2-oxo-1-pyrrolidine derivatives, processes for preparing them and their uses

• US 6,784,197 B2
• Filed: 08/20/2002
• Issued: 08/31/2004
• Est. Priority Date: 02/23/2000
• Status: Expired due to Term

• Current Assignee: UCB Biopharma SRL (UCB SA)
• Original Assignee: UCB SA
• Inventors: Talaga, Patrice, Pasau, Patrick, Michel, Philippe, Differding, Edmond, Lallemand, Bénédicte, Matagne, Alain, Kenda, Benoît
• Primary Examiner(s): Desai, Rita
• Assistant Examiner(s): Shiao, Robert
• Application Number:
  US10/204,266
• Publication Number:
  US 20030120080A1
• Time in Patent Office: 742 Days
• Field of Search: 514/381, 514/365, 514/422, 514/408, 514/343, 546/278.4, 548/254, 548/202, 548/527, 548/517, 548/518, 548/400, 548/543
• US Class Current: 514/365
• CPC Class Codes: A61K 31/4015 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/36 : Opioid-abuse
• CPC Class Codes: A61P 27/16 : Otologicals
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/06 : Antiarrhythmics
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 237/12 : having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups peptides C07K
• CPC Class Codes: C07D 207/26 : 2-Pyrrolidones
• CPC Class Codes: C07D 207/27 : with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 207/273 : 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 other ring carbon atoms
• CPC Class Codes: C07D 207/277 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 307/33 : in position 2, the oxygen atom being in its keto or unsubstituted enol form
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems

Abstract

The invention concerns 2-oxo-1-pyrrolidine derivatives of formula (I) wherein the substituents are as defined in the specification, as well as their use as pharmaceuticals. The compounds of the invention are particularly suited for treating neurological disorders such as epilepsy.

Claims

1. A compound having the formula I or a pharmaceutically acceptable salt thereof,

wherein

X is —

CA¹NR⁵R⁶ or —

CA¹—

R⁸;

A¹ and A² are independently oxygen, sulfur or —

NR⁹;

R¹ is hydrogen, alkyl, aryl or —

CH²—

R^1a wherein R^1a is aryl, halogen, hydroxy, amino, nitro or cyano;

R³ is hydrogen, halogen, thiol, nitro, nitrooxy, cyano, azido, carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl, alkenyl, ester, ether, aryl, tetrazolyl, thiazolyl, thienyl, furyl, pyrrolyl, pyridinyl, alkynyloxy, acyloxy, oxyester, oxyamido, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy, arylsulfinyloxy, aryloxy, aralkoxy, alkythio, alkenylthio, alkynylthio, arylthio, formyl, acetyl, propionyl, isobutyryl, valeryl, lauroyl, heptanedioyl, cyclohexanecarbonyl, crotonoyl, furmaroyl, arcyrloyl, benzoyl, naphthoyl, 4-carboxybutanoyl, oxalyl, ethoxalyl, cysteinyl, oxamoyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, alkylsulfinyl, alkenylsulfinyl, alkynylsufinyl or arylsulfinyl,

R^3a is hydrogen, halogen, alkyl, alkenyl, alkynyl or aryl;

R⁵, R⁶ and R⁹ are the same or different and each is independently hydrogen, hydroxy, alkyl, aryl, alkoxy, alkenyloxy, alkynyloxy, acyloxy, oxyester, oxyamido, alkylsufonyloxy, alkylsulfinyloxy, arylsulfonyloxy, arylsufinyloxy, aryloxy or arylalkoxy and

R⁸ is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, alkylthio, alkenylthio, alkynylthio or

with the provisos that at least one of as R³ and R^3a is other than hydrogen; and

that when the compound is a mixture of all possible isomers , X is —

CONR⁵R⁶, A² is oxygen and R¹is hydrogen, methyl, ethyl or propyl then substitution on the pyrrolidine ring is other than mono-, di-methyl or mono-ethyl; and

that when R¹ and R^3a are both hydrogen, A² is oxygen and X is —

CONR⁵R⁶ then R³ is different from carboxy, ester, amido, substituted oxo-pyrrolidine, alkynyloxy, acyloxy, oxyester, oxyarmido, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy, arylsulfinyloxy, aryloxy, aralkoxy, methyl, naphthyl, phenyl optionally substituted by oxy derivatives or in the para position by an halogen atom.

