SK21698A3 - 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 - Google Patents

Abstract

Compounds with an anti-convulsive effect of general formula (1) in which X = hydrogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, halogen and R<1> or R<2> = C1-C4 alkyl, cycloalkyl or heteroalkyl.

Description

- AR (ALK) YLIMIDAZOLINE - 2 - OONS CONTAINING IN POSITION 4 DISUBSTITUTED AMINE RESIDUE AND METHOD OF PREPARATION

Technical field

The invention relates to 1-ar (alk) ylimidazolin-2-ones containing a disubstituted amine residue at the 4-position, to processes for their preparation and to their use as pharmaceutical compositions for the treatment of central nervous system disorders, in particular various forms of epilepsy.

BACKGROUND OF THE INVENTION

The 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 the 4-amino-1 &apos; (alk) ylimidazolin-2-ones prepared in this way gives 3-alkyl- or 1-iminoalkyl-3-alkyl-1-ar (alk) ylimidazolin-2-ones by tautomerization of the amino group 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],

ar (alk) ylimidazolin-2-ones with a disubstituted amine residue at the 4-position have not been described.

A large number of compounds with anticonvulsant activity are known. In fact, even today, all forms of epilepsy cannot be treated satisfactorily.

SUMMARY OF THE INVENTION

Accordingly, the invention is based on the object of making available novel compounds with advantageous pharmacological properties, which can be used, for example, as substances with antiepileptic activity.

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According to the present invention, these novel compounds are 1-ar (alk) ylimidazolin-2-ones of formula 1

where n is 0 or 1, m is 0, 1, 2, 3, 4 or 5, x is hydrogen, C 1 -C 4 -alkyl, C 1 -C ₄ -alkoxy, trifluoromethyl or halogen,

R ¹ and R ² represent C 1 -C ₄ -alkyl, cycloalkyl or heteroalkyl, each alkyl group having 5 to 7 carbon atoms, or

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.

The number of CH ₂ groups is either 0 (1-aryllimidazolin-2-one) or 1 (1-aralkylimidazolin-2-one).

Examples of compounds of formula 1 that may be mentioned are:

- phenyl-4-morpholinoimidazolin-2-one,

- (4-Methoxy) -4-piperidinoimidazolin-2-one,

- (4-chlorophenyl) -4-morpholinoimidazolin-2-one,

- (4-chlorophenyl) -4-piperidinoimidazolin-2-one,

- (4-chlorophenyl) -4-dimethylaminoimidazolin-2-one,

- (4-bromophenyl) -4-morpholinoimidazolin-2-one,

- (3-chlorophenyl) -4-morpholinoimidazolin-2-one,

- (4-chlorophenyl) -4-hexamethyleniminoimidazolin-2-one,

- (4-chlorophenyl) -4- (methylpiperazino) imidazolin-2-one,

- (4-methylphenyl) -4-morpholinoimidazolin-2-one,

- (4-chlorophenyl) -4- (cyclohexylmethylamino) imidazolin-2-one,

- (4 - fluorophenyl) -4 - morpholinoimidazolin - 2 - one a

- benzyl - 4 - morpholinoimidazolin - 2 - one.

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According to the present invention, compounds of formula 1 can be prepared by a novel method of preparation, by reacting compounds of formula 2

H wherein n is 0 or 1, m is 0, 1, 2, 3, 4, or 5, x is H, C C ₄ - alkyl, C _r C ₄ - alkoxy, trifluoromethyl or halogen, with a secondary amine .

Alternatively, the preparation of the compounds of formula 1 can 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.

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.

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.

Medicaments suitable for administration may be prepared by methods well known and customary in pharmaceutical practice.

The compounds of the invention have a pronounced anticonvulsant effect.

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

30894 / H of the International Standard (Pharmac. Weekblad, Sc. Ed. 14, 132 (1992) and Antiepileptic Drugs, 3rd Ed., Raven Press, New York (1989) (Table 1)).

For example, for compound 2, (1- (4-chlorophenyl) -4-morpholinoimidazolin-2-one) in the rat, the ED50 (p.o) dose for the maximum electroshock 21 mg / kg, ED50 in s.c. the penterazole assay was determined to be 16 mg / kg and the NT50 for neurotoxicity was> 400 mg / kg. In contrast, known antiepileptic drugs are effective in a maximum electroshock model or in a pentetrazole assay, or, in the case of relatively high activity, are highly neurotoxic in a PTZ assay.

