NO313829B1 - Anticonvulsant-acting 1-ar (alk) yl-imidazolin-2-ones and their use in the preparation of compounds for the treatment of central nervous system diseases - Google Patents
Anticonvulsant-acting 1-ar (alk) yl-imidazolin-2-ones and their use in the preparation of compounds for the treatment of central nervous system diseases Download PDFInfo
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- NO313829B1 NO313829B1 NO19980906A NO980906A NO313829B1 NO 313829 B1 NO313829 B1 NO 313829B1 NO 19980906 A NO19980906 A NO 19980906A NO 980906 A NO980906 A NO 980906A NO 313829 B1 NO313829 B1 NO 313829B1
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- imidazolin
- morpholino
- compounds
- chlorophenyl
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- 150000001875 compounds Chemical class 0.000 title claims description 22
- 238000002360 preparation method Methods 0.000 title claims description 6
- 208000015114 central nervous system disease Diseases 0.000 title 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 7
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 230000001037 epileptic effect Effects 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000013543 active substance Substances 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- RFOOXLRNUYUJMT-UHFFFAOYSA-N 1-(3-chlorophenyl)-4-morpholin-4-ylimidazolidin-2-one Chemical compound ClC1=CC=CC(N2C(NC(C2)N2CCOCC2)=O)=C1 RFOOXLRNUYUJMT-UHFFFAOYSA-N 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- -1 d-C4-alkoxy Chemical group 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000001961 anticonvulsive agent Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000001773 anti-convulsant effect Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 2
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 238000007126 N-alkylation reaction Methods 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 239000010457 zeolite Substances 0.000 description 2
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- ADOLLNOHUDQRCE-UHFFFAOYSA-N 1-(4-chlorophenyl)-4-morpholin-4-ylimidazolidin-2-one Chemical compound C1=CC(Cl)=CC=C1N1C(=O)NC(N2CCOCC2)C1 ADOLLNOHUDQRCE-UHFFFAOYSA-N 0.000 description 1
- TXULSVVHBXUCFZ-UHFFFAOYSA-N 1-(4-fluorophenyl)-4-morpholin-4-ylimidazolidin-2-one Chemical compound C1=CC(F)=CC=C1N1C(=O)NC(N2CCOCC2)C1 TXULSVVHBXUCFZ-UHFFFAOYSA-N 0.000 description 1
- QYLBODXDNLFDFJ-UHFFFAOYSA-N 1-benzyl-4-morpholin-4-ylimidazolidin-2-one Chemical compound O=C1NC(N2CCOCC2)CN1CC1=CC=CC=C1 QYLBODXDNLFDFJ-UHFFFAOYSA-N 0.000 description 1
- MDYHGFXQHSAJQB-UHFFFAOYSA-N 4-morpholin-4-yl-1-phenylimidazolidin-2-one Chemical compound O=C1NC(N2CCOCC2)CN1C1=CC=CC=C1 MDYHGFXQHSAJQB-UHFFFAOYSA-N 0.000 description 1
- 241000557626 Corvus corax Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- JIYXHCMRGZVYMA-UHFFFAOYSA-N dimethylcarbamic acid;n-methylmethanamine Chemical compound C[NH2+]C.CN(C)C([O-])=O JIYXHCMRGZVYMA-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 231100000189 neurotoxic Toxicity 0.000 description 1
- 230000002887 neurotoxic effect Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
- C07D233/88—Nitrogen atoms, e.g. allantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Neurology (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pain & Pain Management (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Foreliggende oppfinnelse vedrører l-ar(alk)yl-imidazolin-2-oner, som i 4-stilling The present invention relates to 1-ar(alk)yl-imidazolin-2-ones, as in the 4-position
inneholder en disubstituert aminrest og deres anvendelse for fremstilling av et legemiddel for behandling av sykdommer i sentralnervesystemet, spesielt av epilepsier av forskjellig form. Dessuten angår oppfinnelsen farmasøytiske preparater som inneholder minst en av nevnte forbindelser. containing a disubstituted amine residue and their use for the preparation of a medicament for the treatment of diseases of the central nervous system, in particular of epilepsies of various forms. Furthermore, the invention relates to pharmaceutical preparations containing at least one of the aforementioned compounds.