2. The compound according to claim 1 wherein X represents a substituent group selected from,

a) — CONR⁵R⁶;

b) —

CONR⁵R⁶, wherein R⁵ and R⁴ are hydrogen, C1-4-alkyl, phenyl or alkylphenyl;

c) —

CONR⁵R⁶, wherein R⁵ and R⁶ are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2-dimethylpropyl;

d) —

CONR⁵R⁶, wherein R⁵ and R⁶ are independently hydrogen or methyl;

e) —

CONR⁵R⁶, wherein at least one of R⁵ and R⁶ is hydrogen or both are hydrogen;

or

f) —

CONH₂.

3. The compound according to claim 1 wherein R¹ represents a substituent group selected from,

a) hydrogen, alkyl or aryl;

b) hydrogen, C1-12 alkyl or aryl;

c) hydrogen, lower alkyl or phenyl;

d) methyl, ethyl, propyl, isopropyl, butyl, iso- or ter-butyl, 2,2,2-trimethylethyl, each optionally attached via a methylene bridge or the same substituted by at least one halogen atom;

or

e) ethyl.

4. The compound according to claim 1 wherein R^3a is a substituent group selected from,

a) hydrogen, alkyl, aryl or aralkyl;

b) hydrogen, methyl, ethyl, phenyl or benzyl;

c) hydrogen, halogen or methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least one halogen atom.

5. The compound according to claim 4, wherein R^3a represents a substituent group selected from,

a) hydrogen or alkyl;

b) hydrogen or lower alkyl;

or

c) hydrogen.

6. The compound according to claim 1 wherein R³ is a substituent group selected from,

a) hydrogen, C1-12-alkyl each optionally substituted by one or more substituents selected from hydroxy, halogen, cyano, thiocyanato or alkoxy C2-6-alkenyl or -alkynyl, each optionally substituted by one or more halogens;

azido;

cyano;

amido;

carboxy;

tetrazolyl, pyridyl, 1-oxidopyridyl, furyl, pyrrolyl, thiazolyl or thienyl, thiazolyl or thienyl each optionally substituted by one or more substituents selected from halogen, C1-6-alkyl and phenyl and attached to the ring either directly or via a C1-4-alkylene bridge;

naphthyl;

or phenyl, phenylalkyl or phenylalkenyl each optionally substituted by one or more substituents selected from halogen, C1-6-alkyl, C1-6 haloalkyl, C1-6-alkoxy, C1-6-alkylthio, amino, azido, phenyl and nitro;

b) as a) except that any alkyl is C1-6-alkyl and any C1-4 alkylene bridge is methylene;

c) C1-6-alkyl optionally substituted by one or more substituents selected from halogen, thiocyanato, azido, alkoxy, alkylthio, phenylsulfonyl;

nitrooxy;

C2-3-alkenyl or -alkynyl each optionally substituted by one or more halogens or by acetyl;

tetrazolyl, pyridyl, furyl, pyrrolyl, thiazolyl or thienyl;

or phenyl or phenylalkyl each optionally substituted by one or more substituents selected from halogen, C1-6-alkyl, C1-6 haloalkyl, C1-6-alkoxy, amino, azido, phenyl and nitro;

d) hydrogen, halogen or methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least one halogen atom;

e) C1-4-alkyl optionally substituted by one or more substituents selected from halogen, thiocyanato or azido;

C2-5-alkenyl or -alkynyl, each optionally substituted by one or more halogens;

thienyl;

or phenyl optionally substituted by one or more substituents selected from halogen, C1-6-alkyl, C1-6 haloalkyl or azido;

or

f) C1-6-alkyl and C2-6-haloalkenyl.

7. The compound according to claim 1 wherein R¹ is a substituent group selected from,

a) hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl, phenyl, benzyl or the same substituted by at least one halogen atom;

or

b) hydrogen or methyl.

