SK284868B6 - 1-Ar(alk)yl-imidazolin-2-ones, process for their production, use of them and pharmaceutical composition containing them - Google Patents

1-Ar(alk)yl-imidazolin-2-ones, process for their production, use of them and pharmaceutical composition containing them Download PDF

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SK284868B6
SK284868B6 SK216-98A SK21698A SK284868B6 SK 284868 B6 SK284868 B6 SK 284868B6 SK 21698 A SK21698 A SK 21698A SK 284868 B6 SK284868 B6 SK 284868B6
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alk
ylimidazolin
chlorophenyl
morpholinoimidazolin
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Hans-Joachim Lankau
Manfred Menzer
Klaus Unverferth
Karl Gewald
Harry Sch�Fer
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Elbion Ag
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    • 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
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    • 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
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    • 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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Abstract

1-Ar(alk)yl-imidazolin-2-ones of the general formula (I), in which n is 0 or 1, m is 0, 1, 2, 3, 4 or 5, X is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, trifluoromethyl or halogen, R1-R2 are C1-C4-alkyl, cycloalkyl or an alkyl group which contains one or more heteroatoms or R1-R2 together are an alkylene group in which a -CH2- group can be replaced by oxygen, nitrogen or sulphur having anticonvulsive actions are described. These compounds can be prepared by a process organic synthesis. Pharmaceutical composition contains as an active substance at least one of said 1-Ar(alk)yl-imidazolin-2-on. These compounds are useful for the production of medicaments for the treatment of epileptic disorders.

Description

Vynález sa týka l-ar(alk)ylimidazolín-2-ónov, ktoré obsahujú disubstituovaný amínový zvyšok v polohe 4, spôsobov ich prípravy a ich použitia na liečenie porúch centrálneho nervového systému, najmä rôznych foriem epilepsií. Vynález sa tiež týka farmaceutických prostriedkov, ktoré obsahujú tieto zlúčeniny ako aktívne látky.The invention relates to 1-ar (alk) ylimidazolin-2-ones containing a disubstituted amine residue at the 4-position, to methods for their preparation and to their use for the treatment of central nervous system disorders, in particular various forms of epilepsy. The invention also relates to pharmaceutical compositions comprising these compounds as active substances.

Doterajší stav techniky l-Ar(alk)ylimidazolín-2-óny s nesubstituovaným amínovým alebo metylamínovým zvyškom v polohe 4 sa pripravujú podľa doterajšieho stavu techniky reakciou 1-ar(alk)yliminoacetamidov s brómkyánom. N-alkyláciou 4-amino l-ar(alk)ylimidazolín-2-ónov, pripravovaných týmto spôsobom, sa získajú 3-alkyl- alebo l-iminoalkyl-3-alkyl-l-ar(alk)ylimidazolín-2-óny pri tautomerizácii aminoskupiny na iminoskupinu v polohe 4. Ďalšia N-alkylácia vedúca ku zlúčeninám so všeobecným vzorcom (1) teda nie je možná, takže zlúčeniny podľa tohto vynálezu sa nemôžu týmto spôsobom pripravovať [USP 4 044 021, DE 2 251 354], l-Ar(alk)ylimidazolín-2-óny s disubstituovaným amínovým zvyškom v polohe 4 dosiaľ neboli opísané.BACKGROUND OF THE INVENTION 1-Ar (alk) ylimidazolin-2-ones with an unsubstituted amine or methylamine residue at the 4-position are prepared according to the prior art by reacting 1-ar (alk) yliminoacetamides with cyanogen bromide. N-alkylation of 4-amino 1-ar (alk) ylimidazolin-2-ones prepared by this method affords 3-alkyl- or 1-iminoalkyl-3-alkyl-1-ar (alk) ylimidazolin-2-ones by tautomerization Thus, further N-alkylation leading to the compounds of formula (1) is not possible, so that the compounds of the present invention cannot be prepared in this way [US 4 044 021, DE 2 251 354], 1-Ar (alk) ylimidazolin-2-ones with a disubstituted amine residue at the 4-position have not been described.

