CZ2001450A3 - Novel 4-amino-1-arylpyridin-2-ones exhibiting anticonvulsive activity and process of their preparation - Google Patents

Abstract

The present invention relates to novel 4-amino-1-aryl-pyridine-2-ones of formula (1) wherein n = 0,1, 2, 3,4, 5 and X is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, trifluoromethyl, trifluoromethoxy or a halogen atom and A is amino, C 1 -C 21 -alkylamino. CrC4- dialkylamino, morpholino, piperidino or pyrrolidino. Also it relates to a method of preparing these substances and their use as medicaments, especially for the treatment of various forms of epilepsy.

Description

The invention relates to novel 4-amino-1-arylpyridin-2-ones, to a process for their preparation and to their use as medicaments, in particular the treatment of various forms of epilepsy.

BACKGROUND OF THE INVENTION

4-Aminopyridin-2-ones unsubstituted at position 1 are obtained, according to the state of the art, by reaction of 4-hydroxy-1H-pyridin-2-one with amine derivatives [Synthesis; 9 (1984); 765-766)). Further arylation at the 1-position to obtain compounds of formula 1 is not possible, so that the compounds of the present invention cannot be prepared in this way.

Another method describes the synthesis of 1-aryl-4-amino-3-cyano-5alkoxycarbonylpyridin-2-ones [Chem. Ber. 114 (11); (1981); 34713484]. Since dimeric cyanoacetic esters are used as starting materials in this process, the substituents must be in positions 3 and 5 on pyridin-2-one, so that the compounds of the present invention cannot be obtained in this way either.

The 4-amino-1-arylpyridin-2-ones of formula (1) have not yet been described.

A large number of compounds having anticonvulsant activity are known. However, there remains a great need for new anticonvulsants, because even now, a large number of epileptic disorders cannot be satisfactorily treated.

The present invention is based on the production of available novel compounds having favorable pharmacological properties and which can be used in particular as medicaments having an antiepiieptic effect.

SUMMARY OF THE INVENTION

The present invention relates to novel compounds which are the 4 amino-1-arylpyridin-2-ones of formula 1

n

0, 1, 2, 3, 4, 5 in which

X = hydrogen, C 1 -C ₄ -alkyl, C 1 -C ₄ -alkoxy, trifluoromethyl, trifluoromethoxy or halogen; and

A = amino, C 1 -C ₄ -alkylamino, C 1 -C ₄ -dialkylamino, morpholino, piperidino or pyrrolidino.

Examples of compounds of Formula 1 are: 4-amino-1-phenylpyridin-2-one 4-amino-1- (2-chlorophenyl) pyridin-2-one 4-amino-1- (4-chlorophenyl) pyridin-2-one 4-Amino-1- (2-methylphenyl) pyridin-2-one

-3-4-amino-1- (3-methylphenyl) pyridin-2-one

4-Amino-1- (4-methylphenyl) pyridin-2-one

4-Amino-1- (4-methoxyphenyl) pyridin-2-one

4-amino-1- (4-trifluoromethoxyphenyl) pyridin-2-one

4-amino-1- (2,6-dichlorophenyl) pyridin-2-one

4-amino-1- (2-fluorophenyl) pyridin-2-one

4-amino-1- (4-fluorophenyl) pyridin-2-one

4-amino-1- (2,6-difluorophenyl) pyridin-2-one

4-Amino-1- (2-chloro-4-fluorophenyl) pyridin-2-one

1- (2-chlorophenyl) -4-dimethylaminopyridin-2-one

1- (2-Chloro-phenyl) -4- (4-morpholino) -pyridin-2-one

According to the present invention, compounds of formula 1 may be prepared in a novel manner by reacting compounds of formula 2

in which

X = hydrogen, C 1 -C ₄ -alkyl, C 1 -C ₄ -alkoxy, trifluoromethyl, trifluoromethoxy or halogen and R = C 1 -C ₄ -alkyl.

The pyrimidine derivatives of formula 2 can be synthesized in a simple manner (Chem. Heterocycl. Compd .; 24 (8); (1988); 914-919; Khim. Geterotsikl. Soedin .; 8; (1988);

1109-1114).

• «

The compounds of formula 1 are prepared in two steps. The pyrimidine derivatives of formula 2 are heated to a temperature of 50 ° C to 150 ° C in an alkaline medium, preferably 5 to 50% sodium hydroxide solution for 0.1 to 10 hours, preferably for one hour. The mixture is then heated to 100 ° C to 200 ° C with strong acids, preferably 50 to 98% sulfuric acid for 10 to 30 minutes. The primary amino group may be mono- or dialkylated by known methods. The alkylation is preferably carried out using dimethyl sulfate, methyl iodide, 1,4-dibromobutane, 1,5-dibromopentane or di (2-chloroethyl) ether.

The compounds of formula (1) of the present invention are suitable for the manufacture of pharmaceutical compositions. These pharmaceutical compositions comprise at least one compound of formula 1 according to the present invention.

Conventional pharmaceutical excipients and agents may be used to make the pharmaceutical compositions.

