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BG63917B1 - 1-ar(alk)yl-imidazolin-2-ones with disubstituted amine residue in the 4th place, with anti-convulsive effect and method for their preparation - Google Patents

1-ar(alk)yl-imidazolin-2-ones with disubstituted amine residue in the 4th place, with anti-convulsive effect and method for their preparation Download PDF

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BG63917B1
BG63917B1 BG102287A BG10228798A BG63917B1 BG 63917 B1 BG63917 B1 BG 63917B1 BG 102287 A BG102287 A BG 102287A BG 10228798 A BG10228798 A BG 10228798A BG 63917 B1 BG63917 B1 BG 63917B1
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imidazolin
morpholino
chlorophenyl
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alk
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Hans-Joachim Lankau
Manfred Menzer
Klaus Unverferth
Karl Gewald
Harry Schaefer
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Arzneimittelwerk Dresden Gmbh
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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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    • 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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Abstract

The compounds demonstrate anti-convulsive effect. The new 1-ar(alk)yl-imidazolin-2-diones have the general formula wherein X means halogen, C1-4 alkyl or C1-4 alkoxy group, n has the value of 0 or 1, and m is 0 or 1, R is a morpholine, piperidine, methylpiperazine residue, hexamethyleneamino group, dimethylamine or cyclohexyl methylamine group. 7 claims

Description

Област на техникатаTechnical field

Изобретението се отнася до 1-ар(алк)ил- 10 имидазолин-2-они, които съдържат на четвърто място дизаместен аминов остатък, метод за тяхното получаване и използването им като фармацевтични средства за лечение на заболявания на централната нервна система, по- 15 специално на различни форми на епилепсия.The invention relates to 1-ar (alk) yl-10-imidazolin-2-ones, which contain a fourth disubstituted amine residue, a method for their preparation and their use as pharmaceuticals for the treatment of diseases of the central nervous system, especially of various forms of epilepsy.

Предшестващо състояние на техникатаBACKGROUND OF THE INVENTION

1-ар(алк)ил-имидазалин-2-онис незамес- 20 тен аминов остатък или метиламинов остатък на 4-място се получават съгласно предшестващото ниво на техниката чрез взаимодействие на ар (алк) иламиноацетамиди с бромоциан. Чрез N-алкилиране на така получените 4-амино-1- 25 ар(алк)ил-имидазолин-2-они се получават 3-алкилили 1-иминоалкил-3-алкил-1-ар(алк) ил-имвдазолин-2-они, при което аминогрупата в 4 място се превръща в тавтомерната иминогрупа. Понататъшно N-алкилиране до съединения с об- 30 ща формула I поради това не е възможно, така че съединенията съгласно изобретението не могат да се получат по този метод [USP 4044021; DE 225 1354].1-ar (alk) yl-imidazalin-2-oneis unsubstituted amine moiety or methylamine moiety in 4-position was prepared according to the prior art by reacting a? (Alk) ylaminoacetamides with bromocyanine. N-alkylation of the 4-amino-1- 25 ar (alk) yl-imidazolin-2-one thus obtained yields 3-alkylily 1-iminoalkyl-3-alkyl-1-ar (alk) yl-imvdazolin-2- they, in which the amino group in the 4th place becomes the tautomeric amino group. Further N-alkylation to compounds of general formula I is therefore not possible, so that the compounds of the invention cannot be prepared by this method [USP 4044021; DE 225 1354].

1-ар(алк)ил-имидазолин-2-онисдизамес- 35 тен аминов остатък на четвъртото място досега не са описани.The 1-ar (alk) yl-imidazolin-2-one disubstituted amine residue in the fourth position has not been described so far.

Известни са много съединения с антиконвулсивно действие. До днес обаче не могат да се лекуват задоволително всички епилеп- 40 тични заболявания.Many compounds with anticonvulsant activity are known. However, to date, not all epileptic diseases can be treated satisfactorily.

Задача на настоящото изобретение е да се създадат нови съединения със задоволителни фармакологични свойства, които могат да се използват като антиепилептично действащи 45 лекарствени средства.It is an object of the present invention to provide novel compounds with satisfactory pharmacological properties that can be used as anti-epileptically acting 45 drugs.

