Indian Patents. 269633:A METHOD FOR THE PREPARATION OF N-CARBAMOYLMETHYL-4-(R)-PHENYL-2-PYRROLIDINONE

Title of Invention	A METHOD FOR THE PREPARATION OF N-CARBAMOYLMETHYL-4-(R)-PHENYL-2-PYRROLIDINONE
Abstract	The invention relates to the R cnantiomer of N-carbamoylmethyl-4-phenyl -2 pyrrolidinone (R-Carphedon) of phar macological value. The melhod of its preparation includes the N-alkylation of 4(R)-phenyl 2 pyrrolidinone with ethyl bromoacetate in the presence of a strong base and the treatment of intermediate N-ethoxycarbonylmethyl-4(R)-phenyl-2 pyrrolidinone with ammonia.

Full Text	Method of preparation and use of pharmacologically active N-carbamoylmethyl-4(R)-phenyl-2-pyrrolidinone Background of the invention 5 The invention relates to the discovery of the biologically active R-enantiomer of N- carbamoylmethyl-4-aryl-2-pyrrolidinone and easy and effective method of its preparation. It is known that humans in a stress situation or under psycho-emotional strain exhibit irrational and inadequate forms of behavior, disorders of mental capacity, declined speed of reaction, and increased number of erroneous decisions etc. 10 Therefore discovery of pharmaceuticals abating and preventing the effect of a stress factor is of substantial importance. For this purpose the nootropic GABA derivatives: Phenibut and Baclofen are applied, even though their use is followed by drowsiness, depression, dizziness, lowered psychomotor reactions etc. In comparison to GABA derivatives another agent widely used for this purpose N- 15 carbamoylmethyl-4-aryl-2-pyrrolidinone (Carphedon, INN) could be regarded as a much more perspective psycho-stimulator due to the less pronounced side effects. The R- and S- enantiomeric forms of Carphedon and their pharmacologic properties are not known. The pharmacologic properties of only the racemic Carphedon are published today and there is no data concerning possible differences of pharmacological properties for its 20 separate R- and S-enantiomers. The absence of this highly important information also does not allow to adequately estimate the real pharmaceutical potential of Carphedon already used in medicine, because in reality it is represented by a mixture of R- and S- enantiomers, which may exhibit different pharmacologic properties. In the present invention we have developed methods for preparation of pure R- and S- 25 Carphedon and unexpectedly discovered that R-Carphcdon as an antideprcssant, analgesic, muscle relaxant and psycho-stimulating compound is more effective than the racemic Carphedon or 5-Carphedon. Summary and detailed description. 30 The invention relates to the R-enantiomer of 4-phenyl-1-pyrrolidineacetic acid amide. More particularly, the invention relates to N-carbamoylmethyl-4(R)-phcnyl-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 have discovered, the preparation of R-Carphedon 4 the same as S-Carphedon 4a can be easily achieved by the means of the N-alkylation of available 4(R)-phenyl-2- pyrrolidinone (1) or 4(S)-phenyl-2-pyrrolidinone (la) with ethyl bromoacetate (2) in the presence of a strong base and by the following transformation of ethoxycarbonyl group in the intermediate 2-pyrrolidinones 3 and 3a into carbamoyl function by the treatment with ammonia. Example 1 N-Carbamoylmethyl-4(R)-phenyl-2-pyrrolidinone (4). The solution of 4(R)-phenyl-2- pyrrolidinone (1) (345 mg, 2.14 mM) in 1,4-dioxane (30 ml) was added to the suspension of sodium hydride (56 mg, 2.35 mM) in 1,4-dioxane (30 ml). The mixture was heated at 80-90°C during 30 min and then cooled to room temperature. Ethyl bromoacetate (393 mg, 2.37 mM) was added and the reaction mixture was re fluxed at 110-20°C for 6 hours. Obtained mixture was concentrated under reduced pressure. Residue was purified by column chromatography on silicagel with ethylacetate-hexane mixture 1:1, giving N-ethoxycarbonylmethyl-4(/?)-phenyl-2- pyrrolidinone (3) (338 mg, 64%). [α]D20=+4.6°(c=3, MeOH). lH NMR (CDC1.0, 8: 1.28 (3H, t, CH2CH3); 2.59 (1H, d, d, 3-CH2); 2.87 (1H, d, d, 3-CH2); 3.54 (1H, t, 5-CH2); 3.64 (1H, 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, C6H5). The solution of N-ethoxycarbonylmethyl-4(i?)