IL123333A

IL123333A - 1-ar(alk)ylimidazolin-2-ones, their preparation and pharmaceutical compositions containing them

Info

Publication number: IL123333A
Application number: IL12333396A
Authority: IL
Original assignee: Dresden Arzneimittel
Priority date: 1995-09-05
Filing date: 1996-07-26
Publication date: 2001-10-31
Also published as: BG102287A; NO980906L; NO980906D0; EP0863880A1; LT4482B; JP4030578B2; HK1015776A1; HUP9802941A3; EE9800063A; FR13C0049I2; ATE254606T1; FR13C0049I1; DE59610827D1; BR9610359A; MX9801742A; NO313829B1; JPH11512101A; DE19532668A1; CN1103762C; PL325413A1

Abstract

Anti-convulsive compounds of the formula in which X = hydrogen, C1-C4-alkyl, C1-C4-alkoxy, trifluoromethyl or halogen; R1 and R2 = C1-C4 - alkyl, cycloalkyl or heteroalkyl where the alkyl group in each case contains 5-7 carbon atoms or R1 and R2 together are an alkylene group having 2-6 carbon atoms in which a -CH2- group can be replaced by oxygen, nitrogen or sulfur. 2637 י" ד בחשון התשס" ב - October 31, 2001

Description

ΏΤΗΗ rnnpii >wssr) taiwDii ,0 N-2- mi>tt>Ni>Ht?*N)ii-l l-ar(alk)ylimidazolin-2-ones their preparation and pharmaceutical compositions containing them Arzneimittelwerk Dresden GmbH C.109968 Novel 1-ar (alk) ylimidazolin-2 -ones having anticonvul- amine sive activity, which contain a disubstituted^radical in the 4 -position, and processes for their preparation The invention relates to 1-ar (alk) ylimidazolin-2 -ones which contain a disubstituted amine radical in the 4 -position, processes for their preparation and their use as pharmaceutical agents for the treatment of disorders of the central nervous system, in particular of epilepsies of various forms. 1-Ar (alk) ylimidazolin-2 -ones having an unsubstituted amine or methylamine radical in the 4 -position are prepared according to the prior art by reaction of ar- (alk) ylaminoacetamides with cyanogen bromide. By N-alkylation of the 4-amino-l-ar (alk) ylimidazolin-2 -ones prepared in this way, 3-alkyl- or l-iminoalkyl-3-alkyl-l-ar (alk) ylimidazolin-2 -ones are obtained, the amino group in the 4 -position being tautomerized to an imino group. A further N-alkylation to give compounds of the general formula 1 is therefore not possible, so that compounds according to the invention cannot be prepared by this process [USP 4044021; DE 2251354] . 1-A (alk) ylimidazolin-2 -ones having a disubstituted amine radical in the 4 -position have not been described until now.

A multiplicity of compounds having anticonvulsive activity are known. However, even today not all epileptic disorders can be treated satisfactorily.

The invention is thus based on the object of making available novel compounds having favorable pharmacological properties which can be employed, for example, as medicaments having antiepileptic activity.

According to the present invention, these novel compounds are 1-ar (alk) ylimidazolin-2-ones of the general formula 1 in which X = hydrogen, Ci-C^-alkyl, Ci-C4-alkoxy, trifluoromethyl or halogen R1 and R2 = Ci-C^-alkyl, cycloalkyl or heteroalkyl where the alkyl group in each case contains 5-7 carbon atoff [sic] atoms or R1 and R2 together are an alkylene group having 2-6 carbon atoms in which a -CH2- group can be replaced by oxygen, nitrogen or sulfur.

The number of CH2 groups is either 0 (1-arylimidazolin-2-ones) or 1 (l-aralkylimidazolin-2-ones) .

Examples of compounds of the general' formula I [sic] which may be mentioned are: l-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-hexamethyleneiminoimidazolin-2-one 1- (4-chlorophenyl) -4- (4-methylpiperazino) imidazolin-2-one 1- (4-methylphenyl) -4-morpholinoimidazolin-2-one 1- (4-chlorophenyl) -4- (cyclohexylmethylamino) imidazolin- 2-one 1- (4-fluorophenyl) -4-morpholinoimidazolin-2-one ENDED SH l-benzyl-4-morpholinoimidazolin-2-one According to the present invention, the compounds of the general formula 1 can be prepared by a novel process by reaction of the compounds of the general formula 2 in which X = hydrogen, C1-C4-alkyl, trifluoromethyl or halogen with a secondary amine .

The preparation of the compounds of the formula 1 can alternatively be carried out in a solvent or in excess secondary amine at temperatures between 50°C and 160°C. Suitable solvents are preferably aromatic hydrocarbons, for example 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 addition of generally customary condensation catalysts such as 4-toluenesulfonic acid.

The compounds according to the invention are suitable for the preparation of pharmaceutical compositions. The pharmaceutical compositions can contain one or more of the compounds according to the invention. The customary pharmaceutical excipients and auxiliaries can be used to prepare the pharmaceutical preparations.

The medicaments can be administered parenterally (for example intravenously, intramuscularly or subcutaneous-ly) or orally.

The administration forms can be prepared by processes which are generally known and customary in pharmaceutical practice.

The compounds according to the invention have strong anticonvulsive actions.