Техническа същност на изобретениетоSUMMARY OF THE INVENTION

Съгласно изобретението тези нови съе- 50 динения са 1-ар(алк)ил-имидазолин-2-они с обща формула IAccording to the invention, these new compounds are 1-ar (alk) yl-imidazolin-2-ones of general formula I

(I) в която:(I) in which:

X означава халоген, Смалкил или С14 алкоксигрупа;X represents halogen, C 1-4 alkyl or C 14 alkoxy;

η означава 0 или 1;η is 0 or 1;

ш означава 0 или 1;y is 0 or 1;

R означава морфолинов, пиперидинов, метилпиперазинов остатък, хексаметиленимино група, диметиламинова или циклохексилметиламинова група.R represents a morpholine, piperidine, methylpiperazine residue, hexamethyleneimino group, dimethylamine or cyclohexylmethylamine group.

Като примери на съединения с обща формула I могат да се посочат.Examples of compounds of general formula I may be cited.

-фенил-4-морфолино-имидазолин-2-он;-phenyl-4-morpholino-imidazolin-2-one;

- (4-метоксифенил) -4-пиперидино-имидазолин-2-он;- (4-methoxyphenyl) -4-piperidino-imidazolin-2-one;

- (4-хлорофенил) -4-морфолино-имидазолин-2-он;- (4-chlorophenyl) -4-morpholino-imidazolin-2-one;

- (4-хлорофенил) -4-пиперидино-имидазолин-2-он;- (4-chlorophenyl) -4-piperidino-imidazolin-2-one;

- (4-хлорофенил) -4-диметиламино-имидазолин-2-он;- (4-chlorophenyl) -4-dimethylamino-imidazolin-2-one;

- (4-бромофенил) -4-морфолино-имидазолин-2-он;- (4-bromophenyl) -4-morpholino-imidazolin-2-one;

- (3-хлорофенил) -4-морфолино-имидазолин-2-он;- (3-chlorophenyl) -4-morpholino-imidazolin-2-one;

- (4-хлорофенил) -4-хексаметиленаминоимидазолин-2-он;- (4-chlorophenyl) -4-hexamethyleneaminoimidazolin-2-one;

- (4-хлорофенил) -4- (4-метилпиперазино) -имидазолин-2-он;- (4-chlorophenyl) -4- (4-methylpiperazino) -imidazolin-2-one;

- (4-метилфенил) -4-морфолино-имидазолин-2-он;- (4-methylphenyl) -4-morpholino-imidazolin-2-one;

- (4-хлорофенил) -4- (циклохексил-метиламино) -имидазолин-2-он;- (4-chlorophenyl) -4- (cyclohexyl-methylamino) -imidazolin-2-one;

- (4-флуорофенил) -4-морлфолино-имидазолин-2-он;- (4-fluorophenyl) -4-morpholino-imidazolin-2-one;

-бензил-4-морфолино-имидазолин-2-он. Съгласно изобретението съединенията с обща формула I се получават от съединения с обща формула II-benzyl-4-morpholino-imidazolin-2-one. According to the invention, the compounds of general formula I are prepared from compounds of general formula II

в която:wherein:

X означава халоген, Смалкил или См алкокси група;X stands for halogen, C 1-4 alkyl or C 1-4 alkoxy;

η означава 0 или 1;η is 0 or 1;

m означава 0 или 1;m is 0 or 1;

с вторичен амин RH, при което R има посочените по-горе значения.with a secondary amine RH, wherein R has the meanings indicated above.

Получаването на съединенията с обща формула I може да се осъществи по избор в 5 разтворител или в излишък от вторичния амин, при температури между 50°С и 160°С. Като разтворители се имат предвид за предпочитане ароматни въглеводороди например бензен, толуен, хлоробензен или дихлоробензен.The preparation of the compounds of general formula I can be carried out optionally in 5 solvent or in excess of the secondary amine at temperatures between 50 ° C and 160 ° C. Preferably, solvents are aromatic hydrocarbons, for example benzene, toluene, chlorobenzene or dichlorobenzene.