8. The compound according to claim 1, wherein,

A2 is oxygen;

X is —

CONR⁵R⁶ or —

CO—

R⁸;

R¹ is hydrogen or alkyl, aryl, halogen, hydroxy, amino, nitro, cyano;

R³ is hydrogen or halogen, nitro, cyano, acyl, acyloxy, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, carboxy, ester, ether, amido, sulfonic acid, sulfonamide, alkoxycarbonyl, alkylthio, alkenylthio, alkynylthio, arylthio, alkyl, oxyester, oxyamido, aryl, alkynyloxy, acyloxy, oxyester, oxyamido, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy, arylsulfinyloxy, aryloxy, aralkoxy, tetrazolyl, thiazolyl, thienyl, furyl, pyrrolyl, pyridinyl, vinyl and R3 may additionally represent C2-5 alkenyl, C2-5 alkyrnyl or azido each optionally substituted by one or more halogen, cyano, thiocyano, azido, cyclopropyl, acyl and/or phenyl;

or phenylsulfonyloxy whereby any phenyl moiety may be substituted by one or more halogen, alkyl, haloalkyl, alkoxy, nitro, amino, and/or phenyl;

R^3a is hydrogen;

R⁵ and R⁶ are the same or different and each is independently hydrogen, hydroxy, alkyl, aryl alkoxyl, alkenyloxy, alkynyloxy, acyloxy, oxyester, oxyamido, alkylfonyloxy, alkylsulfinyloxy, arylsulfonyloxy, arylsulfinyloxy, aryloxy or arylalkoxy; and

R⁸ is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, alkylthio, alkylthio, alkenylthio, alkynylthio or arylthio.

9. The compound according to claim 8, wherein

R¹ is methyl, ethyl, propyl, isopropyl, butyl or isobutyl;

R³ is C1-5 alkyl, C2-5 alkenyl, C2-C5 alkynyl, cyclopropyl, azido, each optionally substituted by one or more halogen, cyano, thiocyano, azido, alkylthio, cyclopropyl, acyl and/or phenyl;

phenyl;

phenylsulfonyl;

phenylsulfonyloxy, tetrazole, thiazole, thienyl, furyl, pyrrole, pyridine, whereby any phenyl moiety may be substituted by one or more halogen, alkyl, haloalkyl, alkoxy, nitro, amino, and/or phenyl;

X is —

COOH or —

CONH₂.

10. The compound according to claim 9, wherein

R¹ is methyl, ethyl or n-propyl;

and

X is —

CONH₂.

11. The compound according to claim 1, wherein

X is —

CA¹NH₂, —

CA¹NHCH₃ or —

CA¹N (CH₃)₂;

R¹ is alkyl or phenyl;

R³ is alkyl, alkenyl, alkynyl, cyano, isothiocyanato, ether, carboxyl, amido, aryl tetrazolyl, thiazolyl, thienyl, furyl, pyrrolyl, pyridinyl;

or

R³ is C₂R¹⁰ wherein R¹⁰ hydrogen, cycloalkyl, oxyester, oxyalkylsulfonyl, oxyarylsufonyl, aminoalkylsulfonyl, aminoarylsulfonyl, nitrooxy, cyano, isothiocyanato, azido, alkylthio, arylthio, alkylsulfinyl, alkylsulfonyl, tetrazolyl, thiazolyl, thienyl, furyl, pyrrolyl, pyridinyl, aryloxy, alkoxy or trifluoroethyl;

R^3a is hydrogen, alkyl or aryl;

or

R³ and R^3a form a cycloalkyl.

12. The compound according to claim 1, wherein

R¹ is alkyl;

R^3a is hydrogen;

R³ is hydrogen;

C1-12-alkyl optionally substituted by one or more substituents selected from hydroxy, halogen, cyano, thiocyanato or alkoxy;

C2-6-alkenyl or -alkynyl, each optionally substituted by one or more halogens;

azido;

cyano;

amido;

carboxy;

tetrazolyl, pyridyl, 1-oxidopyridyl, furyl, pyrrolyl, thiazolyl or thienyl each optionally substituted by one or more substituents selected from halogen, C1-6-alkyl and phenyl and attached to the ring either directly or via a C1-4-alkylene bridge;

naphthyl;

or phenyl, phenylalkyl or phenylalkenyl each optionally substituted by one or more substituents selected from halogen, C1-6-alkyl, C1-6 haloalkyl, C1-6-alkoxy, C1-6-alkylthio, amino, azido, phenyl and nitro.

13. The compound according to claim 12, wherein, R¹ is a substituent group selected from

a) C1-12-alkyl;

b) C1-6-alkyl;

or

c) ethyl;

and any C1-4-alkylene bridge present is methylene.