l-ar(alk)yl-imidazolin-2-oner med en usubstituert amin- eller metylaminrest i 4-stilling fremstilles ifølge teknikkens stand ved omsetning av ar(alk)ylaminoacetamider med bromcyan. Ved N-alkylering av de på denne måten fremstilte 4-amino-l-ar(alk)yl-imidazolin-2-onene oppnås 3-alkyl- eller l-iminoalkyl-3-alkyl-l-ar(alk)yl-imidazolin-2- 1-ar(alk)yl-imidazolin-2-ones with an unsubstituted amine or methylamine residue in the 4-position are prepared according to the state of the art by reacting ar(alk)ylaminoacetamides with cyanogen bromide. By N-alkylation of the 4-amino-1-ar(alk)yl-imidazolin-2-ones prepared in this way, 3-alkyl- or 1-iminoalkyl-3-alkyl-1-ar(alk)yl-imidazoline is obtained -2-
oner, hvorved aminogruppen i 4-stilling er tautomerisert til en iminogruppe. En ytter- ones, whereby the amino group in the 4-position is tautomerized to an imino group. An outer
ligere N-alkylering til forbindelser med generell formel 1 er derfor ikke mulig, slik at forbindelser ifølge oppfinnelsen ikke kan fremstilles ved denne fremgangsmåten [USP 4044021; DE 2251354]. l-ar(aIk)yl-imidazolin-2-oner med en disubstituert aminrest i 4-stillingen er hittil ikke beskrevet. Further N-alkylation to compounds of general formula 1 is therefore not possible, so that compounds according to the invention cannot be prepared by this method [USP 4044021; DE 2251354]. 1-ar(aIk)yl-imidazolin-2-ones with a disubstituted amine residue in the 4-position have not been described so far.
Kjent er et stort antall antikonvulsivt virksomme forbindelser. Likevel kan fremdeles ikke A large number of anticonvulsant active compounds are known. Yet still can't
alle epileptiske sykdommer i dag behandles på tilfredsstillende måte. all epileptic diseases are currently treated satisfactorily.
Til grunn for oppfinnelsen ligger følgelig den oppgave å tilveiebringe nye forbindelser The invention is therefore based on the task of providing new compounds
med gunstige farmakologiske egenskaper, som eksempelvis er anvendbare som anti-epileptisk virksomme legemidler. with favorable pharmacological properties, which are, for example, usable as anti-epileptic drugs.
Ifølge oppfinnelsen er det således tilveiebrakt nye l-ar(alk)yl-imidazolin-2-oner kjennetegnet ved den generelle formel 1 According to the invention, new l-ar(alk)yl-imidazolin-2-ones characterized by the general formula 1 have thus been provided
hvori in which
X = hydrogen, Ci-C4-alkyl, Ci-C4-alkoksy, trifluormetyl, halogen, X = hydrogen, C1-C4-alkyl, C1-C4-alkoxy, trifluoromethyl, halogen,
R<1> hhv. R<2> = Ci-C4-alkyl R<1> or R<2> = C1-C4 alkyl
eller or
R<1> og R<2> betyr sammen en alkylengruppe med 2-6 karbonatomer hvori en -CH2-gruppe kan være erstattet med oksygen eller nitrogen, eventuelt substituert med Ci-C4-alkyl. R<1> and R<2> together mean an alkylene group with 2-6 carbon atoms in which a -CH2 group can be replaced by oxygen or nitrogen, optionally substituted by C1-C4 alkyl.
Antallet CEb-grupper utgjør enten 0 (l-aryl-imidazolin-2-oner) eller 1 (1-aralkyl-imidazolin-2-oner). The number of CEb groups is either 0 (1-aryl-imidazolin-2-ones) or 1 (1-aralkyl-imidazolin-2-ones).