За предпочитане се работи в присъствие на свързващи водата средства като зеолити или натриев сулфат. Реакцията може да бъде ускорена чрез прибавяне на обичайни за кондензация катализатори като 4-толуенсулфонова киселина.Preferably, it is present in the presence of water binders such as zeolites or sodium sulfate. The reaction can be accelerated by the addition of conventional condensation catalysts such as 4-toluenesulfonic acid.

Съединенията съгласно настоящото изобретение са подходящи за приготвяне на фармацевтични състави.The compounds of the present invention are suitable for the preparation of pharmaceutical compositions.

Фармацевтичните състави могат да съдържат едно или повече от съединенията съгласно изобретението. За приготвянето или фармацевтичните препарати могат да се използват обичайни фармацевтични носители и помощни вещества.The pharmaceutical compositions may contain one or more of the compounds of the invention. Conventional pharmaceutical carriers and excipients may be used for the preparation or pharmaceutical preparations.

Лекарствените средства могат да се прилагат парентерално (например венозно, мускулно, подкожно) или орално.The drugs may be administered parenterally (eg, intravenously, intramuscularly, subcutaneously) or orally.

Формите за приложение могат да се приготвят съгласно общоизвестни и обичайни във фармацевтичната практика методи.Formulations for administration may be prepared according to conventional and conventional pharmaceutical methods.

Съединенията съгласно изобретението показват силно антиконвулсивно действие.The compounds of the invention exhibit a strong anticonvulsant activity.

Те се изпитват за антиконвулсивно дей10 ствие in vivo, след i.p. приложение на мишки или на плъхове (р.о. прилагане), по обичайни международни стандарти (Pharm. Weekblad, Sc.Ed. 14,132 (1992) и Antiepileptic Drugs, Third Ed., Raven Press, New York 1989) Таблица 1.They are tested for anticonvulsant activity in vivo after i.p. administration of mice or rats (p.o. administration), by conventional international standards (Pharm. Weekblad, Sc.Ed. 14,132 (1992) and Antiepileptic Drugs, Third Ed., Raven Press, New York 1989) Table 1.

Например, за съединението 2 (1-(4-хлорофенил)-4-морфолино-имидазолин-2-он) се определя при плъхове, за максимален електрошок, EDM (р.о.) 21 mg/kg, при s.c. пентетразолов тест EDJ0 е 16 mg/kg и за невротоксич20 ност NTJ0 е > 400 mg/kg. В сравнение с това, познатите антиепилептици, които действат или при модела на максимален електрошок, или при пентетразолов тест, или при по-силно действие в пентетразолов тест, са силно невротоксични.For example, for compound 2 (1- (4-chlorophenyl) -4-morpholino-imidazolin-2-one) was determined in rats, for maximum electroshock, ED M (p.o.) 21 mg / kg, for the pentetrazole test ED J0 is 16 mg / kg and for neurotoxicity NT J0 is> 400 mg / kg. In comparison, known anti-epileptics, which act in either the maximal electroshock model, or the pentetrazole test, or more potently in the pentetrazole test, are highly neurotoxic.

Таблица 1.Table 1.

Съединение съгл. пример Compound acc. an example log Р*1 log P * 1 о№— oh Доза*’ Dose * ' Действие01 Action 01 MES MES 100 100 30 30 1 1 0,64 0.64 PTZ PTZ 100 100 30 30 MES MES 300 300 30 30 2 2 1,48 1.48 PTZ PTZ 30 30 70 70 MES MES 100 100 100 100 3 3 2,29 2.29 PTZ PTZ 100 100 100 100 MES MES 300 300 30 30 4 4 0,48 0.48 PTZ PTZ 300 300 30 30 MES MES 300 300 100 100 5 5 2,17 2.17 PTZ PTZ 300 300 100 100 MES MES 300 300 100 100 6 6 1,61 1.61 PTZ PTZ 100 100 20 20 MES MES 300 300 300 300 7 7 1,53 1.53 PTZ PTZ 100 100 100 100 MES MES 300 300 30 30 8 8 1,45 1.45 PTZ PTZ 100 100 100 100 MES MES 100 100 30 30 9 9 0,97 0.97 PTZ PTZ 100 100 100 100 MES MES 300 300 10 10 10 10 1,28 1,28 PTZ PTZ 300 300 70 70 MES MES 300 300 100 100 11 11 2,56 2.56 PTZ PTZ 300 300 40 40