Je známy veľký počet zlúčenín s antikonvulzívnou aktivitou. V podstate ani dnes nemôžu byť všetky formy epilepsie uspokojivo liečené.A large number of compounds with anticonvulsant activity are known. In fact, even today, all forms of epilepsy cannot be treated satisfactorily.

Podstata vynálezuSUMMARY OF THE INVENTION

Vynález sa teda zakladá na vytvorení l-ar(alk)ylimidazolín-2-ónov s výhodnými farmakologickými vlastnosťami, ktoré môžu byť využité napríklad ako látky s antiepileptickou aktivitou.The invention is therefore based on the generation of 1-ar (alk) ylimidazolin-2-ones with advantageous pharmacological properties which can be used, for example, as substances with antiepileptic activity.

Podľa tohto vynálezu týmito zlúčeninami sú l-ar(alk)yIimidazolin-2-óny so všeobecným vzorcom (1)According to the invention, these compounds are 1-ar (alk) ylimidazolin-2-ones of the general formula (1)

kde n je 0 alebo 1, m je 0, 1, 2, 3,4 alebo 5, x znamená atóm vodíka, Cr C4- alkyl, Cr C4- alkoxyskupinu, trifluórmetyl alebo atóm halogénu,wherein n is 0 or 1, m is 0, 1, 2, 3,4 or 5, x is H, C r C 4 - alkyl, C r C 4 - alkoxy, trifluoromethyl or halogen,

R1 a R2 predstavujú C,- C4- alkyl, cykloalkyl alebo heteroalkyl, pričom alkylová skupina obsahuje vždy 5 až 7 atómov uhlíka, aleboR 1 and R 2 are C 1 -C 4 -alkyl, cycloalkyl or heteroalkyl, each alkyl having 5 to 7 carbon atoms, or

R1 a R2 tvoria dohromady alkylénová skupinu s 2 až 6 atómami uhlíka, kde -CH2- skupina môže byť nahradená kyslíkom, dusíkom alebo sírou.R 1 and R 2 together form an alkylene group having 2 to 6 carbon atoms, wherein the -CH 2 - group may be replaced by oxygen, nitrogen or sulfur.

Počet CH2 skupín je buď 0(l-arylimidazolín-2-óny), alebo 1 (1 -aralkylimidazolín-2-óny).The number of CH 2 groups is either 0 (1-aryllimidazolin-2-ones) or 1 (1-aralkylimidazolin-2-ones).

Príklady 1-ar(alk)ylimidazolín-2-ónov so všeobecným vzorcom (1), ktoré je možné uviesť, sú: l-fenyl-4-morfolinoimidazolm-2-ón, l-(4-metoxy)-4-piperidínoimidazolín-2-ón, l-(4-chlórfenyl)-4-morfolinoimidazolín-2-ón, l-(4-chlórfenyl)-4-piperidínoimidazolín-2-ón, l-(4-chlórfenyl)-4-dimetylamínoimidazolín-2-ón, l-(4-brómfenyl)-4-morfolinoimidazolín-2-ón, l-(3-chlórfenyl)-4-morfolinoimidazolin-2-ón, l-(4-chlórfenyl)-4-hexametyléniminoimidazolín-2-ón, l-(4-chlórfenyl)-4-(metylpiperazíno)imidazolín-2-ón, l-(4-metylfenyl)-4-morfolinoimidazolín-2-ón, l-(4-chlórrfenyl)-4-(cyklohexylmetylamíno)imidazolín-2-ón,Examples of 1-ar (alk) ylimidazolin-2-ones of general formula (1) which may be mentioned are: 1-phenyl-4-morpholinoimidazol-2-one, 1- (4-methoxy) -4-piperidinoimidazoline- 2-one, 1- (4-chlorophenyl) -4-morpholinoimidazolin-2-one, 1- (4-chlorophenyl) -4-piperidinoimidazolin-2-one, 1- (4-chlorophenyl) -4-dimethylaminoimidazolin-2- one, 1- (4-bromophenyl) -4-morpholinoimidazolin-2-one, 1- (3-chlorophenyl) -4-morpholinoimidazolin-2-one, 1- (4-chlorophenyl) -4-hexamethyleniminoimidazolin-2-one, 1- (4-chlorophenyl) -4- (methylpiperazino) imidazolin-2-one, 1- (4-methylphenyl) -4-morpholinoimidazolin-2-one, 1- (4-chlorophenyl) -4- (cyclohexylmethylamino) imidazoline- 2-one,

