinyl)-2,4,6-trimethoxychinolin, 3-(l-Pentinyl)-2,4,6-trimethoxychinolin, 6-Ethoxy-2,4-dimethoxy-3 -(1 -heptinyl)-chinolin,3- (l-heptinyl) -2,4,6-trimethoxyquinoline, 3- (l-hexynyl) -2,4,6-trimethoxyquinoline, 3- (l-pentynyl) -2,4,6-trimethoxyquinoline, 6- Ethoxy-2,4-dimethoxy-3 - (1-heptinyl) quinoline, 15 6-Ethoxy-2,4-dimethoxy-3 -(1 -hexinyl)-chinolin,15 6-ethoxy-2,4-dimethoxy-3 - (1-hexynyl) -quinoline, 6-Ethoxy-2,4-dimethoxy-3-(l-pentinyl)-chinolin, 3-(l-Heptinyl)-2,4,6,8-tetramethoxychinolin, 3-(l-Hexinyl)-2,4,6,8-tetramethoxychinolin, 3-(l-Pentinyl)-2,4,6,8-tetramethoxychinolin,6-ethoxy-2,4-dimethoxy-3- (l-pentinyl) quinoline, 3- (l-heptinyl) -2,4,6,8-tetramethoxyquinoline, 3- (l-hexynyl) -2,4, 6,8-tetramethoxyquinoline, 3- (l-pentynyl) -2,4,6,8-tetramethoxyquinoline, 20 7-Chlor-3-(l -heptinyl)-4-methoxychinolin,20 7-chloro-3- (l-heptinyl) -4-methoxyquinoline, 7-Chlor-3 -(1 -hexinyl)-4-methoxychinolin, 7-Chlor-4-methoxy-3-(l-pentinyl)-chinolin, 2,4-Dimethyl-3-(l-heptinyl)-chinolin, 2,4-Dimethyl-3 -( 1 -hexinyl)-chinolin,7-chloro-3 - (1-hexynyl) -4-methoxyquinoline, 7-chloro-4-methoxy-3- (l-pentynyl) quinoline, 2,4-dimethyl-3- (l-heptynyl) quinoline, 2,4-dimethyl-3 - (1-hexynyl) quinoline, 25 2,4-Dimethyl-3 -( 1 -pentinyl)-chinolin,25 2,4-dimethyl-3 - (1-pentynyl) quinoline, 3 -( 1 -Heptinyl)-4-hydroxy-2-methylchinolin, 3 -( 1 -Hexmyl)-4-hydroxy-2-methylchinolin, 4-Hydroxy-2-methyl-3 -( 1 -pentinyl)-chinolin, 7-Chlor-3 -( 1 -heptinyl)-4-methylchinolin,3 - (1-heptinyl) -4-hydroxy-2-methylquinoline, 3 - (1-hexyl) -4-hydroxy-2-methylquinoline, 4-hydroxy-2-methyl-3 - (1-pentinyl) quinoline, 7-chloro-3 - (1-heptinyl) -4-methylquinoline, 30 7-Chlor-3 -(1 -hexinyl)-4-methylchinolin, 7-Chlor-4-methyl-3-(l-pentinyl)-chinolin,30 7-chloro-3 - (1-hexynyl) -4-methylquinoline, 7-chloro-4-methyl-3- (l-pentynyl) quinoline, 2-Hydroxy-3 -(1 -heptinyl)-4-methoxychinolin,2-hydroxy-3 - (1-heptinyl) -4-methoxyquinoline, 2-Hydroxy-3 -(1 -hexinyl)-4-methoxychinolin,2-hydroxy-3 - (1-hexynyl) -4-methoxyquinoline, 2-Hydroxy-4-methoxy-3 -(1 -pentinyl)-chinolin, oder physiologisch verträglichen Derivaten oder Analoga davon.2-Hydroxy-4-methoxy-3 - (1-pentynyl) quinoline, or physiologically acceptable derivatives or analogues thereof. Chinolin-Derivat gemäß Anspruch 4, ausgewählt aus der Gruppe bestehend aus 3 -( 1 -Heptinyl)-2-hydroxy-4-methylchinolin, 3 -( 1 -Hexinyl)-2-hydroxy-4- methylchinolin and 2-Hydroxy-4-methyl-3-(l-pentinyl)-chinolin oder physiologisch verträglichen Derivaten oder Analoga davon.Quinoline derivative according to claim 4, selected from the group consisting of 3 - (1-heptinyl) -2-hydroxy-4-methylquinoline, 3 - (1-hexynyl) -2-hydroxy-4-methylquinoline and 2-hydroxy-4 -methyl-3- (l-pentinyl) quinoline or physiologically acceptable derivatives or analogues thereof. Chinolin-Derivat der allgemeinen FormelQuinoline derivative of the general formula
Figure imgf000059_0001
Figure imgf000059_0001
 zur Prophylaxe und Therapie von Natriumkanal-abhängigen Erkrankungen, wobeifor the prophylaxis and therapy of sodium channel-dependent diseases, whereby R1 ein geradkettiger oder verzweigter, cyclischer und/oder acyclischer Alkylrest mit 1 bis 15 C-Atomen ohne oder mit 1 bis drei Hydroxylgruppen; ein geradkettiger oder verzweigter, cyclischer und/oder acyclischer Alkenyl- oder Alkinyl- sowie Oxy- Alkinylrest (-O-CC-) mit 1 bis 15 C-Atomen, sowie 1 bis 3 ungesättigten C-C- Bindungen mit oder ohne Substituenten, wie z. B. Hydroxylgruppen (1 bis 3 Stück), Ethergruppen, substituierten oder unsubstituierten Arylresten, wie p-Tolyl- oder