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

Suitable forms of administration are prepared by methods well known and conventional in the pharmaceutical practice.

Examination of the compounds of the present invention has shown that these compounds have potent anticonvulsant activity.

The compounds of the present invention have been tested for:

Their anticonvulsant activity in vivo after i.p. administration to mice or (after p.o. administration) to rats according to international customary standards (Pharmac. Weekblad. Sc. Ed. 14, 132 (1992) and Antiepileptic Drugs, Third Ed., Raven Press, New York 1989).

For example, in the 4-amino-1-phenylpyridin-2-one compound (Example 1) in rats, the ED ₅₀ o (po) was determined to be 3.1 mg / kg for maximum electroshock and ED ₅₀ = 200 mg / kg for rotorod. In contrast, known antiepileptic drugs either act only at relatively high doses in the maximum electroshock model or have relatively strong adverse (neurotoxic) side effects.

Table 1

Compounds and according to example C. X AND Test ¹ Dose ² Operation ² 1 H nh ₂ MES Rotorod 10 100 ALIGN! 30 40 2 4-C1 nh ₂ MES Rotorod 100 ALIGN! 300 30 0 3 _4-CH3 nh ₂ MES Rotorod 30 30 100 ALIGN! 0 4 2-CH3 nh ₂ MES Rotorod 30 100 ALIGN! 70 0 5 4-CH 3 -O nh ₂ MES Rotorod 30 300 30 0 6 4-CF 3 -O nh ₂ MES Rotorod 100 ALIGN! 300 70 0

• · · · · · · · · · · · • · • · • · • ·

7 3-CH ₃ nh ₂ MES Rotorod 30 30 100 ALIGN! 0 8 3-C1 nh ₂ MES 100 ALIGN! 50 Rotorod 100 ALIGN! 15 Dec 9 2-C1 nh ₂ MES 100 ALIGN! 70 Cl Rotorod 300 0 10 4-F nh ₂ MES 10 30 Rotorod 100 ALIGN! 0 11 2-C1, 3- nh ₂ MES 30 30 Cl Rotorod 100 ALIGN! 30 12 2-F nh ₂ MES 30 100 ALIGN! Rotorod 100 ALIGN! 15 Dec 13 2-C1 nh ₂ MES 10 70 Rotorod 30 15 Dec 14 2-F, 6-F nh ₂ MES 30 100 ALIGN! Rotorod 30 0 15 Dec 2-C1, 4- nh ₂ MES 10 100 ALIGN! F Rotorod 100 ALIGN! 30 16 2-C1 N _(CH3) 2 MES 30 30 Rotorod 30 0 17 2-C1 N (CH ₂ CH ₂ ) 0 MES 30 100 ALIGN! Rotorod 30 0 Comparative substance Carbamazepine MES 100 ALIGN! 100 ALIGN! Rotorod 100 ALIGN! 60 Valproate MES 100 ALIGN! 10 Rotorod 100 ALIGN! 0

Notes on Table 1:

1) Mouse i.p .: MES neurotoxicity maximal electroshock Rotorod · · ····· · · ·····

2) in mg / kg

3) in% of protected animals resp. % of animals having a visible neurotoxic effect

The anticonvulsant effect found and the low side effects of the claimed compounds allow the preparation of new drugs for the treatment of epilepsy of various forms.

DETAILED DESCRIPTION OF THE INVENTION

The preparation of the compounds of the present invention is explained in more detail in the following examples.

The examples provide only an illustrative list, which is not a limitation of the present invention.

General Preparation of Compounds of Formula 1 of Table 1, Examples 1-15

General method of synthesis

0.05 mol of the pyrimidine derivative of formula 2 is heated at reflux for 1 hour in 100 ml of 10% sodium hydroxide solution. After cooling, the reaction mixture is filtered and the filtered residue is washed twice with 50 ml of water each time. The solid is treated with 100 mL of 75% sulfuric acid and heated to 180 ° C in a preheated oil bath. After a few minutes (reaction time according to Table 2), the reaction mixture is cooled rapidly, diluted with 200 ml of water and basified using ammonium solution. The precipitate is separated and recrystallized.

· * Φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ · · · · · · · • ·· · ·· · · ·

General Preparation of the Compounds of Formula 1 of Table 1, Examples 16 and 17

The 4-aminopyridin-2-one (Examples 1-15), prepared according to the general synthesis method, is alkylated using a suitable alkylating agent such as dimethyl sulfate or di (2-chloroethyl) ether in the presence of sodium methoxide. The reaction mixture was poured into water. The precipitate is separated and recrystallized.