-(4-fluórfenyl)-4-morfolinoimidazolín-2-ón a l-benzyl-4-morfolinoimidazolín-2-ón.- (4-fluorophenyl) -4-morpholinoimidazolin-2-one and 1-benzyl-4-morpholinoimidazolin-2-one.

Podľa tohto vynálezu sa môžu zlúčeniny so všeobecným vzorcom (1) pripravovať novým spôsobom prípravy, reakciou zlúčenín so všeobecným vzorcom (2)According to the invention, the compounds of the general formula (1) can be prepared by a new method of preparation, by reacting the compounds of the general formula (2)

kde n je 0 alebo 1, m je 0,1,2,3, 4 alebo 5, x znamená atóm vodíka, CrC4-alkyl, CrC4-alkoxyskupinu, trifluórmetyl alebo atóm halogénu, so sekundárnym amínom.wherein n is 0 or 1, m is 0,1,2,3, 4, or 5, x is H, C r C 4 -alkyl, C r C 4 -alkoxy, trifluoromethyl or halogen, with a secondary amine.

Príprava zlúčenín so vzorcom (1) sa môže inak uskutočniť v rozpúšťadle alebo v nadbytku sekundárneho amínu pri teplotách medzi 50 °C a 160 °C. Vhodné rozpúšťadlá sú predovšetkým aromatické uhľovodíky, napríklad benzén, toluén, chlórbenzén alebo dichlórbenzén.Alternatively, the preparation of compounds of formula (1) may be carried out in a solvent or in an excess of the secondary amine at temperatures between 50 ° C and 160 ° C. Suitable solvents are, in particular, aromatic hydrocarbons, for example benzene, toluene, chlorobenzene or dichlorobenzene.

Reakcia sa predovšetkým uskutočňuje v prítomnosti látok viažucich vodu, ako zeolitov alebo síranu sodného. Reakcia môže byť urýchlená pridaním všeobecne užívaného katalyzátora kondenzácie, ako je 4 - toluénsulfónová kyselina.In particular, the reaction is carried out in the presence of water binders, such as zeolites or sodium sulfate. The reaction may be accelerated by the addition of a commonly used condensation catalyst such as 4-toluenesulfonic acid.

Zlúčeniny podľa vynálezu sú vhodné na prípravu farmaceutických prostriedkov. Farmaceutické prostriedky môžu obsahovať jednu alebo viacero zlúčenín podľa vynálezu. Na prípravu farmaceutických prostriedkov sa môžu použiť zvyčajné farmaceutické excipienty a pomocné látky.The compounds of the invention are suitable for the preparation of pharmaceutical compositions. The pharmaceutical compositions may contain one or more compounds of the invention. Conventional pharmaceutical excipients and excipients may be used to prepare the pharmaceutical compositions.

Lieky vhodné na podávanie sa môžu pripravovať spôsobmi, ktoré sú všeobecne známe a zvyčajné vo farmaceutickej praxi.Medicaments suitable for administration may be prepared by methods well known and customary in pharmaceutical practice.

Zlúčeniny podľa vynálezu majú výrazný antikonvulzívny účinok.The compounds of the invention have a pronounced anticonvulsant effect.

Pre svoj antikonvulzívny účinok boli testované in vivo po i. p. (interperitoneálnom) podaní myšiam alebo krysám (p .o. - perorálne podanie), podľa medzinárodne zvyčajného štandardu (Pharmac. Weekblad, Sc. Ed. 14. 132 (1992) a Antiepileptic Drugs, 3. Vyd., Raven Press, New York (1989) (tabuľka 1)).Because of their anticonvulsant effect, they were tested in vivo after i. p. (interperitoneal) administration to mice or rats (p.o. - oral administration), according to an international standard (Pharmac. Weekblad, Sc. Ed. 14, 132 (1992) and Antiepileptic Drugs, 3rd Ed., Raven Press, New York) (1989) (Table 1)).

