LT4482B - Novel 1-ar(alk)yl-imidazolin-2-ones containing a disubstituted amine radical in the 4th position, having an anticonvulsive 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

wherein: X is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl or halogen: R ¹ and R ² are C ¹ -C ₄ alkyl, cycloalkyl or heteroalkyl.

The present invention relates to 1-aryl (alkyl) imidazolin-2-ones having a disubstituted amino group at the 4-position, processes for their preparation and their use as pharmaceuticals for the treatment of central nervous system disorders, in particular various forms of epilepsy.

In the prior art, 1-aryl (alkyl) imidazolin-2-ones having an unsubstituted amino or methylamino group at the 4-position are obtained by reacting aryl (alkyl) aminoacetamides with bromocyano. N-alkylating the 4-amino-1-aryl (alkyl) imidazolin-2-one thus obtained gives 3-alkyl- or 1-iminoalkyl-3alkyl-1-aryl (alkyl) imidazolin-2-one, in addition to amino group 4. position tautomerizes to the iminogroup. As a result, further N-alkylation to obtain compounds of general formula 1 is not possible, and the corresponding compounds of the present invention cannot be obtained in this way (U.S. Patent No. 4,404,402;

2251354).

-Aryl (alkyl) imidazolin-2-ones having a substituted amino group at the 4-position are not yet described.

Numerous compounds with antispasmodic activity are known. However, the treatment of all epileptic syndromes is still not satisfactory.

Thus, it is an object of the present invention to provide novel compounds having favorable pharmacological properties which can be used, for example, as pharmaceutical preparations, and which possess antispasmodic activity.

According to the present invention, those novel compounds are 1-ary (alkyl) imidazolin-2-ones of the general formula 1:

n = 0.1; m = 0.1, 2, 3, 4, 5; where:

X is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, trifluoromethyl or halogen;

R ¹ and R ² are CpCA-alkyl, eicycloalkyl or heteroalkyl, wherein the alkyl group optionally contains 5 to 7 carbon atoms, or

R ¹ and R ² together form an alkylene group having from 2 to 6 carbon atoms, wherein the -CH ₂ io group may be replaced by oxygen, nitrogen or sulfur.

The number of CH ₂ groups is equal to either 0 (1-arylimidazolin-2-one) or 1 (1-arylalkylimidazolin-2-one).

Examples of compounds of general formula 1 are: 1-phenyl-4-morpholinimidazolin-2-one

1- (4-Methoxy) -4-piperidinimidazolin-2-one

1- (4-Chlorophenyl) -4-morpholinimidazolin-2-one 1- (4-chlorophenyl) -piperidinimidazolin-2-one 1- (4-chlorophenyl) -4-dimethylaminoimidazolin-2-one 1- (4-bromophenyl) -4-morpholinimidazolin-2-one

1- (3-chlorophenyl) -4-morpholinimidazolin-2-one

1- (4-Chlorophenyl) -4-hexamethyleniminoimidazolin-2-one

1- (4-Chlorophenyl) -4- (4-methylpiperazino) imidazolin-2-one

1- (4-Methylphenyl) -4-morpholinimidazolin-2-one

1- (4-Chlorophenyl) -4- (cyclohexylmethylamino) imidazolin-2-one

1- (4-Fluorophenyl) -4-morpholinimidazolin-2-one

1-Benzyl-4-morpholinimidazolin-2-one.

The compounds of the general formula 1 according to the present invention can be obtained in a novel manner by reacting the compounds of the general formula 2

H n = 0.1; m = 0,1,2,3,4,5;

wherein X is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, trifluoromethyl or halogen;

with a secondary amine.

Alternatively, the compounds of Formula 1 may be obtained in a solvent or in an excess of secondary amide at 50 to 160 ° C. Suitable preferred solvents are aromatic hydrocarbons such as benzene, toluene, chlorobenzene or dichlorobenzene.

The reaction is preferably carried out in the presence of water-binding substances such as zeolites or sodium sulfate. The reaction can be accelerated by the addition of conventional condensation catalysts such as 4-toluenesulfonic acid.

