NZ315624A - 1-phenyl(or phenylalkyl)-4 (disubstituted amino)-imidazolin-2-one derivatives and medicaments - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 315624 New Zealand No. 315624 International No. PCT/EP96/03295 TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates: 05.09.1995; Complete Specification Filed: 26.07.1996 Classification:^) C07D233/88; C07D401/04; A61K31/415,445,45,535 Publication date: 25 November 1998 Journal No.: 1434 Title of Invention: Novel 1 -ar(alk)ylimidazolin-2-ones having anti-convulsive activity, which contain a disubstituted amine radical in the 4-position, and processes for their preparation Name, address and nationality of applicant(s) as in international application form: ARZNEIMITTELWERK DRESDEN GmbH, Meissner Strasse 35, D-01445 Radebeul, Federal Republic of Germany NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION 24 -ia- NOVEL l-AR(ALK) YLIMIDAZOLIN-2-ONES HAVING ANTICONVULSIVE ACTIVITY, WHICH CONTAIN A DISUBSTITUTED AMINE 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-Ar(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 antie'pileptic activity. (followed by pagj ffljUSCIUALP™™" umuL 19 AUG 1998 RECEIVED According to the present invention, these novel compounds are 1-ar(alk)ylimidazolin-2-ones of the general formula 1 (followed by page 2) AMENDED SHEET INTaLECTUAL PROPERTY OFRCE OF NZ 1 9 AUG 1998 RECEIVED m = 0,' 1,2, 3,4,5 in which X = Ci -C4-alkyl, C-]-C^alkoxy, trifluoromethyl or halogen R1 and R2 = Ci-C^-alkyl, cycloalkyl or heteroalkyl where the alkyl group in each case contains 5-7 carbon atcms 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 1 which may be mentioned are: 1-phenyl-4-morpholinoimidazolin-2-one 1-(4-methoxyphenyl)-4-piperidinoimidazolin-2-one 1- (4-chlorophenyl) -4-morpholinoimidazolin-2'-one 1-(4-chlorophenyl)-4-piperidinoimidazolin-2-one 1- (4-chloro'phenyl) -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 l-benzyl-4-morpholinoimidazolin-2-one AMENDED SHEET INTELLECTUAL PROPERTY OFRCE OF NZ 19 AUG 1998 RECEIVED WO 97/09314 3*X ^ *£$ ®*"l?cf/EP9 6/032 95 2i, 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 ^/V(CH2)„s H ft—r1H n = 0,1 o-O^O m = 0,1,2, 3,4, 5 in which X = Ci-C4-alkyl, Ci-C4-alkoxy, 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.

INTELLECTUAL PROPERTY OFFICE OF N.Z. 19 AUG 1998 RECEIVED 31562 WO 97/09314 4 PCT/EP96/03295 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. Weekblad, 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. 3156 WO 97/09314 5 PCT/EP96/03295 Table 1 Compound according to Log P2> Test3' Dose41 Action5' Examples MES 100 1 0.64 PTZ 100 MES 300 2 1.48 PTZ 70 MES 100 100 3 2.29 PTZ 100 100 MES 300 4 0.48 PTZ 300 MES 300 • 100 2.17 PTZ 300 100 MES 300 100 6 1. 61 PTZ 100 MES 300 100 7 1.53 PTZ 100 • 100 MES 300 8 1.45 PTZ 100 100 MES 100 9 0. 97 PTZ 100 100 MES 300 1.28 PTZ 300 70 MES 300 100 11 2.56 PTZ 300 40 31562 WO 97/09314 6 PCT/EP96/03295 Comparison substance Test3> Dose4' Action5' MES 100 100 Carbamazepine PTZ 100 0 Valproate MES PTZ 100 100 0 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 ) 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- 31562 WO 97/09314 7 PCT/EP96/03295 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-2,4-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 HC1 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 l-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.