They were tested for their anticonvulsive action in vivo after i.p. administration to mice or rats (p.o. administration) according to the internationally customary standard (Pharmac. eekblad, Sc. Ed. 14, 132 (1992) and Antiepileptic Drugs, Third Ed., Raven Press, New York (1989) (Table 1) .

For example, for the compound 2 (1- (4-chlorophenyl) -4-morpholinoimidazolin-2-one) in the rat the ED50 (p.o.) for the maximum electroshock was determined to be 21 mg/kg, the ED50 in the s.c. pentetrazole test was determined to be 16 mg/kg and the NT50 for the neurotoxicity was determined to be > 400 mg/kg. In comparison to this, known antiepileptics are active either in the maximum electroshock model or in the pentetrazole test or, in the case of relatively high activity, are severely neurotoxic in the PTZ test.

Table 1 Compound according Log P2> Test3' Dose41 Action51 to Examples MES 100 30 1 0.64 PTZ 100 30 MES 300 30 2 1.48 PTZ 30 70 MES 100 100 3 2.29 PTZ 100 100 MES 300 30 4 0.48 PTZ 300 30 MES 300 100 5 2.17 PTZ 300 100 MES 300 100 6 1.61 PTZ 100 20 MES 300 100 7 1.53 PTZ 100 100 MES 300 30 8 1.45 PTZ 100 100 MES 100 30 9 0.97 PTZ 100 100 MES 300 10 10 1.28 PTZ 300 70 MES 300 100 11 2.56 PTZ 300 40 Notes for Table 1 : 1) For numbering of the compounds see working examples 2) Octanol/water partition coefficient 3) MES = maximum electroshock, PTZ = s.c. pentetrazole 4) in mg/kg 5) in % of the protected animals The preparation of the novel compounds of the general formula 1 will be illustrated in greater detail with the aid of working examples .

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

Variant A 0.05 mol of l-arylimidazolin-2 , 4-dione of the general formula 2 (n=0) [lacuna] 200 mg of 4-toluenesulfonic acid [lacuna] added to 100 ml of an appropriate secondary amine. The mixture is then heated under reflux in a Soxhlet extractor, the extraction thimble previously being filled with about 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 approximately half the volume in a rotary evaporator. The clear solution is cooled in an ice bath and the crystal magma obtained is separated off from the amine. Starting substance contained in the crude product is extracted with 50 ml of hot acetone. The product is recrystallized from n-propanol.

About 0.02 mol of unreacted l-arylimidazolin-2 , 4-dione can be recovered from the separated amine .

Variant B 0.05 mol of l-aralkylimidazolin-2 , -dione of the general formula 2 (n=l) is reacted with a sec. amine as described under A. After a reaction time of 8 to 30 hours, the solution is filtered hot and then concentrated to dryness in a rotary evaporator. 50 ml of methylene chloride and 50 ml of 2N HCl are added to the residue. The organic phase is separated off and the aqueous phase is extracted a further two times with methylene chloride. The aqueous phase isolated is rendered alkaline with 50 ml of 10% strength NaOH and the 1-4-amino-l-aralkylimidazolin-2 -one [sic] 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 0.05 mol of 1-ar (alk) ylimidazolin-2 , 4-dione of the general 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.

Table 2 recovered starting material was taken into account when calculating the yield

Claims

Patent Claims

1. Novel compounds of the general formula 1 in which X = hydrogen, Ci-C^-alkyl, Ci-Ci-alkoxy, trifluoromethyl or halogen R1 and R2 = C1-C4-alkyl, cycloalkyl or heteroalkyl where the alkyl group in each case contains 5-7 carbon atoff [sic] atoms or R1 and R2 together are an alkylene group having 2-6 carbon atoms in which a -CH2- group can be replaced by oxygen, nitrogen or sulfur.

2. Compounds according to claim 1, l-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-hexamethyleneiminoimidazolin-2-one 1- (4-chlorophenyl) -4- (4-methylpiperazino) imidazolin-2-one 1- (4-methylphenyl) -4-morpholinoimidazolin-2-one 1- (4-chlorophenyl) -4- (cyclohexylmethylamino) imidazolin- 2-one 1- ( -fluorophenyl) -4-morpholinoimidazolin-2-one l-benzyl-4-morpholinoimidazolin-2-one AMENDED SHEET 123333/2 10

3. Process for the preparation of the compounds of the general formula 1, characterized in that a [sic] compounds of the general formula 2 ° N H in which X = hydrogen, C1-C4-alkyl, C1-C4-alkoxy, trifluoromethyl or halogen are reacted with - a secondary amine HNR1R2 at temperatures between 50 °C and 160 °C, R1 and R2 having the meaning indicated.

4. Pharmaceutical preparations characterized in that, as active substance, they contain at least one compound of the general formula 1 and, if appropriate, pharmaceutical excipients and auxiliaries.

5. Pharmaceutical preparations according to claim characterized in that, as active substance, they contain at least one of the compounds according to claim 2.

6. Use of the compounds, of the general formula 1 for the production of medicaments^ for the treatment of epileptic disorders^substantially as described in the specification.

7. Use of the compounds according to claim 2 for the production of medicaments^ for the treatment of epileptic disorders substantially, as described in the specification. For the Applicants HNHOLD COHN AND PARTNERS