HU213104B - Process for producing 4-methyl-2-imidazolinone derivatives and pharmaceutical compositions containing them - Google Patents

Abstract

The present invention relates to a novel 2-imidazolinone derivative of formula (I) wherein Z is> C = O or> CH-OH; X is 1 or 2; R1 and R2, together with the nitrogen atom to which they are attached, a hexamethyleneimine ring, phenyl, halo-fluoro, 213 104 B Scope of the description: 6 pages (including 1 sheet)

Description

The compounds of the present invention are cerebrovascular and antihypoxic.

forming a piperazine ring substituted with a nyl, benzyl, diphenylmethyl and 2-pyrimidinyl group or a 1,2,3,6-tetrahydropyridine or piperidine ring substituted with a phenyl or halophenyl group, provided that Z is > C = O and n is 1, Ri and _R2 are the subject of the hoe associated invention (I) 2imidazolinon derivatives of formula - wherein Z is> C = O or>CH-OH; n is 1 or 2;

R 1 and R ₂ together with the nitrogen atom to which they are attached form a hexamethylenimine ring, a piperazine ring substituted by phenyl, halophenyl, benzyl, diphenylmethyl and 2-pyrimidinyl, or a phenyl or halophenyl group substituted by 1,2 , 3,6-tetrahydropyridine or piperidine ring, with the proviso that when Z is> C = O and n is 1 then R 1 and R _2, together with the nitrogen atom to which they are attached, are other than the piperazine and the acid addition salts thereof; for the preparation of pharmaceutical compositions containing these compounds as active ingredients, mainly for improving cerebral circulation and having anti-hypoxic activity.

The compounds of the present invention are useful for improving cerebral blood flow, preventing antihypoxic conditions, and controlling memory disorders caused by antihypoxia.

Compounds of formula I are not known in the literature. Only a few 5-methyl-2-imidazolinon-4-yl-3- (4-benzylpiperazine) derivatives have been reported (see C.A. 110, 23,790m (1989)) to have a positive inotropic effect.

In the process of the invention, the 2-imidazolinone derivatives of the formula I are used

wherein the substituents have the meanings given above, are prepared by:

a) a compound of formula II wherein n is 1 or 2, X is halogen with an amine of formula R ₁ -NH-R ₂

Ri and _R2 are as defined above - are reacted, or

b) for the preparation of a compound of formula I wherein Z, R 1 and R ₂ are as defined above and n is 2, a compound of formula ΠΙ wherein R is methyl: with an amine of formula R ₁ -NH-R ₂ R 1 and R ₂ are as defined above and are reacted with paraformaldehyde

c) for the preparation of a compound of general formula (Ib), wherein n, R 1 and R ₂ are as defined above, a narrow group of compounds of formula (I) wherein n, R 1 and R ₂ is as defined above, and optionally converting the 2-imidazolinone derivatives of formula (I) obtained by process a), b) or c) into an acid addition salt.

According to the present invention, the compounds of formula I, when Z is C = O, are reacted with the halo ketones of formula (ahol), wherein n is 1 or 2 and X is halogen, and the corresponding amine. , in an organic solvent in the presence of an acid scavenger.

The solvent may be an apolar solvent, preferably toluene or a dipolar aprotic solvent, preferably methyl isobutyl ketone.

The acid acceptor may be an organic base, preferably triethylamine or the reactant amine itself, or an inorganic base, preferably potassium carbonate.

The amount of the acid-binding base can be 1-3 moles, depending on whether the amine used is added as the base or as its hydrochloride salt.

The reaction is carried out at the boiling point of the solvent for 2-40 hours with stirring. The progress of the re25 action was followed by thin layer chromatography. The resulting compounds of formula (I) are isolated by evaporation of the reaction mixture, followed by filtration or extraction after mixing with water. The product is recrystallized if desired.

In the case where the reactant amine is used as an acid scavenger, the residue is recrystallized from an organic solvent, preferably a lower alcohol, after evaporation of the reaction mixture.

In the case where n = 2 and Z is -C-, ||

The compounds of formula (I) can then be prepared by the Mannich reaction of the ketone of formula (III) with the corresponding amine [Arch. Pharm., 250, 647 (1912)]. This reaction clearly occurs on the methyl group adjacent to the carbonyl group and does not affect the ureido moiety. In this case, a lower alcohol, preferably ethanol, is used as the solvent. The ketones of formula (II) and (III) can be prepared in a known manner by the Friedel-Crafts reaction. [J. Chem. Soc. 68, 2350 (1946)].

The compound of formula (I) of the present invention, when Z is -CH, is provided

I

OH base ketones can be prepared from base metal complexes by reduction with complex metal hydrides in an organic solvent.