Субстанция за сравнение Comparison substance Опит3’Experience 3 ' Доза*’ Dose * ' Действие9'Action 9 ' MES MES 100 100 100 100 Карбамазепин Carbamazepine PTZ PTZ 100 100 0 0 MES MES 100 100 о Fr. Валпроат Valproate PTZ PTZ 100 100 ί 30 ί 30

Забележка към таблица 1:Note to Table 1:

1) Номериране на съединенията в примерите за изпълнение1) Numbering of the compounds in the embodiments

2) Коефициент на разпределение етанол/ вода2) Ethanol / water partition coefficient

3) Мишки i.p.: MES = максимален електрошок,3) Mice i.p .: MES = maximum electroshock,

PTZ = s.c. пентетразолPTZ = s.c. pentetrazole

4) в mg/kg4) in mg / kg

5) в % от защитените животни5) in% of protected animals

Примери за изпълнение на изобретениетоExamples of carrying out the invention

Получаването на новите съединения с обща формула I се изяснява по-добре въз основа на примерите за изпълнение.The preparation of the new compounds of general formula I is better elucidated based on embodiments.

Обща методика за получаването на съединенията с формула I съгласно таблица 1, примери 1-11.General procedure for the preparation of the compounds of formula I according to Table 1, Examples 1-11.

Вариант АOption A

0,05 mol 1-арил-имидазолин-2,4-дион с обща формула II (п=О) и 200 mg 4-толуенсулфонова киселина се прибавят към 100 ml съответен вторичен амин. След това се нагрява под обратен хладник в Сокслет-екстрактор, при което екстракционната гилза е напълнена предварително с около 25 g свързващо водата твърдо вещество (подходящи са калц. натриев сулфат, магнезиев сулфат, NaOH, КОН, зеолит). След 8 до 30 h реакционно време разтворът се филтрира на горещо и на ротационен изпарител се дестилира до около половината от обе10 ма. Бистрият разтвор се охлажда на ледена баня и изпадащата кристална каша се отделя от амина. Полученото като суров продукт изходно вещество се екстрахира с 50 ml горещ ацетон. Продуктът се прекристализира из нормпропанол.0.05 mol of 1-aryl-imidazoline-2,4-dione of general formula II (n = O) and 200 mg of 4-toluenesulfonic acid are added to 100 ml of the corresponding secondary amine. It is then refluxed in a Soxhlet extractor, whereby the extraction sleeve is pre-filled with about 25 g of a water binder (calcium sulphate, magnesium sulfate, NaOH, KOH, zeolite). After 8 to 30 hours of reaction time, the solution was filtered hot and the rotary evaporator distilled to about half of both 10 mA. The clear solution was cooled in an ice bath and the resulting crystalline slurry was separated from the amine. The starting material obtained as a crude product was extracted with 50 ml of hot acetone. The product was recrystallized from normpropanol.

От отделения амин може да се получи обратно около 0,02 mol непрореагирал 1-арилимидазолин-2,4-дион.About 0.02 mol of unreacted 1-arylimidazoline-2,4-dione can be recovered from the separated amine.

Вариант В.Option B.

0.05 mol 1-аралкил-имидазолин-2,4-дион с обща формула (II) (η-l) взаимодейства с вторичен амин, както е описано в А. След 8 до 30 h реакционно време разтворът се филтрира на горещо и след това се изпарява до сухо на ротационен изпарител. Към остатъка се прибавят 50 ml метиленхлорид и 50 ml 2N НС1. Органичната фаза се отделя и водната фаза се екстрахира още два пъти с метиленхлорид. Отделената водна фаза се алкализира с 50 ml 10%-ен NaOH и 1-(4-амино)-1-аралил-имидазолин-2-он се екстрахира със 100 ml метиленхлорид. Етерните екстрати се сушат с натриев сулфат. След дестилиране на метиленхлорида суровият продукт се прекристализира из етанол и ацетон.0.05 mol of 1-aralkyl-imidazoline-2,4-dione of general formula (II) (η-1) is reacted with a secondary amine as described in A. After 8 to 30 hours the reaction time is filtered hot and then evaporated to dryness on a rotary evaporator. 50 ml of methylene chloride and 50 ml of 2N HCl were added to the residue. The organic phase was separated and the aqueous phase extracted twice more with methylene chloride. The separated aqueous phase was basified with 50 ml of 10% NaOH and 1- (4-amino) -1-aryl-imidazolin-2-one was extracted with 100 ml of methylene chloride. The ether extracts were dried with sodium sulfate. After distillation of the methylene chloride, the crude product was recrystallized from ethanol and acetone.