Foretrukne forbindelser med generell formel I er kjennetegnet ved at de kan velges blant: Preferred compounds of general formula I are characterized in that they can be selected from:
l-fenyl-4-morfolino-imidazolin-2-on 1-phenyl-4-morpholino-imidazolin-2-one
l-(4-metoksy)-4-piperidino-imidazolin-2-on l-(4-klorfenyl)-4-morfolino-imidazolin-2-on l-(4-klorfenyl-4-pipeirdino-imidazolin-2-on l-(4-klorfenyl)-4-dimetylamino-imidazolin-2-on l-(4-bromfenyl)-4-morfolino-imidazolin-2-on 1 -(3 -klorfenyl)-4-morfolino-imidazolin-2-on l-(4-klorfenyl)-4-heksametylenimino-imidazolin-2-on l-(4-klorfenyl-4-(4-metylpiperazino)-imidazolin-2-on l-(4-metylfenyl)-4-morfolino-imidazolin-2-on l-(4-methoxy)-4-piperidino-imidazolin-2-one l-(4-chlorophenyl)-4-morpholino-imidazolin-2-one l-(4-chlorophenyl-4-piperidino-imidazolin-2-one l-(4-chlorophenyl)-4-dimethylamino-imidazolin-2-one l-(4-bromophenyl)-4-morpholino-imidazolin-2-one 1 -(3-chlorophenyl)-4-morpholino-imidazolin-2- on l-(4-chlorophenyl)-4-hexamethyleneimino-imidazolin-2-one l-(4-chlorophenyl-4-(4-methylpiperazino)-imidazolin-2-one l-(4-methylphenyl)-4-morpholino- imidazolin-2-one
l-(4-fluorfenyl)4-morfolino-imidazolin-2-on 1-(4-fluorophenyl)4-morpholino-imidazolin-2-one
1 -benzyl-4-morfolino-imidazolin-2-on 1 -benzyl-4-morpholino-imidazolin-2-one
På en i og for seg kjent fremgangsmåte kan forbindelsene med generell formel 1 fremstilles ved omsetning av forbindelsen med generell formel 2 In a method known per se, the compounds of general formula 1 can be prepared by reacting the compound of general formula 2
hvor where
X = hydrogen, Ci-C4-alkyl, Ci-C4-alkoksy, trifluormetyl, halogen, X = hydrogen, C1-C4-alkyl, C1-C4-alkoxy, trifluoromethyl, halogen,
med et sekundært amin. with a secondary amine.
Fremstillingen av forbindelsene med formel 1 kan valgfritt foregå i et oppløsningsmiddel eller i overskudd sekundært amin ved temperaturer mellom 50°C og 160°C. Som oppløsningsmiddel kommer fortrinnsvis aromatiske hydrokarboner, eksempelvis benzen, toluen, klorbenzen eller diklorbenzen, på tale. Fortrinnsvis arbeides det i nærvær av vannbindende stoffer som zeolitter eller natriumsulfat. Reaksjonen kan akselereres ved tilsats av generelt vandige kondensasjonskatalysatorer, som 4-toluensulfonsyre. The preparation of the compounds of formula 1 can optionally take place in a solvent or in an excess of secondary amine at temperatures between 50°C and 160°C. Aromatic hydrocarbons, for example benzene, toluene, chlorobenzene or dichlorobenzene, are preferably used as solvents. Preferably, work is carried out in the presence of water-binding substances such as zeolites or sodium sulphate. The reaction can be accelerated by the addition of generally aqueous condensation catalysts, such as 4-toluenesulfonic acid.
Forbindelsene ifølge oppfinnelsen er egnede for fremstilling av farmasøytiske preparater. Ifølge oppfinnelsen er det ytterligere tilveiebrakt farmasøytiske preparater kjennetegnet ved at de som aktivt stoff inneholder minst en forbindelse med generell formel 1 og eventuelt farmasøytiske bærer- og hjelpestoffer. The compounds according to the invention are suitable for the production of pharmaceutical preparations. According to the invention, there are further provided pharmaceutical preparations characterized in that they contain as active substance at least one compound of general formula 1 and possibly pharmaceutical carriers and auxiliary substances.
Foretrukne trekk ved de farmasøytiske preparater ifølge oppfinnelsen fremgår av medfølgende krav 4. Preferred features of the pharmaceutical preparations according to the invention appear from accompanying claim 4.
