US 6,784,197 B2Granted

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

AssigneeUcb, S.A.

InventorsEdmond Differding, Benoît Kenda, Bénédicte Lallemand, Alain Matagne, Philippe Michel, Patrick Pasau, Patrice Talaga

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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.

Claims31

Dependent claims

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—R1a wherein R1a 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,
R3a 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 R3a 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 R3a 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.

8 more elements

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.

89 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/204,266Filed 20 Aug 2002
Priority: GB 000429723 Feb 2000
Published: US 2003/0120080 A126 Jun 2003
Granted: 31 Aug 2004
Term ends: Not estimatedThe source records don’t support an estimate.

Classification45 codes

C07D 207/26
Oxygen or sulfur atoms: 2-Pyrrolidones
A61K 31/4015
Having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil: having oxo groups…
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/06
Drugs for disorders of the cardiovascular system: antiarrhythmics

Family

US 2003/0120080 A1Pre-grant publication · published 26 Jun 2003
US 6,784,197 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

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—R1a wherein R1a 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,
R3a 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 R3a 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 R3a 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.

8 more elements

Facts

Application

10/204,266Filed 20 Aug 2002

Priority

GB 000429723 Feb 2000

Published

US 2003/0120080 A126 Jun 2003

Granted

31 Aug 2004

Term ends

Not estimatedThe source records don’t support an estimate.

Classification45 codes

C07D 207/26
Oxygen or sulfur atoms: 2-Pyrrolidones
A61K 31/4015
Having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil: having oxo groups…
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/06
Drugs for disorders of the cardiovascular system: antiarrhythmics