Вариант С.Option C.

0,05 mol 1-ар-(алк)ил-имидазолин-2,4-дион с обща формула взаимодейства със 100 ml диметиламониев диметилкарбамат, както е описано в А и В. След 40 h реакционно време се довършва по вариант А или В.0.05 mol of 1-ar- (alk) yl-imidazoline-2,4-dione of the general formula is reacted with 100 ml of dimethylammonium dimethylcarbamate as described in A and B. After 40 hours, the reaction time is completed in option A or B .

Таблица 2.Table 2.

прим. No approx. No η η R R вар. var. pear, време (ч) pear, time (h) Т.Т. (°C) T.T. (° C) добив (%) yield (%) 1 1 -η -η 0 0 —N 0 —N 0 A A 15 15 248 248 ΊΛ ΊΛ 2 2 ~Ο-α ~ Ο- α 0 0 ΓΛ —N 0 \_/ ΓΛ —N 0 \ _ / A A 15 15 266 266 75° 75 ° 3 3 -Ο-01 -Ο -01 0 0 -Ο -Ο A A 20 20 248 248 бб17“bb 17 " 4 4 -Ο -Ο 1 1 -<3° - <3 ° 6 6 15 15 158 158 48 48 5 5 -θ α -θ α 0 0 Λ~\ —Ν^Ν—СН3 Λ ~ \ —Ν ^ Ν — CH 3 A A 12 12 254 254 heF- heF - 6 6 0 0 /СНз “^СНз / CH3 "^ CH3 C C 40 40 292 292 13 13 7 7 -θ-οοπ. -θ-οοπ. 0 0 Ο Ο A A 30 30 190 190 ~52Гг~~ 52 Gg ~ 8 8 -Ό-* -Ό- * 0 0 —N 0 —N 0 A A 15 15 268 268 бв”- bv ” - δ δ -ο -ο 0 0 ΛΑ —N 0 W ΛΑ —N 0 W A A 18 18 255 255 “δΓ “ΔΓ 10 10 0 0 /~\ —N 0 \—/ / ~ \ —N 0 \ - / B B 30 30 237 237 27 27 11 11 O-Cl O- Cl 0 0 Ο I Ο I A A 8 8 216 216 “88^“ "88 ^"

i) регенерираното изходно вещество се взема предвид при изчисляването на добивите 40(i) the recovered starting material is taken into account in the calculation of the yields 40

Claims (5)