The compounds of the present invention are suitable for the preparation of pharmaceutical compositions. The pharmaceutical compositions may contain one or more compounds of the present invention. Conventional pharmaceutical excipients and excipients may be used in the preparation of pharmaceutical preparations.

The drugs may be administered parenterally (for example, intravenously, intramuscularly or subcutaneously) or orally.

The formulations may be formulated according to known and widely used pharmaceutical formulations. ways.

The compounds of the present invention exhibit potent antispasmodic activity.

The antispasmodic activity of these preparations has been tested by in vivo administration to mice intraperitoneally or orally in rats according to international standards (Pharmac. Weekblad, 2nd ed., 14, 132 (1992) and Antiepileptic drugs, 3rd ed., Raven press, New York (1989). ) (Table 1).

For example, the effective dose of compound 2 (1- (4-chlorophenyl) -4-morpholinimidazolin-2-one) for ED ₅₀ (oral) at maximal electroshock rats is 21 mg / kg, ED ₅₀ for subcutaneous administration of pentetrazole is 16 mg / kg. and NT _{50 in} neurotoxicity assays is> 400 mg / kg. In comparison, known antiepileptic drugs are active either in the maximal electroshock model, either after administration of pentetrazole or, at relatively high activities, they exhibit excessive neurotoxicity after administration of pentetrazole.

TABLE

Compound Nos. By Examples ¹¹ log P ²¹ study ³¹ Dose ⁴¹ Impact ⁵¹ 1 0.64 MES PTZ 100 100 30th 30th 2 1.48 MES PTZ 300 30th 30th 70 3 2.29 MES PTZ 100 100 100 100 4 0.48 MES PTZ 300 300 30th 30th 5 2.17 MES PTZ 300 300 100 100 6th 1.61 MES PTZ 300 100 100 20th 7th 1.53 MES PTZ 300 100 100 100 8th 1.45 MES PTZ 300 100 30th 100 9th 0.97 MES PTZ 100 100 30th 100 10th 1.28 MES PTZ '300 300 10th 70 ^11th 2.56 MES · PTZ 300 300 100 40

Comparison Material study ³¹ Dose ⁴¹ Impact ⁵¹ Carbamazepine MES 100 100 PTZ 100 0 Valproate MES 100 0 PTZ 100 30th

Notes:

1) For compound numbering, see marg. examples.

2) Partition coefficient in octanol-water system.

3) MES - maximum electroshock, PTZ - pentetrazole, subcutaneous administration.

4) mg / kg

5)% of protected animals.

The preparation of novel compounds of formula 1 is further illustrated by working examples.

EXAMPLES

General procedure for the preparation of compounds of formula 1 according to Table 1, Examples 1-11

Option A.

0.05 mol of 1-arylimidazoline-2,4-dione of general formula 2 (n = 0), 200 mg of 4-toluenesulphonic acid were added per 100 ml of the appropriate secondary amine. The mixture was then refluxed in a Soxhlet extractor containing 25 g of water-soluble solids (suitable, for example, sodium sulfate, magnesium sulfate, NaOH, KOH, zeolites). After 8-30 hours, the hot mixture was filtered and distilled in a rotary evaporator to about half volume. The clear solution was cooled in an ice bath and the resulting thick crystal aqueous suspension was separated from the amine. Starting material, -. Extract 50 ml of hot acetone in the crude product. The product was recrystallized from n-propanol.

Up to 0.02 mol of unreacted 1aryl imidazoline-2,4-dione can be isolated from the isolated amine.

Option B.

0.05 mol of 1-arylalkylimidazoline-2,4-dione of general formula 2 (n = 1) is reacted with a secondary amine as described in variant A. After 8-30 or. the hot solution is filtered and concentrated to dryness in a rotary evaporator. To the residue are added 50 mL of methylene chloride and 50 mL of 2N HCl. The organic phase is separated off and the aqueous phase is further extracted twice with methylene chloride. The separated aqueous phase is made alkaline by the addition of 50 ml of 10% NaOH and the 1,4-amino-1-arylalkylimidazolin-2-one is extracted with 100 ml of methylene chloride. The extracts are dried over sodium sulfate. After distillation with methylene chloride, the crude product is recrystallized from ethanol or acetone.

