WO2007104780A2 - N- carbamoylmethyl- 4- (r) -phenyl-2-pyrr0lidin0ne, method of its preparation and pharmaceutical use - Google Patents

N- carbamoylmethyl- 4- (r) -phenyl-2-pyrr0lidin0ne, method of its preparation and pharmaceutical use Download PDF

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WO2007104780A2
WO2007104780A2 PCT/EP2007/052424 EP2007052424W WO2007104780A2 WO 2007104780 A2 WO2007104780 A2 WO 2007104780A2 EP 2007052424 W EP2007052424 W EP 2007052424W WO 2007104780 A2 WO2007104780 A2 WO 2007104780A2
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phenyl
pyrrolidinone
carphedon
carbamoylmethyl
compound
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WO2007104780A3 (en
Inventor
Grigory Veinberg
Maksim Vorona
Liga Zvejniece
Aleksandrs Chernobrovijs
Ivars Kalvinsh
Ligita Karina
Maija Dambrova
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Olainfarm AS
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Priority to EEP200800063A priority Critical patent/EE05536B1/en
Priority to HRP20090524AA priority patent/HRP20090524C1/en
Priority to MEP-2009-293A priority patent/ME01192B/en
Priority to DE602007005244T priority patent/DE602007005244D1/en
Priority to US12/226,332 priority patent/US9102615B2/en
Priority to CA2647206A priority patent/CA2647206C/en
Priority to PL07726915T priority patent/PL2013166T3/en
Priority to EA200801978A priority patent/EA014668B1/en
Priority to AT07726915T priority patent/ATE460396T1/en
Application filed by Olainfarm AS filed Critical Olainfarm AS
Priority to EP07726915A priority patent/EP2013166B1/en
Priority to SI200730253T priority patent/SI2013166T1/en
Priority to DK07726915.7T priority patent/DK2013166T3/en
Publication of WO2007104780A2 publication Critical patent/WO2007104780A2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention relates to the discovery of the biologically active i?-enantiomer of N- carbamoylmethyl-4-aryl-2-pyrrolidinone and easy and effective method of its preparation.
  • N- 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 invention relates to the i?-enantiomer of 4-phenyl-l-pyrrolidineacetic acid amide. More particularly, the invention relates to N-carbamoylmethyl-4(i?)-phenyl-2-pyrrolidinone of the formula:
  • i?-Carphedon 4 the same as S-Carphedon 4a can be easily achieved by the means of the N-alkylation of available 4(i?)-phenyl-2- pyrrolidinone (1) or 4(5)-phenyl-2-pyrrolidinone (Ia) 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(i?)-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 refluxed at 110 ⁇ 120°C for 6 hours. Obtained mixture was concentrated under reduced pressure.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Neurology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Psychiatry (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)

Abstract

The invention relates to the R-enantiomer of N-carbamoylmethyl-4-phenyl-2-pyrrolidinone (R- Carphedon) of pharmacological value. The method 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.

Description

Method of preparation and use of pharmacologically active N-carbamoylmethyl-4(J?)-phenyl-2-pyrrolidinone
Background of the invention The invention relates to the discovery of the biologically active i?-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. 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- 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 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- Carphedon and unexpectedly discovered that i?-Carphedon as an antidepressant, analgesic, muscle relaxant and psycho-stimulating compound is more effective than the racemic Carphedon or S-Carphedon.
Summary and detailed description. The invention relates to the i?-enantiomer of 4-phenyl-l-pyrrolidineacetic acid amide. More particularly, the invention relates to N-carbamoylmethyl-4(i?)-phenyl-2-pyrrolidinone of the formula:
Figure imgf000003_0001
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 i?-Carphedon 4 the same as S-Carphedon 4a can be easily achieved by the means of the N-alkylation of available 4(i?)-phenyl-2- pyrrolidinone (1) or 4(5)-phenyl-2-pyrrolidinone (Ia) 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.
HNa,
Figure imgf000003_0002
HNa,
Figure imgf000003_0003
Following examples illustrate the synthetic part of invention.
Example 1 N-Carbamoylmethyl-4(R)-phenyl-2-pyrrolidinone (4). The solution of 4(i?)-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 refluxed at 110÷120°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(i?)-phenyl-2- pyrrolidinone (3) (338 mg, 64%). [α]D 20=+4.6°(c=3, MeOH). 1H NMR (CDCl3), δ: 1.28 (3H, t, CH2CH3); 2.59 (IH, d, d, 3-CH2); 2.87 (IH, d, d, 3-CH2); 3.54 (IH, t, 5-CH2); 3.64 (IH, quintet, 4-CH); 3.83 (IH, 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 ethylacetate-hexane mixture 1:1 silicagel giving N-carbamoylmethyl-4(i?)-phenyl-2- pyrrolidinone (4a) (187 mg, 85%). M.p. 107.5-108 0C. [α]D 20=+8.5° (c=3, MeOH). 1H NMR
(CDCl3), δ: 2.61 (IH, d, d, 3-CH2); 2.87 (IH, d, d, 3-CH2); 3.54 (IH, t, 5-CH2); 3.66 (IH, quintet, 4-CH); 3.89 (IH, 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).
Example 2
N-Carbamoylmethyl-4(S)-phenyl-2-pyrrolidinone (4a). Substituting pyrrolidinone 1 in Example 1 by 4(5)-phenyl-2-pyrrolidinone (Ia) ^-enantiomeric N-carbamoylmethyl-4(5)- phenyl-2-pyrrolidinone (4a) was obtained. [α]D 20=-8.3° (c=3, MeOH). 1U NMR (CDCl3), δ: 2.61 (IH, d, d, 3-CH2); 2.87 (IH, d, d, 3-CH2); 3.54 (IH, t, 5-CH2); 3.66 (IH, quintet, 4-CH); 3.89 (IH, 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).
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 i?-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 i?-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 Lp. administration of the test compounds in equal 50 mg/kg doses caused prolonged and stable increase in animal activity in the case of i?-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 i?-Carphedon than the same of S-Carphedon.
Table 1.
Antidepressant properties of test compounds according to Porsolt* forced swim test (FST)**
Figure imgf000005_0001
* R.D.Porsolt , et.al, Arch. Intern. Pharmacodynamic, 1977, vol. 229, p. 327-336
** i.p. administration of compounds 1 hour before the test in male ICR mice in the dosage of
100 mg/kg #/> >0.05 rø control M P >0.001 rø control
Table 2.
Characteristics of locomotor activity* after Lp. administration of tested compounds in male ICR mice in dosage of 50 mg/kg *
Figure imgf000006_0001
M.L.Weischer, Psychopharmacology 1976; 50; 275 5 # P < 0.05 ANOVA test followed Studen's t-test
Table 3.
Effective dosages of test compounds responsible for the same muscle relaxant activity and analgesic effect in male ICR mice
Figure imgf000006_0002
* i.p. administration in dosages 50; 100; 250 and 500 mg/kg 1 N.W.Dunham, et.al, J.Am.Pharm.Assoc.,46:208, 1957. 10 2 N.B.Eddy, D.Leimbach, J. Pharmacol. Experimental Therapy, 1953, vol. 107, N 3, p. 358-393.
The obtained results prove the high therapeutic value for i?-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.