The organic solvent used is a lower alcohol or a mixture of such alcohol and acetonitrile at a temperature between 20-50 ° C.

Preferably, the reducing agent is sodium tetrahydroborate (III). The progress of the reaction was monitored by thin layer chromatography. Isolate the product by pouring the reaction mixture into water and then pouring it

HU 213 104 Β followed by filtration. The product is recrystallized from an organic solvent if desired.

The reduction of the ketone compounds of formula (I) can be accomplished by the Meerwein-Ponndorf-Verley reduction [Ann. Chem., 444, 224 (1926); Angew. Chem., 39, 138 (1926)], for example in an isopropanolic medium with aluminum isopropylate.

The compounds of formula (I) may be converted, if desired, into an acid addition salt by reaction with an organic acid, preferably tartaric acid or an inorganic acid, preferably sulfuric acid, phosphoric acid, hydrochloric acid.

The structure of the compounds of formula I is clearly confirmed by spectroscopic data.

The biological activity of the compounds of the invention has been studied in detail.

To study the oxygen deficiency of the brain, Cartheuser [Cqnad. Physiol. Pharmacol., 66, 1389 (1988)], whereby the animal becomes unconscious to gradually withdraw oxygen from the inhaled air and the electrical activity (EEG) of brain function becomes isoelectric (iEEG). The model is usually used on an anesthetized (anesthetized) animal; measure the time to the appearance of the iEEG (T _iEEG ).

Adult male, adult Hannover-Wistar rats weighing 350-400 g, prepared for chronic EEG, were used in these studies. The compounds were administered orally at a dose of 50 mg / kg, and after 30 minutes the animals were individually enclosed in transparent chambers. The chambers were purged with nitrogen gas (1.67 rpm).

^The Thi-C was measured and ^the percent effect of the compounds on control was calculated using the following formula:

effect% = [10 ^{ΓιΕΕθ / 46} · ⁵ -1] * 100

In this experiment, lunarizine, nimodipine and vinpocetine, commonly used in cerebrovascular disease, reduced T _iEEG by 16-18%, while the new compounds of formula I reduced _TIEEG by _32-39 % (Table 1).

Table 1. Effect of Reference Materials and Compounds of Formula (I) on TiEEG in Control Rat (N)

Number of animals TjEEG (average) Effect control (53) 28.1 - flunarizine (6) 24.8 -18 nimodipine (6) 25.1 -16 vinpocetine (6) 25.1 -16 Example 7 - (I) (5) 20.6 -39 Example 6- (I) (12) 21.7 -32

Based on the results of the study, compounds of formula I can be used in cerebrovascular (cerebral haemorrhage, embolism, thrombosis, spasm) and constrictive (tumor, hematoma, hydrocephalus) processes, cerebral injuries (commotio, contusion, surgery, edema), respiratory paralysis and cardiac arrest. consequences.

The daily dose of the compound of formula (I) is 0.1 mg / kg body weight, administered once or repeatedly, orally or parenterally.

The active compounds of formula (I) may be formulated in pharmaceutical compositions with non-toxic, inert solid or liquid carriers and / or excipients suitable for parenteral or enteral administration. Suitable carriers include, for example, water, gelatine, lactose, starch, pectin, magnesium stearate, talc, vegetable oils and the like.

The active ingredient may be in the form of conventional pharmaceutical compositions, in particular solid forms such as round or square tablets, dragees, capsules such as gelatin capsules, pills, suppositories and the like.

The amount of solid active ingredient may vary over a wide range, preferably from about 25 mg to about 1 g. The formulations may also contain conventional pharmaceutical excipients, such as preservatives. They may be prepared by conventional techniques such as sieving, mixing, granulating and pressing components for solid formulations. The compositions may also be subjected to other conventional pharmaceutical techniques, such as sterilization in the case of injection.

The invention is illustrated by the following embodiments:

Example 1 1- (5-Methyl-2-imidazolinon-4-yl) -2-hexamethylene-imino-ethanone hydrochloride

5.22 g (0.03 mol) of 4- (chloroacetyl) -5-methyl-2-imidazolone and 6.15 g, 7.0 ml (0.061 mol) of hexamethyleneimine are suspended in 80 ml of toluene and refluxed for 3 hours. After completion of the reaction, the reaction mixture was concentrated in vacuo and the resulting residue was added with water (30 mL) and extracted with chloroform (30 mL).

The organic layers were combined and acidified to pH 2 with hydrochloric acid ethyl alcohol after drying over sodium sulfate. The resulting suspension is triturated with ether. The product was filtered off and recrystallized from methanol.