Dessuten er det tilveiebrakt en anvendelse av forbindelser med henholdsvis generell formel 1 eller ifølge krav 2 for fremstilling av legemidler for behandling av epileptiske sykdommer. Furthermore, a use of compounds with general formula 1 or according to claim 2, respectively, for the production of pharmaceuticals for the treatment of epileptic diseases has been provided.
Legemidlet kan anvendes parenteralt (f.eks. intravenøst, intramuskulært, subkutant) eller oralt. Preparatformene kan fremstilles ifølge fremgangsmåter som er generelt kjente og vanlige innen den farmasøytiske praksis. The drug can be used parenterally (eg intravenously, intramuscularly, subcutaneously) or orally. The preparation forms can be prepared according to methods that are generally known and common in pharmaceutical practice.
Forbindelsene ifølge oppfinnelsen oppviser sterke antikonvulsive virkninger. De ble testet in vivo etter i.p.-tilførsel til mus eller rotter (p.o.-tilførsel) i henhold til den internasjonalt vanlige standarden (Pharmac. Weekblad, Sc.Ed. 14, 132 (1992) og Antiepileptic Drugs, tredje utg., Raven Press, New York 1989) med henblikk på antikonvulsiv virkning (tabell 1). Eksempelvis ble for forbindelse 2 (l-(4-klorfenyl)-4-morfolino-imidazolin-2-on) hos rotte for det maksimale elektrosjokk bestemt ED50 (p.o.) på 21 mg/kg, i s.c. pentetrazol-test ED50 på 16 mg/kg og for neurotoksisitet NT50 > 400 mg/kg. Sammenlignet med dette virker kjente antiepileptika hverken i modellen med maksimalt elektrosjokk eller i pentetrazol-testen eller er ved sterkere virkning i PTZ-testen sterkt neurotoksiske. The compounds according to the invention exhibit strong anticonvulsant effects. They were tested in vivo after i.p. administration to mice or rats (p.o. administration) according to the internationally common standard (Pharmac. Weekblad, Sc.Ed. 14, 132 (1992) and Antiepileptic Drugs, third ed., Raven Press , New York 1989) for anticonvulsant action (Table 1). For example, for compound 2 (1-(4-chlorophenyl)-4-morpholino-imidazolin-2-one) in rats for the maximum electroshock, an ED50 (p.o.) of 21 mg/kg was determined, in s.c. pentetrazole test ED50 of 16 mg/kg and for neurotoxicity NT50 > 400 mg/kg. Compared to this, known antiepileptic drugs work neither in the model with maximum electroshock nor in the pentetrazole test, or are strongly neurotoxic if they have a stronger effect in the PTZ test.
Anmerkninger til tabell 1: Notes to Table 1:
1) Nummerering av forbindelsene, se utførelseseksempler 1) Numbering of the connections, see design examples
2) Fordelingskoeffisient octanol/vann 2) Partition coefficient octanol/water
3) Mus i.p.: MES = maksimalt elektrosjokk, PTZ = s.c. pentetrazol 3) Mouse i.p.: MES = maximal electroshock, PTZ = s.c. pentetrazole
4) i mg/kg 4) in mg/kg
5) i % av beskyttede dyr 5) in % of protected animals
Fremstillingen av de nye forbindelsene med generell formel 1 skal beskrives nærmere ved hjelp av utførelseseksemplene. The production of the new compounds with general formula 1 shall be described in more detail by means of the design examples.
Utførelseseksempler Execution examples
Generelle forskrifter for fremstilling av forbindelsene med formel 1 ifølge tabell 1, eksempler 1-11. General regulations for the preparation of the compounds of formula 1 according to table 1, examples 1-11.