Phenylgruppen, substituierten Carbonyl- oder Oxycarbonylgruppen oder Silylgruppen; ein geradkettiger oder verzweigter, cyclischer und/oder acyclischer Alkoxyrest; ein Wasserstoffatom; oder eine Hydroxylgruppe ist; R2 ein geradkettiger oder verzweigter, cyclischer und/oder acyclischer Alkylrest mit 1 bis 15 C-Atomen, mit oder ohne Substituenten wie z. B. Hydroxylgruppen (1 bis 3 Stück). Alkoxygruppen mit 1 bis 5 C-Atomen; ein geradkettiger oder verzweigter, cyclischei und/oder acyclischer Alkenyl- oder Alkinylrest mit 1 bis 15 C-Atomen, sowie 1 bis 3 ungesättigten C-C-Bindungen mit oder ohne Substituenten, wie Hydroxylgruppen (1 bis 3 Stück), Ethergruppen, Alkoxygruppen mit 1 bis 5 C-Atomen, substituierten odei unsubstituierten Arylresten, wie p-Tolyl- oder Phenylgruppen, substituierten Carbonyl- oder Oxycarbonylgruppen, Silylgruppen, substituierten oder unsubstituierter Cyclohexylgruppen ist;R 1 is a straight-chain or branched, cyclic and / or acyclic alkyl radical with 1 to 15 C atoms without or with 1 to three hydroxyl groups; a straight-chain or branched, cyclic and / or acyclic alkenyl or alkynyl and oxyalkynyl radical (-O-CC-) having 1 to 15 carbon atoms, and 1 to 3 unsaturated CC bonds with or without substituents, such as. B. hydroxyl groups (1 to 3 pieces), ether groups, substituted or unsubstituted aryl radicals, such as p-tolyl or phenyl groups, substituted carbonyl or oxycarbonyl groups or silyl groups; a straight-chain or branched, cyclic and / or acyclic alkoxy radical; a hydrogen atom; or is a hydroxyl group; R 2 is a straight-chain or branched, cyclic and / or acyclic alkyl radical having 1 to 15 carbon atoms, with or without substituents such as. B. hydroxyl groups (1 to 3 pieces). Alkoxy groups with 1 to 5 carbon atoms; a straight-chain or branched, cyclic and / or acyclic alkenyl or alkynyl radical with 1 to 15 carbon atoms, and 1 to 3 unsaturated CC bonds with or without substituents, such as hydroxyl groups (1 to 3 pieces), ether groups, alkoxy groups with 1 to 5 C atoms, substituted or unsubstituted aryl radicals, such as p-tolyl or phenyl groups, substituted carbonyl or oxycarbonyl groups, silyl groups, substituted or unsubstituted cyclohexyl groups; R3 ein Wasserstoffatom, eine Hydroxylgruppe, ein geradkettiger oder verzweigte! Alkoxyrest mit 1 bis 5 C-Atomen, ein geradkettiger oder verzweigter Alkylrest mit 1 bis 5 C-Atomen ohne oder mit 1 bis 3 Hydroxylgruppen oder eine substituierte Carbonylgruppe ist;R 3 is a hydrogen atom, a hydroxyl group, a straight-chain or branched! Alkoxy radical having 1 to 5 carbon atoms, a straight-chain or branched alkyl radical having 1 to 5 carbon atoms without or with 1 to 3 hydroxyl groups or a substituted carbonyl group; R4, R5, R6 und R7 jeweils gleich oder verschieden und von einander unabhänging eir Wasserstoffatom; ein geradkettiger oder verzweigter, cyclischer und/oder acyclischei Alkylrest mit 1 bis 4 C-Atomen, wie ein Cyclohexyl-, Alkylcyclohexylrest mit 1 bis 4 C-Atomen im Alkylteil, ein Cycloheptyl- oder Cyclooctylrest; ein substituierter odei unsubstituierter Arylrest, wie ein Phenylrest, der durch Halogen, wie Fluor, Chlor odei Brom, einen geradkettigen oder verzweigten Alkylrest mit 1 bis 4 C-Atomen sowie einen geradkettigen oder verzweigten Alkoxyrest mit 1 bis 3 C-Atomen mono- odei disubstituiert sein kann; ein geradkettiger oder verzweigter, cyclischer und/odei acyclischer Alkoxyrest mit 1 bis 3 C-Atomen; ein substituierter oder unsubstituierteiR 4 , R 5 , R 6 and R 7 are each the same or different and are independent of each other eir hydrogen atom; a straight-chain