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Table 1

the compound according to Ex. Log p ² ' Test ³¹ Batch ⁴ ' Efficiency ⁵ ' 1 MES 100 30 0, 64 PTZ 100 30 2 MES 300 30 1, 48 PTZ 30 70 3 MES 100 100 2, 29 PTZ 100 100 4 MES 300 30 0, 48 PTZ 300 30 5 MES 300 100 2, 17 PTZ 300 100 6 MES 300 100 1, 61 PTZ 100 20 7 MES 300 100 1.53 PTZ 100 100 8 MES 300 30 1, 45 PTZ 100 100 9 MES 100 30 0, 97 PTZ 100 100 10 MES 300 10 1.28 PTZ 300 70 11 MES 300 100 2, 56 PTZ 300 40

Reference substance Test ³ ' Batch ⁴ ' Efficiency ⁵ ' carbamazepine MES 100 100 PTZ 100 0 valproate MES 100 0 PTZ 100 30

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Notes to Table 1:

1) For compound numbering, see p. working examples

2) Octanol / water partition coefficient

3) MES = maximum electroshock, PTZ = pentetrazole administered s.c.

4) in mg / kg

5) in% of protected animals

DETAILED DESCRIPTION OF THE INVENTION

The preparation of the novel compounds of formula 1 will be explained in more detail by way of working examples.

Working examples

General Procedure for the Preparation of Compounds of Formula 1 according to Table 1, Examples 1 to 11.

Variant A

0.05 mol of 1-arylimidazoline-2,4-dione of 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 with an extraction tube (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.

From the non-separated amine, about 0.02 mol of unreacted 1-arylimidazoline-2,4-dione can be recovered.

Variant B

0.05 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

30894 / H in 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 was basified with 50 ml of 10% NaOH and the 1-4 amino-1-aralkylimidazolin-2-one was 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 C

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.

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Table 2

Pr. R ¹ R ² boiling Response time (hours) Temp. top.fC) yield (%) 1 -about - \ / ° A 15 248 42 ¹ ) 2 / "X - N 0 A 15 266 75 n 3 -ABOUT" -3 A 20 246 60 ¹ ) 4 - ^ch 4F) - ^N \ z ° B 15 158 48 5 C ^α / - \ - N N-CM \ t A 12 254 68 ¹ ) 6 ~ Ό ^ ^α CH., From ^J - N CH, C '40 292 13 7 -about A 30 190 52U 8 - Nl \ __ Q A 15 268 65 ¹ ) 9 - \ / ° A 18 255 54 O 10 Cl -about - t / \> B 30 237 27 11 -ABOUT A 8 216 88 ¹ )

^{1) The} recovered starting materials were included in the yield calculation

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Claims (7)

A novel compound of formula 1 wherein n is 0 or 1, m is 0, 1, 2, 3, 4 or 5, x is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, trifluoromethyl or halogen, R ¹ and R ² are C 1 -C ₄ -alkyl, cycloalkyl or heteroalkyl wherein the alkyl group I ¹ always contains 5 to 7 carbon atoms, or 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. A compound 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, - | - (4-fluorophenyl) -4-morpholinoimidazolin-2-one a 1-Benzyl-4-morpholinoimidazolin-2-one. 30894 / H 3. A process for the preparation of compounds of general formula 1, characterized in that the compound of formula 2 (2) wherein X is hydrogen, Cr C ₄ - alkyl, C _r C ₄ - alkoxy, trifluoromethyl or halogen, are reacted with a secondary amine of the formula HNR ¹ R ² , wherein R ¹ and R ² are as defined above, at a temperature of from 50 ° C to 160 ° C. Pharmaceutical composition, characterized in that it contains at least one compound of the general formula 1 as active substance and optionally pharmaceutical excipients and auxiliaries. Pharmaceutical composition according to claim 4, characterized in that it contains as active substances at least one of the compounds according to claim 2. Use of a compound of formula 1 for the manufacture of a medicament for the treatment of epileptic disorders. Use of a compound according to claim 2 for the manufacture of a medicament for the treatment of epileptic disorders.