RS20100352A2 - METHOD OF PREPARATION AND USE OF PHARMACOLOGICAL ACTIVE N-CARBAMYLMETHYL-4 (R) -Phenyl-2-Pyrrolidinone - Google Patents

Abstract

Invention herewith described refers to the R-enantiomer of N-carbamoylmethyl-4-phenyl-2-pyrrolidinone (R-Carphedon) of pharmacological value. The method of its preparation includes compounds (I) according to claim 1 with N-alkylation of 4(R)-phenyl-2-pyrrolidinone with ethyl bromoacetate which is followed by the carbamoylation of the intermediate N-ethoxycarbonylmethyl-4(R)-aryl-2-pyrrolidinone with ammonia.

Description

Method of preparation and use of pharmacologically active N-carbamoylmethyl-4(R)-phenyl-2-

pyrrolidinone

State of the art

The invention relates to the discovery of the biologically active R-enantiomer of N-carbamoylmethyl-4-aryl-2-pyrrolidinone and a simple and effective method of its preparation.

It is known that people in a stressful situation or under psycho-emotional stress show irrational and inappropriate forms of behavior, disorders of mental ability, reduced speed of reaction and increased number of wrong decisions, etc.

Therefore, the discovery of drugs that alleviate and prevent the effect of the stress factor is of significant importance. Nootropic CABA derivatives are used for this purpose: Phenibut and Baclofen, although their use is accompanied by drowsiness, depression, dizziness, reduced psychomotor reactions, etc.

In comparison with GABA derivatives, another agent that is widely used for this purpose, N-carbamoylmethyl-4-aryl-2-pyrrolidinone (Carphedon (Caprhedon engl., INN),) could be considered a much more promising psychostimulant due to less pronounced side effects.

The R- and S- enantiomeric forms of carphedon and their pharmacological properties are not known. To date, only the pharmacological properties of racemic carphedon have been published, and there is no information on possible differences in pharmacological properties for its separate R- and S-enantiomers. The lack of this very important information also does not allow an adequate assessment of the real pharmacological potential of carphedon, which is already used in medicine, because in reality it is represented by a mixture of R- and S- enantiomers, which can show different pharmacological properties.

In the present invention, we developed methods for the preparation of pure R- and S-carphedone and unexpectedly discovered that R-carphedone as an antidepressant, analgesic, muscle relaxant and psychostimulant compound is more effective than racemic carphedone or S-carphedone.

Abstract and detailed description

The invention relates to the R-enantiomer of 4-phenyl-1-pyrrolidineacetic acid amide. In particular, the invention relates to N-carbamoylmethyl-4(R)-phenyl-2-pyrrolidinone of the formula:

a new chemical compound of pharmacological value and a method of its production.

Detailed description of the invention

As we discovered, the preparation of R-carphedone 4 as well as S-carphedone 4ase can be easily achieved by N-alkylation of available 4(R)-phenyl-2-pyrrolidinone (1) or 4(S)-phenyl-2-pyrrolidinone (1a) with ethyl bromoacetate (2) in the presence of a strong base and subsequent transformation of the ethoxycarbonyl group in the intermediate 2-pyrrolidinones 3 and 3 to the carbamoyl function by treatment with ammonia.

The following examples show the synthetic part of the invention.

Example 1

N-carbamoylmethyl-4(R)-phenyl-2-pyrrolidinone (4).Solution of 4(R)-phenyl-2-pyrrolidinone (1)

(345 mg, 2.14 mM) in 1,4-dioxane (30 ml) was added to a solution of sodium hydride (56 mg, 2.35 mM) in 1,4-dioxane (30 ml). The mixture was heated to 80-90°C for 30 minutes and then

cooled to room temperature. It has been added! bromoacetate (393 mg, 2.37 mM) and the reaction mixture was refluxed at 110-120°C for 6 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate-hexane 1:1 to give N-ethoxycarbonylmethyl-4(R)-phenyl-2-pyrrolidinone (3)

(338 mg, 64%). [α]D<OH>=+4.6°(c=3, MeOH).<»>H NMR (CDCl 3 ), δ: 1.28 (3H, t, CH 2 CH 3 ); 2.59 (1H, d, d, 3-CH2); 2.87 (1H, d, d, 3-CH2); 3.54 (1H, t, 5-CH2); 3.64 (IH, quintet, 4-CH); 3.83 (1H, t, 5-CH2); 4.11 (2H, s, NCH2CO); 4.20 (2H, q, CH2CH3); 7.20-7.39 (5H, m, C5H5).