Option C.

0.05 mol of 1-aryl (alkyl) imidazoline-2,4-dione of general formula 2 is reacted with 100 ml of dimethylammoniodimethylcarbamate as described in variants A and B. After 40 or so. the mixture is treated according to variant A or B.

TABLE

For example, No. R ¹ R ² Variant- it Reaction time- mh ~ O _j Yield (%) 1 \ _ / A 15th 248 42 ¹⁾ 2 -O- ^ci _n A 15th 266 75 ⁿ 3 ~ CG ^ci -o A 20th .248 60 ¹⁾ 4 - ^{c H} t —fr. ~ 2> -O B 15th 158 48 5 - n (\ —CH J A 12th 254 68 ¹⁾ 6th —One ^ ~ ^c ' CH, -N ZZ ³ H j C 40 292 13th 7th -O- ^OCH 3 -O A 30th 190 52 ¹⁾ 8th -O A 15th 268 65 ⁿ 9th ~ O ^F -O A 18th 255 54 ¹ ' 10th -O B 30th 237 27th 11th GG ^ci -O A 8th 216 88 ¹⁾

(1) isolated starting material is included in the yield assessment.

Claims (7)

DEFINITION OF INVENTION 5 1. Novel compounds of general formula 1 n = 0, 1, m = 0, 1, 2, 3, 4, 5, wherein X is hydrogen, Ci-C ₄ -alkyl, CRC _4-alkoxy, trifluoromethyl or halogen io ; R ¹ and R ² are C ₁ -C ₄ alkyl, cycloalkyl or heteroalkyl wherein the alkyl group optionally contains 5 to 7 carbon atoms, or R ¹ and R ² together form an alkylene group having from 2 to 6 carbon atoms, wherein the -CH ₂ group may be replaced by oxygen, nitrogen or sulfur. Compounds according to claim 1, characterized in that they are 1-phenyl-4-morpholinimidazolin-2-one 1- (4-methoxy) -4-piperidinimidazolin-2-one 20 1- (4-Chlorophenyl) -4-morpholinimidazolin-2-one 1- (4-Chloro-phenyl) -piperidinimidazolin-2-one 1- (4-chloro-phenyl) -4-dimethylamino-imidazolin-2-one 1- (4-bromo-phenyl) -4-morpholinimidazolin-2-one 1- (3-chloro-phenyl) -4-morpholinimidazolin-2-one 1- (4-Chlorophenyl) -4-hexamethyleniminoimidazolin-2-one 1- (4-Chlorophenyl) -4- (4-methylpiperazino) imidazolin-2-one 1- (4-methylphenyl) -4-morpholinimidazolin-2-one 1- (4-chlorophenyl) -4- (cyclohexylmethylamino) imidazolin- 2-one 1- (4-fluorophenyl) -4-morpholinimidazolin-2-one 1- (4-Fluorophenyl) -4-morpholinimidazolin-2-one 1-Benzyl-4-morpholinimidazolin-2-one. 3. A process for the preparation of compounds of general formula 1, characterized in that the compounds of general formula 2 H wherein: X is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxyl, trifluoromethyl or halogen, reacts with the secondary amine HNR ¹ R ^{2 in the range of} 50-160 ° C, and R ¹ and R ² are as defined above. Pharmaceutical preparations, characterized in that they contain as active ingredient at least one compound of the general formula 1 and, optionally, pharmaceutical excipients and excipients. Pharmaceutical preparations according to claim 4, characterized in that they contain, as active ingredient, at least one compound according to claim 2. Use of compounds of general formula 1 in the manufacture of a medicament for the treatment of epileptic syndromes. Use of compounds according to claim 2 for the manufacture of a medicament for the treatment of epileptic syndromes.