WO2002046163A2 - Derives de quinoleine et leur utilisation - Google Patents

Derives de quinoleine et leur utilisation 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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WO
WIPO (PCT)
Prior art keywords
quinoline
hydroxy
methylquinoline
radical
methyl
Prior art date
Application number
PCT/DE2001/004452
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German (de)
English (en)
Other versions
WO2002046163A3 (fr
Inventor
Michael Wackernagel
Original Assignee
Michael Wackernagel
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Michael Wackernagel filed Critical Michael Wackernagel
Priority to AU2002216939A priority Critical patent/AU2002216939A1/en
Priority to DE10195304T priority patent/DE10195304D2/de
Publication of WO2002046163A2 publication Critical patent/WO2002046163A2/fr
Publication of WO2002046163A3 publication Critical patent/WO2002046163A3/fr

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Classifications

    • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux dérivés de quinoléine destinés au traitement prophylactique et thérapeutique de maladies dues au canal sodium, notamment l'épilepsie. La présente invention porte également sur des préparations pharmaceutiques comprenant ces dérivés de quinoléine et sur des méthodes de traitement de maladies dues au canal sodium, notamment l'épilepsie. Par rapport à des composés reflétant l'état actuel de la technique, lesdits dérivés de quinoléine allient une haute efficacité à une très faible toxicité.
PCT/DE2001/004452 2000-12-04 2001-11-27 Derives de quinoleine et leur utilisation WO2002046163A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2002216939A AU2002216939A1 (en) 2000-12-04 2001-11-27 Quinoline derivatives and their use as anti-epileptics
DE10195304T DE10195304D2 (de) 2000-12-04 2001-11-27 Chinolin-Derivative und ihre Verwendung

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10060145A DE10060145C1 (de) 2000-12-04 2000-12-04 Chinolin-Derivate, ihre Verwendung und diese enthaltende pharmazeutische Zusammensetzung
DE10060145.6 2000-12-04

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WO2002046163A3 WO2002046163A3 (fr) 2003-02-13

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1908752A1 (fr) * 2005-06-07 2008-04-09 Dainippon Sumitomo Pharma Co., Ltd. Nouveau dérivé de 2-quinolone
WO2008113006A1 (fr) * 2007-03-14 2008-09-18 Xenon Pharmaceuticals Inc. Procédés d'utilisation de composés à base de quinolinone dans le traitement des maladies ou des affections associées aux canaux sodiques
WO2023036995A1 (fr) * 2021-09-13 2023-03-16 Centre National De La Recherche Scientifique Alcynylcarbinols à cytotoxicité élevée

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0326331A2 (fr) * 1988-01-29 1989-08-02 DowElanco Quinoléines et cinnolines substituées
WO1994024116A1 (fr) * 1993-04-09 1994-10-27 Syntex Pharmaceuticals Limited Derives heterocycliques utilises dans le traitement de l'ischemie et d'autres pathologies associees
WO1997014681A1 (fr) * 1995-10-16 1997-04-24 Fujisawa Pharmaceutical Co., Ltd. Composes heterocycliques tels que des h+-atpases

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0326331A2 (fr) * 1988-01-29 1989-08-02 DowElanco Quinoléines et cinnolines substituées
WO1994024116A1 (fr) * 1993-04-09 1994-10-27 Syntex Pharmaceuticals Limited Derives heterocycliques utilises dans le traitement de l'ischemie et d'autres pathologies associees
WO1997014681A1 (fr) * 1995-10-16 1997-04-24 Fujisawa Pharmaceutical Co., Ltd. Composes heterocycliques tels que des h+-atpases

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 122, no. 2, 9. Januar 1995 (1995-01-09) Columbus, Ohio, US; abstract no. 10811s, BHAGAWAT, LALITA P. ET AL.: "Synthesis and solid state polymerization of novel diacetylenes" XP002203884 & POLYM. SCI., Bd. 1, - 1994 Seiten 82-87, -& DATABASE CAPLUS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; Database accession no. 122:10811 XP002203885 *
JOHANNES REISCH ET AL.: "Acetylenchemie. 18. Mitt.: Molek}lvariationen am Rutaceenalkaloid Dictamnin via Pd/Cu katalysierte Alkin-Kupplung" JOURNAL OF HETEROCYCLIC CHEMISTRY., Bd. 28, Nr. 1, - 1991 Seiten 167-171, XP002203883 HETEROCORPORATION. PROVO., US ISSN: 0022-152X *
JOHANNES REISCH ET AL.: "Dictamnin und Derivate durch Pd/Cu-katalysierte Alkin-Kupplung" LIEBIGS ANNALEN DER CHEMIE., Bd. 1, - 1988 Seiten 69-73, XP002203882 VERLAG CHEMIE GMBH. WEINHEIM., DE ISSN: 0170-2041 *
TAKAO SAKAMOTO ET AL.: "A facile synthesis of ethynyl-substituted six-membered N-heteroaromatic compounds" SYNTHESIS., Bd. 4, - 1983 Seiten 312-314, XP002203881 GEORG THIEME VERLAG. STUTTGART., DE ISSN: 0039-7881 *
YAMANAKA H ET AL: "STUDIES OF QUINOLINE AND ISOQUINOLINE DERIVATIVES. II. COUPLING REACTION OF HALOQUINOLINES AND HALOISQUINOLINES WITH MONOSUBSTITUTED ACETYLENES IN THE PRESENCE OF PALLADIUM COMPLEX" CHEMICAL AND PHARMACEUTICAL BULLETIN, PHARMACEUTICAL SOCIETY OF JAPAN. TOKYO, JP, Bd. 27, Nr. 1, 1979, Seiten 270-273, XP000952500 ISSN: 0009-2363 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1908752A1 (fr) * 2005-06-07 2008-04-09 Dainippon Sumitomo Pharma Co., Ltd. Nouveau dérivé de 2-quinolone
EP1908752A4 (fr) * 2005-06-07 2009-09-02 Dainippon Sumitomo Pharma Co Nouveau dérivé de 2-quinolone
WO2008113006A1 (fr) * 2007-03-14 2008-09-18 Xenon Pharmaceuticals Inc. Procédés d'utilisation de composés à base de quinolinone dans le traitement des maladies ou des affections associées aux canaux sodiques
WO2023036995A1 (fr) * 2021-09-13 2023-03-16 Centre National De La Recherche Scientifique Alcynylcarbinols à cytotoxicité élevée

Also Published As

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AU2002216939A1 (en) 2002-06-18
WO2002046163A3 (fr) 2003-02-13
DE10195304D2 (de) 2003-10-23
DE10060145C1 (de) 2002-06-13

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