A solution of N-ethoxycarbonylmethyl-4(R)-phenyl-2-pyrrolidinone (3) (250 mg, 1.01 mM) in methanol (30 ml) was saturated with a stream of ammonia gas for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography with ethyl acetate-hexane 1:1 silica gel to give N-carbamoylmethyl-4(R)-phenyl-2-pyrrolidinone (4a) (187 mg, 85%). T.t. 107.5-108°C. [a]D2O= + 8.5o (c=3, MeOH). 1 H NMR (CDCIb), δ: 2.61 (1H, d, d, 3-CH 2 ); 2.87 (1H, d, d, 3-CH2); 3.54 (1H, t, 5-CH2); 3.66 (IH, quintet, 4-CH); 3.89 (1H, t, 5-CH2); 4.00 (2H, s, NCH2CO); 5.68 and 6.21 (IH and IH, br.s and br.s, NH2); 7.20-7.40 (5H, m, C6H5).

Example2

N-carbamoylmethyl-4(S)-phenyl-2-pyrrolidinone (4a). By substituting pyrrolidinone 1 in Example 1 with 4(S)-phenyl-2-pyrrolidinone (la), the S-enantiomeric N-carbonylmethyl-4(S)-phenyl-2-pyrrolidinone (4a) was obtained. [α]D<20>=-8.3° (c=3, MeOH). 1 H NMR (CDCl 3 ), δ: 2.61 (1H, d, d, 3-CH 2 ); 2.87 (1H, d, d, 3-CH2); 3.54 (1H, t, 5-CH2); 3.66 (IH, quintet, 4-CH); 3.89 (1H, t, 5-CH2); 4.00 (2H, s, NCH2CO); 5.68 and 6.21 (IH and IH, broad singlet (hereinafter referred to as "br.s.", broad singlet engl.) and br.s, NH2); 7.20-7.40 (5H, m, C6H5).

According to the invention, we performed a comparative study of antidepressant, muscle relaxant, locomotor and analgesic activity for R- and S-enantiomers of N-carbamoylmethyl-4-aryl-2-pyrrolidinone and compared them with those of racemic (carphedone) (Table 1-3). Unexpectedly, we found that R-carfedone has more pronounced desirable pharmacological properties compared to S-carfedone.

The data in Table 1 demonstrate excellent antidepressant activity of the R-enantiomer of carphedon using the standard Porsolt forced swim test (FST). After the initial treatment with R-carphedone, the animals did not spend a single moment immobile. Also, in the case of animals treated with racemic carphedone, immobility time was significantly shorter. Contrary to the above, mice in the control and S-carphedone groups showed characteristic behavior for the conditions of the FST test registered as immobility in response to the stress factor. A similar advantage of R-carphedone compared to S-carphedone and the racemate was observed in experiments characterizing the motor activity of mice in a standard open field test (Table 2). i.p. administration of the test compounds at equal doses of 50 mg/kg caused a prolonged and stable increase in the activity of the animals when 0R-carphedone, which at the end of the observation period of 120 minutes was approximately twice as high as the activity induced by S-carphedone.

The data from Table 3 show that lower doses of R-carfedone achieved the same muscle relaxant activity and analgesic effect of the tested compounds compared to equal doses of S-carfedone. The obtained results prove a high therapeutic value for R-carphedone that exceeds the same therapeutic value for racemic carphedone, because the pharmaceutical properties of the latter are negatively affected by the presence of S-carphedone characterized by reduced and in some experiments significantly weaker activity.

Claims (7)

1. N-carbamoylmethyl-4(R)-phenyl-2-pyrrolidinone (I) with neurotropic activity: where<*>denotes a chiral carbon atom. 2. Use of the compound (I) according to claim 1, characterized in that said compound is used as an antidepressant. 3. Use of compound (I) according to claim 1, characterized in that said compound is used as a stress protection agent. 4. Use of the compound (I) according to claim 1, characterized by the fact that said compound is used as a modulator of locomotor activity. 5. Use of the compound (I) according to claim 1, characterized in that said compound is used as a muscle relaxant. 6. The use of the compound (I) according to claim 1, indicated when said compound is used as an analgesic. 7. A method for the preparation of compound (I) according to claim 1, characterized by carrying out N-alkylation of 4(R)-phenyl-2-pyrrolidinone with ethyl bromoacetate followed by carbamoylation of the intermediate N-ethoxycarbonylmethyl-4(R)-aryl-2-pyrrolidinone with ammonia.