Variant A Variant A
0,05 mol l-aryl-imidazolin-2,4-dion med generell formel 2 (n=0), 200m mg 4-toluensulfonsyre ble tilsatt til 100 ml av tilsvarende sekundært amin. Deretter ble det oppvarmet i Soxhlet-ektraktor ved tilbakeløp, hvorved ekstraksjonshylsen på forhånd var fylt med ca. 25 g av et vannbindende faststoff (egnet er calc. natriumsulfat, magnesiumsulfat, NaOH, KOH, zeolitter). Etter 8 til 30 timers reaksjonstid filtreres oppløsningen varm og destilleres til ca. det halve volumet på rotasjonsfordamper. Den klare oppløsningen avkjøles i isbad og den dannede krystallgrøten fraskilles fra aminet. Utgangsstoff inneholdt i råprodukt ekstraheres med 50 ml varm aceton. Produktet omkrystalliseres fra n-propanol. Fra det fraskilte aminet kan det tilbakevinnes ca. 0,02 mol uomsatt l-aryl-imidazolin-2,4-dion. 0.05 mol of 1-aryl-imidazoline-2,4-dione of general formula 2 (n=0), 200 mg of 4-toluenesulfonic acid was added to 100 ml of the corresponding secondary amine. It was then heated in a Soxhlet extractor at reflux, whereby the extraction sleeve was previously filled with approx. 25 g of a water-binding solid (calc. sodium sulfate, magnesium sulfate, NaOH, KOH, zeolites are suitable). After a reaction time of 8 to 30 hours, the solution is filtered hot and distilled to approx. half the volume on the rotary evaporator. The clear solution is cooled in an ice bath and the crystal slurry formed is separated from the amine. Starting material contained in crude product is extracted with 50 ml of hot acetone. The product is recrystallized from n-propanol. From the separated amine, approx. 0.02 mol of unreacted 1-aryl-imidazoline-2,4-dione.
Variant B Variant B
0,05 mol l-aryl-imidazolin-2,4-dion med generell formel 2 (n=l) omsettes med et sek.amin som beskrevet under A. Etter 8 til 30 timers reaksjonstid filtreres oppløsningen varm og inndampes deretter til tørrhet på rotasjonsfordamper. Til resten tilsettes 50 ml metylenklorid og 50 ml 2n HC1. Den organiske fasen fraskilles og den vandige fasen ekstraheres ytterligere to ganger med metylenklorid. Den isolerte vandige fasen gjøres alkalisk med 50 ml 10 % NaOH og l-4-amino-l-aralkyl-inidazolin-2-onet ekstraheres med 100 ml metylenklorid. Eterekstraktene tørkes over natriumsulfat. Etter avdestillering av metylenkloridet omkrystalliseres råproduktet fra etanol eller aceton. 0.05 mol of 1-aryl-imidazoline-2,4-dione with general formula 2 (n=1) is reacted with a sec.amine as described under A. After 8 to 30 hours of reaction time, the solution is filtered hot and then evaporated to dryness on rotary evaporator. 50 ml of methylene chloride and 50 ml of 2N HCl are added to the residue. The organic phase is separated and the aqueous phase is extracted twice more with methylene chloride. The isolated aqueous phase is made alkaline with 50 ml of 10% NaOH and the 1-4-amino-1-aralkyl-inidazolin-2-one is extracted with 100 ml of methylene chloride. The ether extracts are dried over sodium sulfate. After distilling off the methylene chloride, the crude product is recrystallized from ethanol or acetone.
Variant C Variant C
0,05 mol l-ar(alk)yl-imidazolin-2,4-dion med generell formel 2 omsettes med 100 ml dimetylammonium-dimetylkarbamat, som beskrevet under A og B. Etter 40 timers reaksjonstid opparbeides det ifølge variant A eller B. 0.05 mol of 1-ar(alk)yl-imidazoline-2,4-dione with general formula 2 is reacted with 100 ml of dimethylammonium-dimethylcarbamate, as described under A and B. After 40 hours of reaction time, it is worked up according to variant A or B.