14. The compound according to claim 1, which is in racemic form and wherein when X is —

CONR⁵R⁶ and R¹ is hydrogen, methyl, ethyl or propyl, then substitution on the pyrrolidine ring is other than mono-, di-methyl or mono-ethyl.

15. The compound according to claim 1, which is in racemic form and wherein when X is —

CONR⁵R⁶ and R¹ is hydrogen or C1-6-alkyl, C2-6-alkenyl or -alkynyl or cycloalkyl, each unsubstituted, then substitution in the ring is other than by alkyl, alkenyl or alkynyl, each unsubstituted.

16. The compound according to claim 1, wherein,

X is —

CA¹NH₂;

R¹ is hydrogen;

R³ is azidomethyl, iodomethyl, C2-6-alkyl optionally substituted by 1 to 5 halogen atoms, vinyl optionally subsituted by one or two methyls, and/or 1 to 3 halogen atoms, acetylene optionally substituted by C1-4-alkyl, phenyl or halogen and

R^3a is hydrogen or halogen;

as their racemates or in enantiomerically enriched form.

17. The compound according to claim 1, wherein

X is —

CA¹NH₂;

R¹ is H;

R³ is C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl optionally substituted by azido, oxynitro, 1 to 6 halogen atoms; and

R^3a is hydrogen or halogen;

as their racemates or in enantiomerically enriched form.

18. The compound according to claim 1, wherein

A² is oxygen;

R¹ is ethyl;

X is —

CONH₂;

R³ is n-propyl or 2,2-difluorovinyl; and

R^3a is hydrogen.

19. The compound according to claim 1 as a pure enantiomer.

20. The compound according to claim 1, which, when the carbon atom to which R¹ is attached is asymmetric, is in the “

S”

-configuration.

22. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 in combination with a pharmaceutically acceptable diluent or carrier.

23. A method for treating epilepsy, epileptogenesis, seizure disorders, convulsions, bipolar disorders, mania, depression, anxiety, migraine, trigeminal and other neuralgia, chronic pain, neuropathic pain, cerebral ischemia, cardiac arrhythmia, myotonia, cocaine abuse, stroke, myoclonus, neonatal cerebral hemorrhage, amyotrophic lateral sclerosis, spasticity, Parkinson'"'"'s disease, bronchial asthma, asthmatic status and allergic bronchitis, asthmatic syndrome, bronchial hyperreactivity and bronchospastic syndromes as well as allergic and vasomotor rhinitis and rhinoconjunctivitis, in a mammal in need of such treatment, comprising administering a therapeutic dose of at least one compound according claim 1.

24. A method for treating epilepsy, epileptogenesis, seizure disorders, convulsions, bipolar disorders, mania, depression, anxiety, migraine, trigeminal and other neuralgia, chronic pain, neuropathic pain, cerebral ischemia, cardiac arrhythmia, myotonia, cocaine abuse, stroke, myoclonus, neonatal cerebral hemorrhage, amyotrophic lateral sclerosis, spasticity, Parkinson'"'"'s disease, bronchial asthma, asthmatic status and allergic bronchitis, asthmatic syndrome, bronchial hyperreactivity and bronchospastic syndromes as well as allergic and vasomotor rhinitis and rhinoconjunctivitis, in a mammal in need of such treatment, comprising administering a therapeutic dose of at least one compound of formula I as illustrated in claim 1 or a pharmaceutically acceptable salt thereof, wherein the individual substituents are as defined in claim 1 with the provisos that at least one of as R³and R^3a is other than hydrogen;

and that when the compound is a mixture of all possible isomers, X is —

CONR⁵R⁶, A² is oxygen and R¹ is hydrogen, methyl, ethyl or propyl then substitution on the pyrollidine ring is other than mono-, di-methyl or mono-ethyl.

26. The method according to claim 24, wherein the condition to be treated is epilepsy, neuropathic pain, bipolar disorder or migraine.