Claims

We claim:
1. N-carbamoylmethyl-4(i?)-phenyl-2-pyrrolidinone (I) with neurotropic activity:
Figure imgf000008_0001
(I)
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(i?)-phenyl-2-pyrrolidinone with ethyl bromoacetate following by carbamoylation of intermediate N-ethoxycarbonylmethyl-4(i?)-aryl-2-pyrrolidinone with ammonia.
PCT/EP2007/052424 2006-03-16 2007-03-15 N- carbamoylmethyl- 4- (r) -phenyl-2-pyrr0lidin0ne, method of its preparation and pharmaceutical use Ceased WO2007104780A2 (en)

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AT07726915T ATE460396T1 (en) 2006-03-16 2007-03-15 N-CARBAMOYLMETHYL-4-(R)-PHENYL-2-PYRROLIDINONE, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL USE
MEP-2009-293A ME01192B (en) 2006-03-16 2007-03-15 N- carbamoylmethyl- 4- (r) -phenyl-2-pyrr0lidin0ne, method of its preparation and pharmaceutical use
DE602007005244T DE602007005244D1 (en) 2006-03-16 2007-03-15 N-CARBAMOYLMETHYL-4- (R) -PHENYL-2-PYRROLIDINONE, METHOD FOR ITS PREPARATION AND PHARMACEUTICAL USE
US12/226,332 US9102615B2 (en) 2006-03-16 2007-03-15 N-Carbamoylmethy1-4-(R)-phenyl-2-pyrrolidinone, method of its preparation and pharmaceutical use
CA2647206A CA2647206C (en) 2006-03-16 2007-03-15 N-carbamoylmethyl-4-(r)-phenyl-2-pyrrolidinone, method of its preparation and pharmaceutical use
PL07726915T PL2013166T3 (en) 2006-03-16 2007-03-15 N-carbamoylmethyl-4(r)-phenyl-2-pyrrolidinone, method of its preparation and pharmaceutical use
EA200801978A EA014668B1 (en) 2006-03-16 2007-03-15 Method for manufacturing and use of pharmacologically active n-carbamoylmethyl-4(r)-phenyl-2-pyrrolidone
EEP200800063A EE05536B1 (en) 2006-03-16 2007-03-15 N-Carbamoylmethyl-4- (R) -phenyl-2-pyrrolidinone, process for its preparation and pharmaceutical use
EP07726915A EP2013166B1 (en) 2006-03-16 2007-03-15 N-carbamoylmethyl-4(r)-phenyl-2-pyrrolidinone, method of its preparation and pharmaceutical use
HRP20090524AA HRP20090524C1 (en) 2006-03-16 2007-03-15 Method of preparation and use pharmacologically active n-carbamoylmethyl-4(r)-phenyl-2-pyrrolidinone
SI200730253T SI2013166T1 (en) 2006-03-16 2007-03-15 N-carbamoylmethyl-4(r)-phenyl-2-pyrrolidinone, method of its preparation and pharmaceutical use
DK07726915.7T DK2013166T3 (en) 2006-03-16 2007-03-15 N-carbamoylmethyl-4 (R) -phenyl-2-pyrrolidone, process for its preparation and pharmaceutical use
US14/688,633 US9382203B2 (en) 2006-03-16 2015-04-16 N-carbamoylmethyl-4-(R)-phenyl-2-pyrrolidinone, method of its preparation and pharmaceutical use

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LVP-06-45 2006-03-16
LVP-06-45A LV13630B (en) 2006-03-16 2006-03-16 Method of preparation and use of pharmaceutically active n-carbamoylmethyl-4(r)-phenyl-2-pyrrolidinone

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US14/688,633 Division US9382203B2 (en) 2006-03-16 2015-04-16 N-carbamoylmethyl-4-(R)-phenyl-2-pyrrolidinone, method of its preparation and pharmaceutical use

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