Патентни претенцииClaims 1. 1-ар(алк) ил-имидазолин-2-они с об- ща формула I в която:1. 1-ar (alk) yl-imidazolin-2-ones of the general formula I in which: X означава халоген, С14 алкил или С1Ч алкоксигрупа;X represents halogen, C 1-4 alkyl or C 1h alkoxy; η означава 0 или 1;η is 0 or 1; ш означава 0 или 1;y is 0 or 1; R означава морфолинов, пиперидинов, метилпиперазинов остатък, хексаметиленимино група, диметиламинова или циклохексил метиламиновагрупа.R represents a morpholine, piperidine, methylpiperazine residue, hexamethyleneimino group, dimethylamine or cyclohexyl methylamine group. 2. Съединения съгласно претенция 1:Compounds according to claim 1: 1 -фенил -4-морфолино-имидазолин-2-он;1-phenyl-4-morpholino-imidazolin-2-one; 1 - (4-метоксифенил) -4-пиперидино-имидазолин-2-он;1- (4-methoxyphenyl) -4-piperidino-imidazolin-2-one; 1 - (4-хлорофенил) -4-морфолино-имидазолин-2-он;1- (4-chlorophenyl) -4-morpholino-imidazolin-2-one; 1 - (4-хлорофенил) -4-пиперидино-имидазолин-2-он;1- (4-chlorophenyl) -4-piperidino-imidazolin-2-one; 1 - (4-хлорофенил) -4-диметиламино-имидазолин-2-он;1- (4-chlorophenyl) -4-dimethylamino-imidazolin-2-one; 1 - (4-бромофенил) -4-морфолино-имидазолин-2-он;1- (4-bromophenyl) -4-morpholino-imidazolin-2-one; 1 - (3-хлорофенил) -4-морфолино-имидазолин-2-он;1- (3-chlorophenyl) -4-morpholino-imidazolin-2-one; 1 - (4-хлорофенил) -4-хексаметилениминоимидазолин-2-он;1- (4-chlorophenyl) -4-hexamethyleneiminoimidazolin-2-one; 1 - (4-хлорофенил) -4- (4-метилпиперазино) -имидазолин-2-он;1- (4-chlorophenyl) -4- (4-methylpiperazino) -imidazolin-2-one; 1 - (4-метилфенил) -4-морфолино-имидазолин-2-он;1- (4-methylphenyl) -4-morpholino-imidazolin-2-one; 1 - (4-хлорофенил) -4- (циклохексил-метиламино) -имидазолин-2-он;1- (4-chlorophenyl) -4- (cyclohexyl-methylamino) -imidazolin-2-one; 1 - (4-флуорофенил) -4-морфолино-имидазолин-2-он;1- (4-fluorophenyl) -4-morpholino-imidazolin-2-one; 1 -бензил-4-морфолино-имидазолин-2-он.1-Benzyl-4-morpholino-imidazolin-2-one. 3. Метод за получаване на съединения съгласно претенция 1, характеризиращ се с това, че съединения с обща формула II в коятоA method for the preparation of compounds according to claim 1, wherein the compounds of general formula II in which X означава халоген, С14 алкил или С14 алкоксигрупа;X is halogen, C 14 alkyl or C 14 alkoxy; η означава 0 или 1;η is 0 or 1; 5 ш означава 0 или 1;5 is 0 or 1; взаимодействат с вторичен амин с формула RH, в който R има посочените в претенция 1 значения, при температури между 50 и 160°С.is reacted with a secondary amine of formula RH in which R has the meanings given in claim 1 at temperatures between 50 and 160 ° C. 10 4. Фармацевтичен състав, характеризиращ се с това ,че съдържа като активна съставка наймалко едно съединение с формула I и евентуално фармацевтичен носител и помощно средство.4. A pharmaceutical composition comprising at least one compound of formula I as an active ingredient and optionally a pharmaceutical carrier and excipient. 5. Фармацевтичен състав, характеризи15 ращ се с това, че съдържа като активна съставка съединение съгласно претенция 2.A pharmaceutical composition comprising the compound of claim 2 as the active ingredient. 6. Използване на съединение с формула I за приготвяне на лекарствено средство за лечение на епилептични заболявания.Use of a compound of formula I for the preparation of a medicament for the treatment of epileptic diseases. 20 7. Използване на съединение съгласно претенция 2 за приготвяне на лекарствено средство за лечение на епилептични заболявания.Use of a compound according to claim 2 for the preparation of a medicament for the treatment of epileptic diseases.
BG102287A 1995-09-05 1998-02-27 1-ar(alk)yl-imidazolin-2-ones with disubstituted amine residue in the 4th place, with anti-convulsive effect and method for their preparation BG63917B1 (en)

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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

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US20050070537A1 (en) 2002-10-10 2005-03-31 Chris Rundfeldt Use of dihydroimidazolones for the treatment of dogs
BRPI0412512A (en) * 2003-07-11 2006-09-19 Elbion Ag method of treating or preventing central nervous system disorders with compounds having selectivity for the benzodiazepine receptor alpha 3 subunit
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BR112014003061A2 (en) 2011-08-12 2017-02-21 Boehringer Ingelheim Vetmedica Gmbh masked flavor pharmaceutical composition
US9820988B2 (en) 2014-03-24 2017-11-21 Boehringer Ingelheim Vetmedica Gmbh Treatment of epileptic disorders in feline animals
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