Table 2

Ex ad no. X AND React her time (min) Rekrystaliz ace z: Heat the thaw (° C) Yield ek (%) 1 H nh ₂ 15 Dec Ethanol 288 67 2 4-C1 nh ₂ 15 Dec Methanol 312 71 3 _4-CH3 nh ₂ 15 Dec Ethanol 283 38 4 2-CH3 nh ₂ 30 Methanol 267 31 5 4-CH 3 -O nh ₂ 15 Dec Isopropanol 298 21 6 4-CF 3 -O nh ₂ 10 Methanol 296 44 7 3-CH3 nh ₂ 20 May Isopropanol 243 40 8 3-C1 nh ₂ 15 Dec Methanol 285 62

• 9 • - 9 -

9 2-C1 NO. 1 nh ₂ 20 May Isopropanol 282 46 10 4-F nh ₂ 15 Dec Isopropanol 283 58 11 2-C1, 3- NO. 1 nh ₂ 11 Isopropanol 270 32 12 2-F nh ₂ 15 Dec Ethanol 270 55 13 2-C1 nh ₂ 15 Dec Ethanol 259 64 14 2-F, 6-F nh ₂ 15 Dec Isopropanol 216 51 15 Dec 2-C1, 4- F nh ₂ 20 May Isopropanol 255 66 16 2-C1 N _(CH3) 2 15 Dec Isopropanol 185 68 17 2-C1 N (CH ₂ CH ₂ ) O 15 Dec Isopropanol 183 52

Represented by:

dr. 0. Švorčík

JUDr. Otakar Švorčík attorney

Halkova 2,120 00 Prague 2

Claims (11)

PATENT CLAIMS New compounds of the general formula 1 n = 0, 1, 2, 3, 4, 5 in which X = hydrogen, C 1 -C ₄ -alkyl, C 1 -C ₄ -alkoxy, trifluoromethyl, trifluoromethoxy or halogen; and A = amino, C 1 -C ₄ -alkylamino, C 1 -C ₄ -dialkylamino, morpholino, piperidino or pyrrolidino. Compounds according to claim 1: 4-amino-1-phenyl-pyridin-2-one 4-Amino-1- (2-chlorophenyl) pyridin-2-one 4-Amino-1- (4-chlorophenyl) pyridin-2-one 4-Amino-1- (2-methyl-phenyl) -pyridin-2-one 4-Amino-1- (3-methyl-phenyl) -pyridin-2-one 4-Amino-1- (4-methyl-phenyl) -pyridin-2-one 4- amino-1- (4-methoxyphenyl) pyridin-2-one 4-amino-1- (4-trifluoromethoxyphenyl) pyridin-2-one 4-amino-1- (2,6-dichlorophenyl) pyridin-2-one 4- amino-1- (2-fluorophenyl) pyridin-2-one 4-amino-1- (4-fluorophenyl) pyridin-2-one 4-Amino-1- (2,6-difluorophenyl) pyridin-2-one 4-Amino-1- (2-chloro-4-fluorophenyl) pyridin-2-one 1- (2-chlorophenyl) -4-dimethylaminopyridin-2-one 1- (2-Chloro-phenyl) -4- (4-morpholino) -pyridin-2-one A process for the preparation of compounds of formula (1), characterized in that the compound of formula (2) wherein: X = hydrogen, C 1 -C ₄ -alkyl, C 1 -C ₄ -alkoxy, trifluoromethyl, trifluoromethoxy or halogen and R = C 1 -C ₄ -alkyl is heated to 50 ° C to 150 ° C in an alkaline medium after for 0.1 to 10 hours and then heated to 100 ° C to 200 ° C with strong acid for 10 to 30 minutes. Process for the preparation of the compounds of the general formula 1 according to claim 3, characterized in that a 5 to 50% sodium hydroxide solution is preferably used. A process for the preparation of the compounds of formula (1) according to claim 3, characterized in that the heating is carried out preferably for one hour in an alkaline medium. ·> *>>>>>> * * * * * * * * Process for the preparation of the compounds of the general formula 1 according to claim 3, characterized in that 50 to 98% sulfuric acid is preferably used. Ί. A process for the preparation of compounds of formula 1 wherein A = C 1 -C ₄ -alkylamino, C 1 -C ₄ -dialkylamino, morpholino, piperidino or pyrrolidino, characterized in that the compound of formula 2 wherein: X = hydrogen, C 1 -C ₄ -alkyl, C 1 -C ₄ -alkoxy, trifluoromethyl, trifluoromethoxy or halogen and R = C 1 -C ₄ -alkyl is heated to 50 ° C to 150 ° C in an alkaline medium for 0.1 to 10 hours, then heated to 100 ° C to 200 ° C with a strong acid for 10 to 30 minutes and then the alkyl is in an alkaline medium. A process for the preparation of compounds of formula (1) according to claim 7, characterized in that the alkylation is preferably carried out with dimethyl sulphate, methyl iodide, 1,4-dibromobutane, 1,5-dibromopentane or di (2-chloroethyl) ether. Pharmaceutical preparations, characterized in that they are: • 9 9 9 9 9 9 9 «999» · · 9 9 «·· 9« 9 «* 999999 9999999 999 9 9 9 999 99 99 99 99 99 The active ingredient comprises at least one compound of the formula I and, if appropriate, pharmaceutical excipients and agents. Pharmaceutical preparations according to claim 9, characterized in that they contain at least one compound according to claim 2 as active substance. Use of compounds of formula 1 for the preparation of medicaments for the treatment of epileptic disorders of various forms. Use of the compounds according to claim 2 for the preparation of medicaments for the treatment of epileptic disorders of various forms.