Claims (6)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19532668A DE19532668A1 (en) | 1995-09-05 | 1995-09-05 | Novel, anticonvulsant 1-ar (alk) yl-imidazolin-2-ones which contain a disubstituted amine radical in the 4-position, and process for their preparation |
| PCT/EP1996/003295 WO1997009314A1 (en) | 1995-09-05 | 1996-07-26 | Novel 1-ar(alk)yl-imidazolin-2-ones containing a disubstituted amine radical in the 4th position, having an anti-convulsive effect, and process for their production |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO980906L NO980906L (en) | 1998-03-02 |
| NO980906D0 NO980906D0 (en) | 1998-03-02 |
| NO313829B1 true NO313829B1 (en) | 2002-12-09 |
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| Application Number | Title | Priority Date | Filing Date |
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| NO19980906A NO313829B1 (en) | 1995-09-05 | 1998-03-02 | Anticonvulsant-acting 1-ar (alk) yl-imidazolin-2-ones and their use in the preparation of compounds for the treatment of central nervous system diseases |
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| JP (1) | JP4030578B2 (en) |
| CN (1) | CN1103762C (en) |
| AR (1) | AR003502A1 (en) |
| AT (1) | ATE254606T1 (en) |
| AU (1) | AU700602B2 (en) |
| BG (1) | BG63917B1 (en) |
| BR (1) | BR9610359A (en) |
| CA (1) | CA2184871C (en) |
| CZ (1) | CZ291839B6 (en) |
| DE (2) | DE19532668A1 (en) |
| DK (1) | DK0863880T3 (en) |
| EA (1) | EA000535B1 (en) |
| EE (1) | EE03562B1 (en) |
| ES (1) | ES2208758T3 (en) |
| FR (1) | FR13C0049I2 (en) |
| GE (1) | GEP20022652B (en) |
| HK (1) | HK1015776A1 (en) |
| HU (1) | HU225956B1 (en) |
| IL (1) | IL123333A (en) |
| LT (1) | LT4482B (en) |
| LU (1) | LU92263I2 (en) |
| NO (1) | NO313829B1 (en) |
| NZ (1) | NZ315624A (en) |
| PL (1) | PL188287B1 (en) |
| PT (1) | PT863880E (en) |
| SK (1) | SK284868B6 (en) |
| TR (1) | TR199800476T1 (en) |
| TW (1) | TW422838B (en) |
| UA (1) | UA46790C2 (en) |
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| DE19721580A1 (en) * | 1997-05-23 | 1998-11-26 | Dresden Arzneimittel | Use of 1-ar (alk) yl-imidazolin-2-one for the treatment of anxiety and tension |
| US20050070537A1 (en) * | 2002-10-10 | 2005-03-31 | Chris Rundfeldt | Use of dihydroimidazolones for the treatment of dogs |
| RU2354377C2 (en) * | 2003-07-11 | 2009-05-10 | Берингер Ингельхайм Ветмедика Гмбх | Method of treatment or prevention of central nervous system diseases by means of compounds possessing selectivity with respect to alpha-3-subunit of benzodiazepine receptor |
| EP2093218A1 (en) * | 2008-02-22 | 2009-08-26 | Ruggero Fariello | Arylalkyl substituted imidazolidinones |
| KR20140053307A (en) | 2011-08-12 | 2014-05-07 | 베링거잉겔하임베트메디카게엠베하 | Taste masked pharmaceutical composition |
| US9820988B2 (en) | 2014-03-24 | 2017-11-21 | Boehringer Ingelheim Vetmedica Gmbh | Treatment of epileptic disorders in feline animals |
| IT202100000782A1 (en) | 2021-01-18 | 2022-07-18 | Procos Spa | PROCESS FOR THE SYNTHESIS OF IMEPITOIN |
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| US4044021A (en) * | 1971-10-21 | 1977-08-23 | American Cyanamid Company | Tetrasubstituted imidazolidine diuretics useful in the treatment of hyperaldosteronism |
| BE790380A (en) | 1971-10-21 | 1973-04-20 | American Cyanamid Co | NEW (P-CHLORO) PHENYL-1 METHYL-3 IMIDAZOLIDINES, 2,4-DISUBSTITUTIONS USEFUL IN PARTICULAR AS ANTIALDOSTERONE DIURETIC AGENTS AND THEIR PREPARATION PROCESS |
| US3932452A (en) * | 1975-02-07 | 1976-01-13 | Morton-Norwich Products, Inc. | 1-Arylmethyl-2-imidazolidinones |
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