Napríklad pre zlúčeninu 2, (l-(4-chlórfenyl)-4-morfolinoimidazolín-2-on) pri kryse bola stanovená dávka ED50 (p.o) pre maximálny elektrošok 21 mg/kg, ED50 v s.c. penterazolovom teste bola stanovená 16 mg/kg a NT50 pre neurotoxicitu bola stanovená > 400 mg/kg. V porovnaní s tým sú známe antiepileptiká účinné v maximálnom elektrošokovom modeli alebo v pentetrazolovom teste, alebo, v prípade relatívne vysokej aktivity, sú silne neurotoxické v PTZ teste.For example, for compound 2, (1- (4-chlorophenyl) -4-morpholinoimidazolin-2-one) in the rat, the ED 50 (po) dose was determined for a maximum electroshock of 21 mg / kg, the ED 50 in the sc penterazole assay was 16 mg / kg and NT 50 for neurotoxicity were determined to be> 400 mg / kg. In contrast, the known antiepileptic drugs are effective in the maximum electroshock model or in the pentetrazole assay, or, in the case of relatively high activity, are highly neurotoxic in the PTZ assay.

Tabuľka 1Table 1

zlúčenina podľa pr. the compound of Ex. Log p Log p T5StJ) T5St J) Dávka4'Batch 4 ' Účinnosť” efficacy " 1 1 MES MES 100 100 30 30 0, 64 0, 64 PTZ PTZ 100 100 30 30 2 2 MES MES 300 300 30 30 1, 48 1, 48 PTZ PTZ 30 30 70 70 3 3 MES MES 100 100 1CC 1CC 2,29 2.29 PTZ PTZ 100 100 100 100 4 4 MES MES 300 300 30 30 0, 4Θ 0, 4Θ PTZ PTZ 300 300 30 30

zlúčenina podľa pr. the compound of Ex. Log p'1 Log p ' 1 Test3'Test 3 ' Dávka*' * Dose ' Účinnosť51 efficiency 51 b b MES MES 300 300 100 100 1, 61 1, 61 PTZ PTZ 100 100 20 20 7 7 MES MES 300 300 100 100 1,53 1.53 PTZ PTZ 100 100 100 100 8 8 MES MES 300 300 30 30 1,45 1.45 ?TZ ? TZ 100 100 100 100 9 9 MES MES 100 100 30 30 0, 97 0, 97 PTZ PTZ 100 100 100 100 10 10 MES MES 300 300 10 10 1,26 1.26 PTZ PTZ 300 300 70 70 11 11 MES MES 300 300 100 100 2, 56 2, 56 PTZ PTZ 300 300 40 40

Porovnávacia látka Reference substance Test11 Test 11 Dávka*' * Dose ' Účinnosť51 efficiency 51 Karbamazepín carbamazepine MES MES 100 100 100 100 PTZ PTZ 100 100 0 0 VaLproat valproate MES MES 100 100 0 0 PTZ PTZ 100 100 30 30

Poznámky k tabuľke 1:Notes to Table 1:

1. Očíslovanie zlúčenín pozri pracovné príklady1. Refer to Working Examples for compound numbering

2. Rozdeľovači koeficient oktanol/voda2. Octanol / water partition coefficient

3. MES = maximálny elektrošok, PTZ = pentetrazol podaný s. c.3. MES = maximum electroshock, PTZ = pentetrazole administered with s. c.

4. v mg/kg4. mg / kg

5. v % ochránených zvierat5. in% of animals protected

Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION

Príprava nových zlúčenín so všeobecným vzorcom (1) bude bližšie vysvetlená prostredníctvom pracovných príkladov.The preparation of the novel compounds of formula (1) will be explained in more detail by way of working examples.