or branched, cyclic and / or acyclic alkyl radical with 1 to 4 carbon atoms, such as a cyclohexyl, alkylcyclohexyl radical with 1 to 4 carbon atoms in the alkyl part, a cycloheptyl or cyclooctyl radical; a substituted or unsubstituted aryl radical, such as a phenyl radical which is mono-substituted by halogen, such as fluorine, chlorine or bromine, a straight-chain or branched alkyl radical having 1 to 4 carbon atoms and a straight-chain or branched alkoxy radical having 1 to 3 carbon atoms can be; a straight-chain or branched, cyclic and / or acyclic alkoxy radical having 1 to 3 carbon atoms; a substituted or unsubstituted egg Arylrest, wie ein Phenylalkylrest mit 1 bis 4 C-Atomen im Alkylteil, wobei dei Arylke n wie vorstehend beim Phenylrest angegeben substituiert sein kann; eir Halogenatom, wie Fluor, Chlor oder Brom; ein Mono- und/oder Dihydroxyalkylresl mit 1 bis 4 C-Atomen; eine primäre, sekundäre oder tertiäre Aminogruppe; eine Nitrogruppe; oder eine Sulfonylgruppe sind; sowie ein physiologisch verträgliches Derivat oder Analogon davon.Aryl radical, such as a phenylalkyl radical having 1 to 4 carbon atoms in the alkyl part, it being possible for the aryl nucleus to be substituted as indicated above for the phenyl radical; a halogen atom such as fluorine, chlorine or bromine; a mono- and / or dihydroxyalkyl radical with 1 to 4 carbon atoms; a primary, secondary or tertiary amino group; a nitro group; or are a sulfonyl group; and a physiologically acceptable derivative or analog thereof. 7. Chinolin-Derivate gemäß Anspruch 6, wobei die Natriumkanal-abhängiger Erkrankungen Epilepsie, Migräne, neurologische Erkrankungen (z. B. bipolare Störungen), Alkoholentzugserscheinungen, akute und chronische Schmerzen diabetische Neuropathie, cystische Fibröse, nicht epileptische Anfälle wie z. B bei Multipler Sklerose, traumatische neurologische Schädigungen, Neuro Aids Parkinson und Parkinson-Syndrom, Herzrhythmusstörungen, topischen Juckrei2 oder Schmerz sowie neurodegenerative Erkrankungen wie z. B. Morbus Alzheimer umfassen.7. quinoline derivatives according to claim 6, wherein the sodium channel-dependent diseases epilepsy, migraines, neurological diseases (z. B. bipolar disorders), alcohol withdrawal symptoms, acute and chronic pain diabetic neuropathy, cystic fibrosis, non-epileptic seizures such. B for multiple sclerosis, traumatic neurological damage, neuroids Parkinson's and Parkinson's syndrome, cardiac arrhythmias, topical itching or pain, and neurodegenerative diseases such as B. Alzheimer's disease include. 8. Chinolin-Derivat gemäß Anspruch 7, wobei die Epilepsie einfache partielle Anfalle, komplexe partielle Anfälle, grand mal Anfälle und gemischte Epilepsieformen umfasst.8. quinoline derivative according to claim 7, wherein the epilepsy includes simple partial seizures, complex partial seizures, grand mal seizures and mixed forms of epilepsy. Chinolin-Derivat gemäß einem der Ansprüche 6 bis 8,Quinoline derivative according to one of claims 6 to 8, wobeiin which R1 ein Wasserstoffatom, eine Hydroxylgruppe, die Gruppe -OR2, ein Alkyl-, wie ein Methyl- oder ein Alkoxy-, wie ein Methoxyrest ist;R 1 is a hydrogen atom, a hydroxyl group, the group -OR 2 , an alkyl, such as a methyl or an alkoxy, such as a methoxy radical; R2 die in Anspruch 6 angegebene Bedeutung hat; R3 ein Wasserstoffatom, eine Hydroxylgruppe, ein Alkyl-, wie ein Methyl- oder einR 2 has the meaning given in claim 6; R 3 is a hydrogen atom, a hydroxyl group, an alkyl, such as a methyl or a Alkoxy-, wie ein Methoxyrest ist und R4, R5, R6 und R7 jeweils gleich oder verschieden und voneinander unabhängig ein Wasserstoffatom, ein Halogen-, wie ein Chloratom, ein Alkylrest oder ein Alkoxy-, wie ein Methoxy- oder ein Ethoxyrest sind.Alkoxy, such as a methoxy radical, and R 4 , R 5 , R 6 and R 7 are each the same or different and independently of one another, a hydrogen atom, a halogen, such as a chlorine atom, an alkyl radical or an alkoxy, such as a methoxy or Are ethoxy. 