28. The compound according to claim 6, wherein the C1-4-alkylene bridge is methylene.

29. The compound according to claim 9, wherein R³ is methyl, ethyl, propyl, isopropyl, butyl or isobutyl.

30. The compound according to claim 16 wherein R^3a is fluorine and the compound is the pure enantiomer.

31. The compound according to claim 17 wherein R^3a is fluorine and the compound is the pure enantiomer.

21. A compound selected from

(2S)-2-[4-(bromomethyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[(4R)-4-(iodomethyl)-2-oxopyrrolidinyl]butanamide;

(2S)-2-(2-oxo-4-phenyl-1-pyrrolidinyl)butanamide;

(2S)-2-[4-(iodomethyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(chloromethyl)-2-oxo-1-pyrrolidinyl]butanamide;

{1-[(1S)-1-(aminocarbonyl)propyl]-5-oxo-3-pyrrolidinyl}methyl 4-methylbenzenesulfonate;

(2S)-2-[(4R)-4-(azidomethyl)-2-oxopyrrolidinyl]butanamide;

2-[4-(2,2-dibromovinyl)-2-oxo-1-pyrrolidinyl]butanamide;

{1-[(1S)-1-(aminocarbonyl)propyl]-5-oxo-3-pyrrolidinyl}methyl nitrate;

(2S)-2-[2-oxo-4-(1H-tetraazol-1-ylmethyl)-1-pyrrolidinyl]butanamide;

2-(2-oxo-4-vinyl-1-pyrrolidinyl)butanamide;

2-{2-oxo-4-[(phenylsulfonyl)methyl]-1-pyrrolidinyl}butanamide;

(2S)-2-[(4R)-4-(2,2-dibromovinyl)-2-oxopyrrolidinyl]butanamide;

(2S)-2-[(4S)-4-(2,2-dibromovinyl)-2-oxopyrrolidinyl]butananmide;

(2S)-2-[4-(isothiocyanatomethyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[2-oxo-4-(1,3-thiazol-2-yl)-1-pyrrolidinyl]butanamide;

(2S)-2-[2-oxo-4-(2-thienyl)-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(2-methoxyphenyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(3-methoxyphenyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(4-azidophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[2-oxo-4-(3-thienyl)-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(3-azidophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[2-oxo-4-(3-thienyl)-1-pyrrolidinyl]butanamide;

(2S)-2-[(4S)-2-oxo-4-vinylpyrrolidinyl]butanamide;

(2S)-2-[(4R)-2-oxo-4-vinylpyrrolidinyl]butanamide;

2-[4-(2-bromophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[2-oxo-4-(3-pyridinyl)-1-pyrrolidinyl]butanamide;

(2S)-2-(4-[1,1′

-biphenyl]-4-yl-2-oxo-1-pyrrolidinyl)butanamide;

(2S)-2-{4-[(methylsulfanyl)methyl]-2-oxo-1-pyrrolidinyl}butanamide;

2-[4-(iodomethyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[(4R)-4-(iodomethyl)-2-oxo-1-pyrrolidinyl]pentanamide;

(2S)-2-[(4R)-4-(iodomethyl)-2-oxopyrrolidinyl]propanamide;

2-(2-oxo-4-propyl-1-pyrrolidinyl)propanamide;

2-(2-oxo-4-propyl-1-pyrrolidinyl)butanamide;

2-(2-oxo-4-pentyl-1-pyrrolidinyl)butanamide;

(2S)-2-[(4R)-4-(iodomethyl)-2-oxopyrrolidinyl]-N-methylbutanamide;

(2S)-2-(4-neopentyl-2-oxo-1-pyrrolidinyl)butanamide;

(2S)-2-(4-ethyl-2-oxo-1-pyrrolidinyl)butanamide;

2-[4-(2,2-difluorovinyl)-2-oxo-1-pyrrolidinyl)butanamide;

2-[4-(2,2-difluoroethyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[(4S)-2-oxo-4-propylpyrrolidinyl]butanamide;

(2S)-2-[(4R)-2-oxo-4-propylpyrrolidinyl]butanamide;

2-{4-[(Z)-2-fluoroethenyl]-2-oxo-1-pyrrolidinyl}butanamide;

2-[4-(2-methyl-1-propenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-(4-butyl-2-oxo-1-pyrrolidinyl)butanamide;

2-[4-(cyclopropylmethyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-(4-isobutyl-2-oxo-1-pyrrolidinyl)butanamide;

2-[4-(4-chlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-(4-(3-chlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-{2-oxo-4-[2-(trifluoromethyl)phenyl]-1-pyrrolidinyl}butanamide;