Pracovné príkladyWorking examples

Všeobecný postup prípravy zlúčenín so všeobecným vzorcom (1) podľa tabuľky 1, príklady 1 až 11.General Procedure for the Preparation of Compounds of Formula (1) according to Table 1, Examples 1 to 11.

Variant AVariant A

0,05 mol l-arylimidazolín-2,4-dión so všeobecným vzorcom (2) (n = 0), 200 mg 4-toluénsulfónovej kyseliny sa pridá k 100 ml príslušného sekundárneho amínu. Zmes sa potom zahrieva pod spätným chladičom v Soxhletovom extraktore za predchádzajúceho naplnenia extrakčného nadstavca 25 g vodou - viažucou pevné látky (vhodné sú síran sodno - vápenatý, síran horečnatý, NaOH, KOH, zeolity). Po reakčnom čase od 8 do 30 hodín sa roztok prefiltruje za tepla a destiluje do približne polovičného objemu v rotačnej odparke. Číry roztok sa ochladí ľadovým kúpeľom a získaná kryštalická zmes sa oddelí od amínu. Východisková látka obsiahnutá v surovom produkte sa extrahuje 50 ml horúceho acetónu. Produkt sa rekryštalizuje z n-propanolu.0.05 mol of 1-arylimidazoline-2,4-dione of general formula (2) (n = 0), 200 mg of 4-toluenesulfonic acid are added to 100 ml of the corresponding secondary amine. The mixture is then heated to reflux in a Soxhlet extractor with a pre-charge of 25 g of water-binding solids (extraction is sodium-calcium sulfate, magnesium sulfate, NaOH, KOH, zeolites). After a reaction time of 8 to 30 hours, the solution is filtered hot and distilled to approximately half the volume in a rotary evaporator. The clear solution was cooled with an ice bath and the resulting crystalline mixture was separated from the amine. The starting material contained in the crude product is extracted with 50 ml of hot acetone. The product is recrystallized from n-propanol.

Z neoddeleného amínu sa môže znovu získať okolo 0,02 mol nezreagovaného l-arylimidazolín-2,4-diónu.From the non-separated amine, about 0.02 mol of unreacted 1-aryllimidazoline-2,4-dione can be recovered.

Variant BVariant B

0,05 mol l-aralkylimidazolín-2,4-dión so všeobecným vzorcom (2) (n - 1) sa nechá reagovať so sekundárnym amínom, ako je opísané pod A. Po reakčnom čase od 8 do 30 hodín sa roztok za tepla prefiltruje, a potom sa odparí do sucha v rotačnej odparke. K odparku látke sa pridá 50 ml dichlórmetánu a 50 ml 2N (mol/1) HC1. Organická fáza sa oddelí a vodná fáza ešte dvakrát extrahuje dichlórmetánom. Izolovaná vodná fáza sa alkalizuje 50 ml 10 % NaOH a 10.05 mol of 1-aralkylimidazoline-2,4-dione of formula (2) (n-1) is reacted with a secondary amine as described under A. After a reaction time of 8 to 30 hours, the solution is filtered hot. and then evaporated to dryness in a rotary evaporator. To the residue was added 50 mL of dichloromethane and 50 mL of 2N (mol / L) HCl. The organic phase is separated and the aqueous phase is extracted twice more with dichloromethane. The isolated aqueous phase is basified with 50 ml of 10% NaOH and 1

-4-amino-l-aralkylimidazolín-2-ón sa extrahuje 100 ml dichlórmetánu. Esterové extrakty sa sušia síranom sodným. Po oddestilovaní dichlórmetánu sa surový produkt rekryštalizuje z etanolu alebo acetónu.The 4-amino-1-aralkylimidazolin-2-one is extracted with 100 ml of dichloromethane. The ester extracts were dried over sodium sulfate. After distilling off the dichloromethane, the crude product is recrystallized from ethanol or acetone.