10. Chinolin-Derivat gemäß Anspruch 9,10. quinoline derivative according to claim 9, wobei 1 9in which 1 9 R eine Hydroxylgruppe oder die Gruppe -OR ist; R2 die in Anspruch 6 angegebene Bedeutung hat; R3 ein Methylrest ist und R4, R5, R6 und R7 alle Wasserstoffatome sind.R is a hydroxyl group or the group -OR; R 2 has the meaning given in claim 6; R 3 is methyl and R 4 , R 5 , R 6 and R 7 are all hydrogen atoms. 11. Pharmazeutische Zusammensetzung, umfassend ein Chinolin-Derivat gemäß einem der vorstehenden Ansprüche oder ein physiologisch verträgliches Derivat oder Analogon davon.11. A pharmaceutical composition comprising a quinoline derivative according to any one of the preceding claims or a physiologically acceptable derivative or analog thereof. 12. Pharmazeutische Zusamensetzung gemäß Anspruch 11, wobei das Chinolin-12. A pharmaceutical composition according to claim 11, wherein the quinoline Derivat oder ein physiologisch verträgliches Derivat oder Analogon davon in einer wirksamen Menge zur Prophylaxe und Therapie einer Natriumkanal- abhängigen Erkrankung vorliegt.Derivative or a physiologically acceptable derivative or analogue thereof is present in an effective amount for the prophylaxis and therapy of a sodium channel-dependent disease. 13. Pharmazeutische Zusammensetzung gemäß einem der Ansprüche 11 oder 12, wobei das Chinolin-Derivat oder ein physiologisch verträgliches Derivat oder Analogon davon zu 1 bis 95 Gewichts-%, bezogen auf das Gesamtgewicht der Zusammensetzung, vorliegt.13. Pharmaceutical composition according to one of claims 11 or 12, wherein the quinoline derivative or a physiologically acceptable derivative or analogue thereof is present at 1 to 95% by weight, based on the total weight of the composition. 14. Pharmazeutische Zusammensetzung gemäß einem der Ansprüche 11 bis 13, wobei das Chinolin-Derivat oder ein physiologisch verträgliches Derivat oder Analogon davon in einer Einzeldosis von 0,1 bis 1000 mg vorliegt.14. A pharmaceutical composition according to any one of claims 11 to 13, wherein the quinoline derivative or a physiologically acceptable derivative or analog thereof is present in a single dose of 0.1 to 1000 mg. 15. Pharmazeutische Zusammensetzung gemäß einem der Ansprüche 11 bis 14, wobei das Chinolin-Derivat ausgewählt ist aus der Gruppe bestehend aus den in15. Pharmaceutical composition according to one of claims 11 to 14, wherein the quinoline derivative is selected from the group consisting of the in Anspruch 4 genannten Verbindungen oder physiologisch verträglichen Derivaten oder Analoga davon.Compounds or physiologically tolerated derivatives or analogs mentioned above. 16. Pharmazeutische Zusammensetzung gemäß Anspruch 15, wobei das Chinolin- Derivat ausgewählt ist aus der Gruppe bestehend aus 3-(l-Heptinyl)-2-hydroxy- 4-methylchinolin, 3-(l-Hexinyl)-2-hydroxy-4-methylchinolin und 2-Hydroxy-4- methyl-3-(l-pentinyl)-chinolin oder physiologisch verträglichen Derivaten oder Analoga davon.16. The pharmaceutical composition according to claim 15, wherein the quinoline derivative is selected from the group consisting of 3- (l-heptinyl) -2-hydroxy- 4-methylquinoline, 3- (l-hexynyl) -2-hydroxy-4-methylquinoline and 2-hydroxy-4-methyl-3- (l-pentynyl) quinoline or physiologically acceptable derivatives or analogues thereof. 