-phenyl-2-pyrrolidinone (3) (250 mg, 1.01 mM) in methanol (30 ml) saturated by stream of gaseous ammonia for 5 hours. Reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography with cthylacctatc-hcxanc mixture 1:1 silicagel giving N-carbamoylmcthyl-4(i?)-phenyl-2- pyrrolidinone (4a) (187 mg, 85%). M.p. 107.5-108 °C. [α]D20=+8.5° (c=3, MeOH). 1H NMR (CDCl3), 6: 2.61 (1H, d, d, 3-CH2); 2.87 (1H, d, d, 3-CH2); 3.54 (1H, t, 5-CH2); 3.66 (1H, quintet, 4-CH); 3.89 (1H, t, 5-CH2); 4.00 (2H, s, NCH2CO); 5.68 and 6.21 (1H and 1H, br.s and br.s, NH2); 7.20-7.40 (5H, m, C6H5). Example 2 N-Carbamoylmethyl-4(iS)-phenyl-2-pyrrolidinone (4a). Substituting pyrrolidinonc 1 in Example 1 by 4(S)-phenyl-2-pyrrolidinone (1a) S-enantiomeric N-carbamoylmethyl-4(.S)- phenyl-2-pyrrolidinone (4a) was obtained. [a]D2O=-8.3° (c-3, MeOH). 1H NMR (CDC13), 5: 2.61 (1H, d, d, 3-CH,); 2.87 (1H, d, d, 3-CH2); 3.54 (1H, t, 5-CH2); 3.66 (1H, quintet, 4-CH); 3.89 (1H, t, 5-CH2); 4.00 (2H, s, NCH2CO); 5.68 and 6.21 (1H and 1H, br.s and br.s, NH2); 7.20-7.40 (5H, m, C6H5). According to the invention, we have performed the comparative investigation of antidepressant, muscle relaxant, locomotor and analgesic activities for R- and S-enantiomers of N-carbamoylmethyl-4-aryl-2-pyrrolidinone and compared with those of the racemic one (Carphedon) (Table 1-3). We have unexpectedly discovered, that i?-Carphedon possesses more pronounced desired pharmacological properties comparing with S-Carphedon. The data presented in Table 1 demonstrate an excellent antidepressant activity of R- enantiomer of Carphedon using the standard Porsolt forced swim test (FST). After the preliminary treatment with R-Carphedonl, the animals did not spent any time immobile. Also in the case of animals treated with racemic Carphedon, the immobility period was significantly shorter. Contrary to that, mice in the control and S-Carphedon groups demonstrated characteristic behavior for FST test conditions registered as an immobilization in response to stress factor. Similar advantage of R-Carphedon in comparison to S-Carphedon and racemate was observed in experiments characterizing the motor activity of mice in the standard open field test (Table 2). The i.p. administration of the test compounds in equal 50 mg/kg doses caused prolonged and stable increase in animal activity in the case of R-Carphedon, which at the end of the 120 min observation period was about two times higher than activity caused by S- Carphedonl. The data presented in Table 3 show that equal muscle relaxant activity and analgesic effect of tested compounds was achieved by the lower dosages of R-Carphedon than the same of S-Carphedon. The obtained results prove the high therapeutic value for R-Carphedon exceeding the same one for racemic Carphedon, because pharmaceutical properties of the latter are negatively affected by the presence of S-Carphedon, which characterizes by lower and in some experiments by considerably weaker activity. We claim: 1. N-carbamoylmethyl-4(7?)-phenyl-2-pyrrolidinone (I) with neurotropic activity: wherein * marks chiral carbon atom. 2. Use of compound (I) according to the claim 1 as an antidepressant. 3. Use of compound (I) according to the claim 1 as a stress-protective agent. 4. Use of compound (i) according to the claim 1 as a modulator of locomotor activity. 5. Use of compound (I) according to the claim 1 as a muscle relaxant. 6. Use of compound (I) according to the claim 1 as an analgesic. 7. Method of preparation of a compound (I) according to the claim 1 by the N-alkylation of 4(R)-phenyl-2-pyrrolidinone with ethyl bromoacetate following by carbamoylation of intermediate N-ethoxycarbonylmethyl-4(R)-aryl-2-pyrrolidinone with ammonia. The invention relates to the R cnantiomer of N-carbamoylmethyl-4-phenyl -2 pyrrolidinone (R-Carphedon) of phar macological value. The melhod of its preparation includes the N-alkylation of 4(R)-phenyl 2 pyrrolidinone with ethyl bromoacetate in the presence of a strong base and the treatment of intermediate N-ethoxycarbonylmethyl-4(R)-phenyl-2 pyrrolidinone with ammonia.