Variant CVariant C

0,05 mol 1 -ar(alk)ylimidazolín-2,4-diónu so všeobecným vzorcom (2) sa nechá reagovať so 100 ml dimetylamónium dimetylkarbamátu, ako je opísané pod A a B. Po reakčnom čase 40 hodín sa zmes spracuje podľa varianty A alebo B.0.05 mol of 1-ar (alk) ylimidazoline-2,4-dione of formula (2) is reacted with 100 ml of dimethylammonium dimethylcarbamate as described under A and B. After a reaction time of 40 hours, the mixture is worked up according to variant A or B.

Tabuľka 2 r’Table 2 '

Pr. . Pr. . R1 R 1 R2 R 2 Var boiling Reakčný čas(hod) Response time (hours) Tepl. top .PC) Temp. top .PC) Výťažok (%) yield (%) 1 1 -Ό -Ό —\ /° - \ / ° A A í5 i 5 248 248 42 1)42 1 ) 2 2 Z-\ — N OZ - \ - NO A A 15 15 266 266 75 1) 75 1) 3 3 O ABOUT -Ό -Ό A A 20 20 248 248 60 Ί 60 Ί 4 4 r~\ — N O r ~ - N O B B 15 15 168 168 48 48 5 5 f~\ —W N-CH, W f ~ \ —W N-CH, W A A 12 12 254 254 68 ’) 68 ’) 6 6 čFiJ — N CH, čFiJ - N CH, C C 40 40 292 292 13 13 7 7 -O-*. -ABOUT-*. I ,0 I 0 A A 30 30 190 190 8 8 -o -about r~\ —N O r ~ \ —N O A A 15 15 268 268 65 1)65 1 ) 9 9 /—\ — N O V/ / - \ - N O IN/ A A 18 18 255 255 54 1>54 1 > 10 10 Cl Cl —N O —N O B B 30 30 23? 23? 27 27 I O I ABOUT A A 6 6 216 216 6B 1)6B 1 )

1,1 pri počítaní výťažku sa započítali opätovne získané východiskové materiály 1.1 , the recovered starting materials were included in the yield calculation

Claims (7)