17. Pharmazeutische Zusammensetzung gemäß einem der Ansprüche 11 bis 16 zur oralen oder parenteralen Verabreichung.17. Pharmaceutical composition according to one of claims 11 to 16 for oral or parenteral administration. 18. Verwendung eines Chinolin-Derivats gemäß einem der Ansprüche 1 bis 10 oder eines physiologisch verträglichen Derivats oder Analogons davon zur Herstellung eines Arzneimittels zur Prophylaxe und Therapie von18. Use of a quinoline derivative according to any one of claims 1 to 10 or a physiologically acceptable derivative or analogues thereof for the manufacture of a medicament for the prophylaxis and therapy of Natriumkanal-abhängigen Erkrankungen.Sodium channel dependent diseases. 19. Verwendung gemäß Anspruch 18, wobei die Natriumkanal-abhängigen Erkrankungen Epilepsie, Migräne, neurologische Erkrankungen (z. B. bipolare Störungen), Alkoholentzugserscheinungen, akute und chronische Schmerzen, diabetische Neuropathie, cystische Fibröse, nicht epileptische Anfälle wie z. B. bei Multipler Sklerose, traumatische neurologische Schädigungen, Neuro Aids, Parkinson und Parkinson-Syndrom, Herzrhythmusstörungen, topischen Juckreiz oder Schmerz sowie neurodegenerative Erkrankungen wie z. B. Morbus Alzheimer umfassen.19. Use according to claim 18, wherein the sodium channel-dependent diseases epilepsy, migraine, neurological diseases (z. B. bipolar disorders), alcohol withdrawal symptoms, acute and chronic pain, diabetic neuropathy, cystic fibrosis, non-epileptic seizures such. B. in multiple sclerosis, traumatic neurological damage, neuroids, Parkinson's and Parkinson's syndrome, irregular heartbeat, topical itching or pain and neurodegenerative diseases such as. B. Alzheimer's disease include. 20. Verwendung gemäß Anspruch 19, wobei die Epilepsie einfache partielle Anfälle, komplexe partielle Anfälle, grand mal Anfälle und gemischte Epilepsieformen umfasst.20. Use according to claim 19, wherein the epilepsy comprises simple partial seizures, complex partial seizures, grand mal seizures and mixed forms of epilepsy. 21. Verwendung gemäß einem der Ansprüche 18 bis 20, wobei das Chinolin- Derivat oder ein physiologisch verträgliches Derivat oder Analogon davon in einer wirksamen Menge zur Prophylaxe und Therapie einer Natriumkanal- abhängigen Erkrankung vorliegt. 21. Use according to one of claims 18 to 20, wherein the quinoline derivative or a physiologically acceptable derivative or analogue thereof is present in an effective amount for the prophylaxis and therapy of a sodium channel-dependent disease. 22. Verwendung gemäß Anspruch 21, wobei das Chinolin-Derivat oder ein physiologisch verträgliches Derivat oder Analogon davon in einer Einzeldosis von 0,1 bis 1000 mg in dem Arzneimittel vorliegt.22. Use according to claim 21, wherein the quinoline derivative or a physiologically acceptable derivative or analogue thereof is present in the drug in a single dose of 0.1 to 1000 mg. 23. Verwendung gemäß einem der Ansprüche 18 bis 22, wobei das Chinolin-23. Use according to any one of claims 18 to 22, wherein the quinoline Derivat ausgewählt ist aus der Gruppe bestehend aus den in Anspruch 4 genannten Verbindungen oder physiologisch verträglichen Derivaten oder Analoga davon.Derivative is selected from the group consisting of the compounds mentioned in claim 4 or physiologically tolerable derivatives or analogues thereof. 