2-[4-(2-fluorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[4-(3-methylphenyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[2-oxo-4-(2-phenylethyl)-1-pyrrolidinyl]butanamide,

(2S)-2-[4-(3-bromophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-{4-[3,5-bis(trifluoromethyl)phenyl]-2-oxo-1-pyrrolidinyl}butanamide;

2-[4-(3,4-dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[4-(2,4-dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[4-(2-furyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[2-oxo-4-(3-phenylpropyl)-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(3,5-dibromophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[4-(3,4-dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-(2-oxo-4-propyl-1-pyrrolidinyl)butanamide;

2-[4-(3-chlorophenyl)-2-oxo-1pyrrolidinyl]butanamide;

2-(4-ethynyl-2-oxo-1-pyrrolidinyl) butanamide;

2-[4-(2-fluorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[4-(2-fluorophenyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(cyclopropylmethyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[(4S)-4-(2,2-difluorovinyl)-2-oxopyrrolidinyl]butanamide;

(2S)-2-[2-oxo-4-(3,3,3-trifluoropropyl)-1-pyrrolidinyl]butanamide;

2-[4-(3-methylphenyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(cyclopropylmethyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-[(4R)-4-(2,2-difluorovinyl)-2-oxopyrrolidinyl]butanamide;

(2S)-2-[2-oxo-4-(1H-pyrrol-1-yl)-1-pyrrolidinyl]butanamide;

(2S)-2-(4-allyl-2-oxo-1-pyrrolidinyl)butanamide;

(2S)-2-(4-(2-iodopropyl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-(4-allyl-2-oxo-1-pyrrolidinyl)butanamide;

(2S)-2-[2-oxo-4-(2-oxopropyl)-1-pyrrolidinyl]butanamide;

(2S)-2-[4-(2-bromo-1H-pyrrol-1-yl)-2-oxo-1-pyrrolidinyl]butanamide;

(2S)-2-(4-methyl-2-oxo-4-propyl-1-pyrrolidinyl)butanamide;

(2R)-2-[4-(2,2-dichlorovinyl)-2-oxo-1-pyrrolidinyl]butanamide,

2-[4-(bromoethynyl)-2-oxo-1-pyrrolidinyl]butanamide;

2-[(4S)-4-(2,2-difluoropropyl)-2-oxopyrrolidinyl]butanamide;

(2S)-2-[4-(bromoethynyl)-2-oxo-1-pyrrolidinyl]butanamide;

2(2-oxo-4-propyl-1-pyrrolidinyl)pentanamide;

3-cyclopropyl-2-(2-oxo-4-propyl-1-pyrrolidinyl)propanamide;

2-(2-oxo-4-propyl-1-pyrrolidinyl)-3-(1,3-thiazol-4-yl)propanamide;

2-(2-oxo-4-propyl-1-pyrrolidinyl)-4-pentanamide;

ethyl

3-({[(1S)-1-(aminocarbonyl)propyl]amino}methyl)hexanoate hydrochloride;

2-(1-adamantyl)ethyl 3-({[(1S)1-(aminocarbonyl)propyl]amino}methyl)hexanoate hydrochloride;

butyl 3-({[(1S)-1-(aminocarbonyl)propyl]amino}methyl)hexanoate hydrochloride and

isopropyl 3-({[(1S)-1-(aminocarbonyl)propyl]amino}methyl)hexanoate hydrochloride, including all isomeric forms and mixtures thereof or a pharmaceutically acceptable salt thereof.

25. A method for treating epilepsy, epileptogenesis, seizure disorders, convulsions, bipolar disorders, mania, depression, anxiety, migraine, trigeminal and other neuralgia, chronic pain, neuropathic pain, cerebral isehemia, cardiac arrhythmia, myotonia, cocaine abuse, stroke, myoclonus, neonatal cerebral haemorrhage, amyotrophic lateral sclerosis, spasticity, Parkinson'"'"'s disease bronchial asthma, asthmatic status and allergic bronchitis, asthmatic syndrome, bronchial hyperreactivity and bronchospastic syndromes as well as allergic and vasomotor rhinitis and rhinoconjunctivitis, in a mammal in need of such treatment, comprising administering a therapeutic dose of at least one compound according to claim 21.

27. The method according to claim 25, wherein the condition to be treated is epilepsy, neuropathic pain, bipolar disorder or migraine.