Yield: 2.5 g (30.4%) of the title compound.

Melting point: 261-262 ° C.

Example 2 1- (5-Methyl-2-imidazolinon-4-yl) -3- (4-phenylpiperazin-1-yl) -1-propanone hydrochloride

1.97 g (0.01 mol) of 4- (3-chloropropionyl) -5-methyl-2-imidazolinone with 1.7 g (1.6 ml) (0.01 mol) of N-phenylpiperazine and 1 g of 1.4 ml) (0.01 mol) in triethylamine in 50 ml toluene and refluxed for 4 hours. The mixture was concentrated in vacuo and the residue was triturated with water (40 mL). The resulting crystalline material was filtered off and recrystallized from methanol (20 mL).

Yield: 1.4 g (44.6%) of the title compound. Melting point: 217-220 ° C.

After cooling, the precipitate was filtered off and washed with a small amount of ethanol and recrystallized from methanol.

Yield: 1.54 g (44.4%) of the title compound.

Melting point: 241-244 ° C.

Example 3] - (5-Methyl-2-imidazolinon-4-yl) -2- (4-phenyl-1,2,3,6-tetrahydropyridin-1-yl) -ethanone

Following the procedure of Examples 1 and 2, the title product is obtained.

Yield: 84.4%.

Melting point: 225-226 ° C.

Example 4] - (5-methyl-2-imidazolinon-4-yl) -2- [4- (4-chlorophenyl) -1,2,3,6-tetrahydropyridin-1-yl] ethanone

Example 3 gave the title product.

Yield: 75.5%.

Melting point: 247-250 ° C.

Example 5

1-4. In the same manner as in the Examples, the following products were obtained:

1- (5-methyl-2-imidazolinon-4-yl) -2- [4- (diphenylmethyl) -1-piperazinyl] ethanone Yield: 35.9%.

Melting point: 143-146 ° C. 1- (5-methyl-2-imidazolinon-4-yl) -2- [4- (4-chlorophenyl) piperidin-1-yl] ethanone hydrochloride Yield: 75.1%.

Melting point: 250 'C, dec. 1- (5-Methyl-2-imidazolinon-4-yl) -2- (4-phenylpiperazin-1-yl) ethanone Yield: 35.1%.

Melting point: 229-232 ° C. 1- (5-Methyl-2-imidazolinon-4-yl) -2- [4- (2-pyrimidinyl) piperazin-1-yl] ethanone Yield: 46.4%.

Melting point: above 270 ° C. 1- (5-methyl] -2-imidazolinon-4-yl) -2-3- (4-benzylpiperazin-1-yl) -1-propanone hydrochloride Yield: 44.2%.

Melting point: 220-221 ° C. l- (5-methyl-2-imidazolinone-4-yl) -2- [4- (4-fluorophenyl) -1,

2.3.6-Tetrahydropyridin-1-yl] -ethanone Yield: 91.4%.

Melting point: 240-244 ° C (b). 1- (5-Methyl-2-imidazolinon-4-yl) -3- [4- (2-pyrimidinyl) piperazin-1-yl] -propanone hydrochloride

Yield: 94.1%.

Melting point: 250-252 ° C.

Example 6

- (5-Methyl-2-imidazolinon-4-yl) -3- (4-phenyl-1,2,3,6-tetrahydropyridine-propanone hydrochloride 1.4 g (0.01 mole) of 4-acetyl-5- methyl-2-imidazolidinone,

4-Phenyl-1,2,3,6-tetrahydropyridine hydrochloride (1.95 g, 0.01 mole) and paraformaldehyde (0.3 g, 0.01 mole) in boiling ethanol (10 ml) were boiled in ethyl acetate (0.5 ml) for 4 hours. presence. An additional 0.15 g of paraformaldehyde is added and after another 2 hours reflux, another 0.15 g of paraformaldehyde is added. After a total of 30 hours of threading to 10 'C

Example 7 1- (5-Methyl-2-imidazolinon-4-yl) -2- (4-phenyl-1,2,3,6-tetrahydropyridin-1-yl) -ethanol

4.6 g (0.015 mol) of 1- (5-methyl-2-imidazolinon-4-yl) 3- (4-phenyl-1,2,3,6-tetrahydropyridin-1-yl) -ethanone are suspended in 60 ml of methanol. . Sodium petrahydroborate (1H)] (0.8 g) was added in small portions at room temperature, followed by another 0.2 g of sodium tetrahydroborate (III) after stirring for 20 minutes. After stirring for a total of 1 hour, the mixture was poured into 150 ml of water, and after stirring for 10 minutes, the product was filtered off, washed with water and recrystallized from methanol.