1. 1 -Ar(alk)ylimidazolín-2-ón všeobecného vzorca (1) kde n je 0 alebo 1, mje 0,1,2,3,4 alebo 5,A 1-Ar (alk) ylimidazolin-2-one of the general formula (1) wherein n is 0 or 1, m is 0,1,2,3,4 or 5, X znamená atóm vodíka, C1-C4-alkyl, CrC4-alkoxyskupinu, trifluórmetyl alebo atóm halogénu,X is H, C 1 -C 4 alkyl, C r C 4 -alkoxy, trifluoromethyl or halogen, R1 a R2 znamenajú CrC4-alkyl, cykloalkyl alebo heteroalkyl, pričom alkylová skupina obsahuje vždy 5 až 7 atómov uhlíka, aleboR 1 and R 2 denote C r C 4 -alkyl, cycloalkyl or heteroalkyl, wherein each alkyl group has 5-7 carbon atoms, or R1 a R2 tvoria spolu alkylénovú skupinu s 2 až 6 atómami uhlíka, kde -CH2- skupina môže byť nahradená kyslíkom, dusíkom alebo sírou.R 1 and R 2 together form an alkylene group having 2 to 6 carbon atoms, wherein the -CH 2 - group may be replaced by oxygen, nitrogen or sulfur. 2. l-Ar(alk)ylimidazolín-2-ón podľa nároku 1, ktorým je l-fenyl-4-morfolinoimidazolín-2-ón, l-(4-metoxy)-4-piperidinoimidazolín-2-ón, l-(4-chlórfcnyl)-4-morfolinoimidazolín-2-ón, l-(4-chlórfeny1)-4-piperidinoimidazolín-2-ón, l-(4-chlórfenyl)-4-dimetylaminoimidazolín-2-ón, l-(4-brómfenyI)-4-morfolinoimidazolín-2-ón, l-(3-chlórfenyI)-4-morfolinoirnidazolín-2-ón, l-(4-chlórfenyl)-4-hexametyléniminoimidazolín-2-ón, l-(4-chlórfenyl)-4-(metylpiperazino)imidazolín-2-ón, l-(4-metylfenyl)-4-morfolinoimidazolin-2-ón, l-(4-chlórfenyl)-4-(cyklohexylmetylamino)imidazolín-2-ón,1-Ar (alk) ylimidazolin-2-one according to claim 1, which is 1-phenyl-4-morpholinoimidazolin-2-one, 1- (4-methoxy) -4-piperidinoimidazolin-2-one, 1 - ( 4-chlorophenyl) -4-morpholinoimidazolin-2-one, 1- (4-chlorophenyl) -4-piperidinoimidazolin-2-one, 1- (4-chlorophenyl) -4-dimethylaminoimidazolin-2-one, 1- (4- bromophenyl) -4-morpholinoimidazolin-2-one, 1- (3-chlorophenyl) -4-morpholinoimidazolin-2-one, 1- (4-chlorophenyl) -4-hexamethyleniminoimidazolin-2-one, 1- (4-chlorophenyl) -4- (methylpiperazino) imidazolin-2-one, 1- (4-methylphenyl) -4-morpholinoimidazolin-2-one, 1- (4-chlorophenyl) -4- (cyclohexylmethylamino) imidazolin-2-one, 1 -(4-fluórfenyl)-4-morfolinoimidazolín-2-ón alebo l-benzyl-4-morfolinoimidazolín-2-ón.1- (4-fluorophenyl) -4-morpholinoimidazolin-2-one or 1-benzyl-4-morpholinoimidazolin-2-one. 3. Spôsob prípravy 1-ar(alk)ylimidazolín-2-ónu všeobecného vzorca (1), vyznačujúci sa tým, že sa zlúčenina všeobecného vzorca (2)A process for the preparation of 1-ar (alk) ylimidazolin-2-one of formula (1), characterized in that the compound of formula (2) is H kdeH where X znamená atóm vodíka, Ct-C4-alkyl, CrC4-alkoxyskupinu, trifluórmetyl alebo atóm halogénu, nechá reagovať so sekundárnym amínom všeobecného vzorca HNR’R2, kde R1 a R2 majú uvedený význam, pri teplote od 50 °C do 160 °C.X is H, C t -C 4 alkyl, C r C 4 -alkoxy, trifluoromethyl or halogen, is reacted with a secondary amine of the formula HNR 2, where R 1 and R 2 are as defined above, at from 50 ° C to 160 ° C. 4. Farmaceutický prostriedok, vyznačujúci sa tým, že ako aktívnu látku obsahuje aspoň jeden 1-ar(alk)ylimidazolín-2-ón všeobecného vzorca (1) a pripadne farmaceutické excipienty a pomocné látky.Pharmaceutical composition, characterized in that it contains as active substance at least one 1-ar (alk) ylimidazolin-2-one of the general formula (1) and optionally pharmaceutical excipients and auxiliaries. 5. Farmaceutický prostriedok podľa nároku 4, v y značujúci sa tým, že ako aktívnu látku obsahuje aspoň jeden z l-ar(alk)ylimidazolín-2-ónov podľa nároku 2.Pharmaceutical composition according to claim 4, characterized in that it contains at least one of 1-ar (alk) ylimidazolin-2-ones as active substance according to claim 2. 6. Použitie 1 -ar(alk)ylimidazolin-2-ónu všeobecného vzorca (1) na výrobu liečiva na ošetrovanie epileptických porúch.Use of 1-ar (alk) ylimidazolin-2-one of formula (1) for the manufacture of a medicament for the treatment of epileptic disorders. 7. Použitie l-ar(alk)ylimidazolín-2-ónu podľa nároku 2 na výrobu liečiva na ošetrovanie epileptických porúch.Use of 1-ar (alk) ylimidazolin-2-one according to claim 2 for the manufacture of a medicament for the treatment of epileptic disorders.
SK216-98A 1995-09-05 1996-07-26 1-Ar(alk)yl-imidazolin-2-ones, process for their production, use of them and pharmaceutical composition containing them SK284868B6 (en)

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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

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