24. Verwendung gemäß Anspruch 23, wobei das Chinolin-Derivat ausgewählt ist aus der Gruppe bestehend aus 3-(l-Heptinyl)-2-hydroxy-4-methylchinolin, 3- ( 1 -Hexinyl)-2-hydroxy-4-methylchinolin und 2-Hydroxy-4-metlιyl-3-( 1 - pentinyl)-chinolin oder physiologisch verträglichen Derivaten oder Analoga davon.24. Use according to claim 23, wherein the quinoline derivative is selected from the group consisting of 3- (l-heptinyl) -2-hydroxy-4-methylquinoline, 3- (1-hexynyl) -2-hydroxy-4-methylquinoline and 2-hydroxy-4-methyl-3- (1 - pentinyl) quinoline or physiologically acceptable derivatives or analogues thereof. 25. Verwendung gemäß einem der Ansprüche 18 bis 24, wobei das Arzneimittel zur oralen oder parenteralen Verabreichung vorgesehen ist.25. Use according to any one of claims 18 to 24, wherein the medicament is intended for oral or parenteral administration. 26. Verwendung eines Chinolin-Derivats der allgemeinen Formel, wie sie in einem der Ansprüche 1 bis 10 definiert ist, oder eines Derivats oder Analogons davon als Insektizid in der Landwirtschaft.26. Use of a quinoline derivative of the general formula as defined in any one of claims 1 to 10, or a derivative or analogue thereof as an insecticide in agriculture. 27. Verwendung eines Chinolin-Derivats der allgemeinen Formel, wie sie in einem der Ansprüche 1 bis 10 definiert ist, oder eines Derivats oder Analogons davon zur Herstellung einer Zusammensetzung mit insektizider Wirkung.27. Use of a quinoline derivative of the general formula as defined in one of claims 1 to 10, or a derivative or analogue thereof for the preparation of a composition having an insecticidal action. 28. Insektizid wirkende Zusammensetzung, umfassend ein Chinolin-Derivat der allgemeinen Formel, wie sie in einem der Ansprüche 1 bis 10 definiert ist, oder ein Derivat oder Analogon davon. 28. An insecticidal composition comprising a quinoline derivative of the general formula as defined in any one of claims 1 to 10, or a derivative or analog thereof.
PCT/DE2001/004452 2000-12-04 2001-11-27 Quinoline derivatives and their use as anti-epileptics Ceased WO2002046163A2 (en)

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Cited By (3)

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WO2008113006A1 (en) * 2007-03-14 2008-09-18 Xenon Pharmaceuticals Inc. Methods of using quinolinone compounds in treating sodium channel-mediated diseases or conditions
EP1908752A4 (en) * 2005-06-07 2009-09-02 Dainippon Sumitomo Pharma Co Novel 2-quinolone derivative
WO2023036995A1 (en) * 2021-09-13 2023-03-16 Centre National De La Recherche Scientifique Alkynylcarbinols with high cytotoxicity

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IL89026A (en) * 1988-01-29 1993-02-21 Lilly Co Eli Substituted quinolines and cinnolines, process for their preparation and fungicidal, insecticidal and miticidal compositions containing them
US5428037A (en) * 1993-04-09 1995-06-27 Syntex Pharmaceuticals, Ltd. Heterocyclic derivatives in the treatment of Ischaemia and related diseases
JPH11514361A (en) * 1995-10-16 1999-12-07 藤沢薬品工業株式会社 Heterocyclic compounds as H + -ATPase

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1908752A4 (en) * 2005-06-07 2009-09-02 Dainippon Sumitomo Pharma Co Novel 2-quinolone derivative
WO2008113006A1 (en) * 2007-03-14 2008-09-18 Xenon Pharmaceuticals Inc. Methods of using quinolinone compounds in treating sodium channel-mediated diseases or conditions
WO2023036995A1 (en) * 2021-09-13 2023-03-16 Centre National De La Recherche Scientifique Alkynylcarbinols with high cytotoxicity

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