Yield: 3.65 g (81.6%) of the title compound. Melting point: 187-189 ° C.

Example 8

In analogy to Example 7, the following compounds were prepared:

1- (5-Methyl-2-imidazolinon-4-yl) -2- [4- (4-fluorophenyl) 1,2,3,6-tetrahydropyridin-1-yl] ethanol

Yield: 91.7%.

Melting point: 199-202 ° C.

1- (5-methyl-2-imidazolinon-4-yl) -3- [4- (2-pyrimidinyl) piperazin-1-yl] -1-propanol

Yield: 52.9%.

Melting point: 195-200 'C.

1- (5-methyl-2-imidazolinon-4-yl) -3- (4-benzylpiperazin-1-yl) -1-propanol

Yield: 27.7%.

Melting point: 223-225 ° C.

l- (5-methyl-2-imidazolinone-4-yl) -3- (4-phenyl-piperazin-l-yl) -propanol

Yield: 62.0%.

Melting point: 203-207 ° C.

1- (5-methyl-2-imidazolinon-4-yl) -2- [4- (4-chlorophenyl) 1,2,3,6-tetrahydropyridin-1-yl] ethanol

Yield: 95.2%.

Melting point: 196-203 ° C.

- (5-Methyl-2-imidazolinon-4-yl) -3- (4-phenyl-1,2,3,6-tetrahydropyridin-1-yl) -1-propanol

Yield: 82.3%.

Melting point: 176-180 ° C.

- (5-Methyl-2-imidazolinon-4-yl) -2- (4-phenyl-piperidin-1-yl) -ethanol

Yield: 84.1%.

Melting point: 208-212 ° C.

l- (5-methyl-2-imidazolinone-4-yl) -2- (4-benzyl-piperazin-l-yl) ethanol

Yield: 63.3%.

Melting point: 207-211 ° C.

1- (5-methyl-2-imidazolinon-4-yl) -2- [4- (2-pyrimidinyl) piperazin-1-yl] ethanol

Yield: 32.9%.

Melting point: 191-193 ° C.

Claims (5)

PATENT CLAIMS A process for the preparation of 2-imidazolinone derivatives of formula I wherein Z is> C = O or> CH-OH; n is 1 or 2; R 1 and R ₂ together with the nitrogen atom to which they are attached form a hexamethylenimine ring, a piperazine ring substituted by phenyl, halophenyl, benzyl, diphenylmethyl and 2-pyrimidinyl, or a phenyl or halophenyl group substituted by 1,2 , 3,6-tetrahydropyridine or piperidine ring, with the proviso that when Z is > C = O and n is 1, then R 1 and R _2, together with the nitrogen atom to which they are attached, are different from the piperazine group and acid addition salts thereof. that a) a compound of formula II wherein n is 1 or 2, X is halogen with an amine of formula R ₁ -NH-R ₂ R 1 and R ₂ are as defined above, or b) for the preparation of compounds of formula I wherein Z, R 1 and R ₂ are as defined above and n is 2 for a compound of formula ΠΙ wherein R is methyl, with an amine of formula R ₁ -NH-R ₂ R ₂ is as defined above - are introduced and reacted with paraformaldehyde or c) for the preparation of a compound of general formula (Ib), wherein n, R 1 and R ₂ are as defined above, a narrow group of compounds of formula (I), wherein n, R 1 and R ₂ has the meaning given above - and if desired, a), The 2-imidazolinone derivatives of formula I obtained by process b) or c) are converted into the acid addition salt. Process (a) according to claim 1, characterized in that the reaction is carried out in an aprotic solvent in the presence of an acid scavenger at the boiling point of the solvent. Process b) according to claim 1, characterized in that the reaction is carried out in a C 1 -C 6 alkanol. Process c) according to Claim 1, characterized in that the reduction is carried out with a metal hydroborate in a C 1 -C 4 alcohol or a mixture thereof with acetonitrile. A process for the preparation of a pharmaceutical composition comprising a compound of formula (I) wherein the substituents are as defined in claim 1, characterized in that the compound of formula (I) wherein: Z is> C = O or> CH-OH; n is 1 or 2; R 1 and R ₂ together with the nitrogen atom to which they are attached form a hexamethylenimine ring, a piperazine ring substituted by phenyl, halophenyl, benzyl, diphenylmethyl and 2-pyrimidinyl, or a phenyl or halophenyl group substituted by 1,2 , 3,6-tetrahydropyridine or piperidine ring, with the proviso that when Z is > C = O and n is 1, then R 1 and R ₂ are not piperazine substituted with benzyl and the acid addition salts thereof are known per se mixed with a pharmaceutical carrier and / or excipient to form a pharmaceutical composition.