Full Text

Method of preparation and use of pharmacologically active
N-carbamoylmethyl-4(R)-phenyl-2-pyrrolidinone
Background of the invention
5 The invention relates to the discovery of the biologically active R-enantiomer of N-
carbamoylmethyl-4-aryl-2-pyrrolidinone and easy and effective method of its preparation.
It is known that humans in a stress situation or under psycho-emotional strain exhibit
irrational and inadequate forms of behavior, disorders of mental capacity, declined speed of
reaction, and increased number of erroneous decisions etc.
10 Therefore discovery of pharmaceuticals abating and preventing the effect of a stress
factor is of substantial importance. For this purpose the nootropic GABA derivatives: Phenibut
and Baclofen are applied, even though their use is followed by drowsiness, depression, dizziness,
lowered psychomotor reactions etc.
In comparison to GABA derivatives another agent widely used for this purpose N-
15 carbamoylmethyl-4-aryl-2-pyrrolidinone (Carphedon, INN) could be regarded as a much more
perspective psycho-stimulator due to the less pronounced side effects.
The R- and S- enantiomeric forms of Carphedon and their pharmacologic properties are
not known. The pharmacologic properties of only the racemic Carphedon are published today
and there is no data concerning possible differences of pharmacological properties for its
20 separate R- and S-enantiomers. The absence of this highly important information also does not
allow to adequately estimate the real pharmaceutical potential of Carphedon already used in
medicine, because in reality it is represented by a mixture of R- and S- enantiomers, which may
exhibit different pharmacologic properties.
In the present invention we have developed methods for preparation of pure R- and S-
25 Carphedon and unexpectedly discovered that R-Carphcdon as an antideprcssant, analgesic,
muscle relaxant and psycho-stimulating compound is more effective than the racemic Carphedon
or 5-Carphedon.
Summary and detailed description.
30 The invention relates to the R-enantiomer of 4-phenyl-1-pyrrolidineacetic acid amide. More
particularly, the invention relates to N-carbamoylmethyl-4(R)-phcnyl-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 have discovered, the preparation of R-Carphedon 4 the same as S-Carphedon 4a
can be easily achieved by the means of the N-alkylation of available 4(R)-phenyl-2-
pyrrolidinone (1) or 4(S)-phenyl-2-pyrrolidinone (la) with ethyl bromoacetate (2) in the
presence of a strong base and by the following transformation of ethoxycarbonyl group in the
intermediate 2-pyrrolidinones 3 and 3a into carbamoyl function by the treatment with ammonia.

Example 1
N-Carbamoylmethyl-4(R)-phenyl-2-pyrrolidinone (4). The solution of 4(R)-phenyl-2-
pyrrolidinone (1) (345 mg, 2.14 mM) in 1,4-dioxane (30 ml) was added to the suspension of
sodium hydride (56 mg, 2.35 mM) in 1,4-dioxane (30 ml). The mixture was heated at 80-90°C
during 30 min and then cooled to room temperature. Ethyl bromoacetate (393 mg, 2.37 mM) was
added and the reaction mixture was re fluxed at 110-20°C for 6 hours. Obtained mixture was
concentrated under reduced pressure. Residue was purified by column chromatography on
silicagel with ethylacetate-hexane mixture 1:1, giving N-ethoxycarbonylmethyl-4(/?)-phenyl-2-
pyrrolidinone (3) (338 mg, 64%). [α]D20=+4.6°(c=3, MeOH). lH NMR (CDC1.0, 8: 1.28 (3H, t,

CH2CH3); 2.59 (1H, d, d, 3-CH2); 2.87 (1H, d, d, 3-CH2); 3.54 (1H, t, 5-CH2); 3.64 (1H, 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,
C6H5).
The solution of N-ethoxycarbonylmethyl-4(i?)-phenyl-2-pyrrolidinone (3) (250 mg, 1.01 mM) in
methanol (30 ml) saturated by stream of gaseous ammonia for 5 hours. Reaction mixture was
concentrated under reduced pressure and the residue was purified by column chromatography
with cthylacctatc-hcxanc mixture 1:1 silicagel giving N-carbamoylmcthyl-4(i?)-phenyl-2-
pyrrolidinone (4a) (187 mg, 85%). M.p. 107.5-108 °C. [α]D20=+8.5° (c=3, MeOH). 1H NMR
(CDCl3), 6: 2.61 (1H, d, d, 3-CH2); 2.87 (1H, d, d, 3-CH2); 3.54 (1H, t, 5-CH2); 3.66 (1H,
quintet, 4-CH); 3.89 (1H, t, 5-CH2); 4.00 (2H, s, NCH2CO); 5.68 and 6.21 (1H and 1H, br.s and
br.s, NH2); 7.20-7.40 (5H, m, C6H5).
Example 2
N-Carbamoylmethyl-4(iS)-phenyl-2-pyrrolidinone (4a). Substituting pyrrolidinonc 1 in
Example 1 by 4(S)-phenyl-2-pyrrolidinone (1a) S-enantiomeric N-carbamoylmethyl-4(.S)-
phenyl-2-pyrrolidinone (4a) was obtained. [a]D2O=-8.3° (c-3, MeOH). 1H NMR (CDC13), 5: 2.61
(1H, d, d, 3-CH,); 2.87 (1H, d, d, 3-CH2); 3.54 (1H, t, 5-CH2); 3.66 (1H, quintet, 4-CH); 3.89
(1H, t, 5-CH2); 4.00 (2H, s, NCH2CO); 5.68 and 6.21 (1H and 1H, br.s and br.s, NH2); 7.20-7.40
(5H, m, C6H5).
According to the invention, we have performed the comparative investigation of
antidepressant, muscle relaxant, locomotor and analgesic activities for R- and S-enantiomers of
N-carbamoylmethyl-4-aryl-2-pyrrolidinone and compared with those of the racemic one
(Carphedon) (Table 1-3). We have unexpectedly discovered, that i?-Carphedon possesses more
pronounced desired pharmacological properties comparing with S-Carphedon.
The data presented in Table 1 demonstrate an excellent antidepressant activity of R-
enantiomer of Carphedon using the standard Porsolt forced swim test (FST). After the
preliminary treatment with R-Carphedonl, the animals did not spent any time immobile. Also in
the case of animals treated with racemic Carphedon, the immobility period was significantly
shorter. Contrary to that, mice in the control and S-Carphedon groups demonstrated
characteristic behavior for FST test conditions registered as an immobilization in response to
stress factor.
Similar advantage of R-Carphedon in comparison to S-Carphedon and racemate was
observed in experiments characterizing the motor activity of mice in the standard open field test
(Table 2). The i.p. administration of the test compounds in equal 50 mg/kg doses caused

prolonged and stable increase in animal activity in the case of R-Carphedon, which at the end of
the 120 min observation period was about two times higher than activity caused by S-
Carphedonl.
The data presented in Table 3 show that equal muscle relaxant activity and analgesic
effect of tested compounds was achieved by the lower dosages of R-Carphedon than the same of
S-Carphedon.

The obtained results prove the high therapeutic value for R-Carphedon exceeding the
same one for racemic Carphedon, because pharmaceutical properties of the latter are negatively
affected by the presence of S-Carphedon, which characterizes by lower and in some experiments
by considerably weaker activity.

We claim:
1. N-carbamoylmethyl-4(7?)-phenyl-2-pyrrolidinone (I) with neurotropic activity:

wherein * marks chiral carbon atom.
2. Use of compound (I) according to the claim 1 as an antidepressant.
3. Use of compound (I) according to the claim 1 as a stress-protective agent.
4. Use of compound (i) according to the claim 1 as a modulator of locomotor activity.
5. Use of compound (I) according to the claim 1 as a muscle relaxant.
6. Use of compound (I) according to the claim 1 as an analgesic.
7. Method of preparation of a compound (I) according to the claim 1 by the N-alkylation
of 4(R)-phenyl-2-pyrrolidinone with ethyl bromoacetate following by carbamoylation
of intermediate N-ethoxycarbonylmethyl-4(R)-aryl-2-pyrrolidinone with ammonia.

The invention relates to the R cnantiomer of N-carbamoylmethyl-4-phenyl -2 pyrrolidinone (R-Carphedon) of phar macological value. The melhod of its preparation includes the N-alkylation of 4(R)-phenyl 2 pyrrolidinone with ethyl bromoacetate in the presence of a strong base and the treatment of intermediate N-ethoxycarbonylmethyl-4(R)-phenyl-2 pyrrolidinone with ammonia.

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Patent Number

269633

Indian Patent Application Number

4069/KOLNP/2008

PG Journal Number

45/2015

Publication Date

06-Nov-2015

Grant Date

29-Oct-2015

Date of Filing

06-Oct-2008

Name of Patentee

AKCIJU SABIEDRIBA OLAINFARM

Applicant Address

RUPNICU IELA 5, 2114 OLAINE

Inventors:

#	Inventor's Name	Inventor's Address
1	VORONA, MAKSIM	DAMMES IELA 40-70, LV-1069 RIGA
2	VEINBERG, GRIGORY	BRIVIBASGATVE 236-33, LV-1039 RIGA
3	ZVEJNIECE, LIGA	ROSTOKAS IELA 34-16, LV-1029 RIGA
4	CHERNOBROVIJS, ALEKSANDRS	PARKA IELA 1-13, LV-2114 OLAINE
5	KALVINSH, IVARS	LIBIESU IELA 25, LV-5052 IKSKILE
6	KARINA, LIGITA	MARKALNES IELA 3-11, LV-1024 RIGA
7	DAMBROVA, MAIJA	GRINA BULV. 15-7, LV-1002 RIGA

PCT International Classification Number

C07D 207/26

PCT International Application Number

PCT/EP2007/052424

PCT International Filing date

2007-03-15

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	P-06-45	2006-03-16	Latvia