WO2003094913A1 - Utilisation de derives de 2-oxo-1-pyrrolidone pour la preparation d'un medicament - Google Patents

Utilisation de derives de 2-oxo-1-pyrrolidone pour la preparation d'un medicament Download PDF

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WO2003094913A1
WO2003094913A1 PCT/EP2003/004982 EP0304982W WO03094913A1 WO 2003094913 A1 WO2003094913 A1 WO 2003094913A1 EP 0304982 W EP0304982 W EP 0304982W WO 03094913 A1 WO03094913 A1 WO 03094913A1
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derivative
hydrogen
alkyl
aryl
halogen
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PCT/EP2003/004982
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English (en)
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Roy Massingham
Yves Lamberty
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Ucb, S.A.
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    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the use of 2-oxo-l-pyrrolidone derivatives and in particular (S)-(-)- ⁇ -et) ⁇ yl-2-oxo-l-pyrrolidineacetamide for the preparation of drugs effective for the prevention or treatment of an excitatory state at the induction of or during emergence from anaesthesia.
  • Emergence agitation can be defined as a state of hyper-responsiveness (culminating in crying or thrashing behavior that requires restraint; see Cravero et al.) at the emergence from anaesthesia. It is synonymous with post-operative agitation.
  • Anaesthesia-induced hyperactivity can be defined as a paradoxical state of restlessness and agitation and is observed, instead of sedation, at the induction of anaesthesia (see Bunt and Towbin).
  • Confusion or mental confusion can be defined as a state of physical disorientation, impaired judgement, inability to concentrate and diminished ability to communicate with or understand others.
  • Hyperactivity, agitation at the induction of anaesthesia or post-operative agitation, confusion and excessive pain at the emergence from anaesthesia are believed to be due to the same phenomenon of a transitory excitatory state of the brain. This excitatory state appears to result from an increased synaptic facilitation and relate to alterations at GABA A and NMDA receptors (see Roth et al., 1999, 2001).
  • levorotatory (S)- -ethyl-2-oxo-l-pyrrolidineaceta-mide also known as levetiracetam as a protective agent for the treatment and prevention of hypoxic and ischaemic type aggressions of the central nervous system is described in the European patent application EP-A-0162 036.
  • This compound can also be employed in the treatment of epilepsy, a therapeutic indication for which it has been demonstrated that its dextrorotatory enantiomer, (R)-(+)- ⁇ -ethyl-2-oxo-l-pyrrolidine-acetamide, is completely devoid of activity (A. J. GOWER et al, Eur. J. Pharmacol., 222, (1992), 193-203).
  • Levetiracetam has also been described in European patent application EP- A-0 645 139 for the treatment of anxiety.
  • EP-A-162 036 cited above also describes methods for preparing (S)-(-)- ⁇ -ethyl- 2-oxo-l-pyrrolidine- acetamide which require the synthesis of a starting reactant obtained by resolution of the corresponding racemate.
  • British patent application GB- A-2 225 322 describes a method for preparing the desired isomer which offers the advantage of using a natural amino acid which already has the desired stereochemical configuration as the starting material, thus dispensing with any laborious separation of the enantiomers.
  • 2-oxo-l-pyrrolidine derivatives as well as their use as pharmaceuticals are described in the international patent application having publication number WO 01/62726.
  • the derivatives are particularly suited for treating neurological disorders such as epilepsy.
  • Levetiracetam revealed to be far more potent (around 5-10 times) than piracetam in selected preclinical experiments. Moreover, experimental evidence suggests a quite different mechanism of action between piracetam and levetiracetam.
  • the present invention thus relates to the use of an active compound selected from the group consisting of (S)-(-)- ⁇ -ethyl-2-oxo-l- pyrrolidineacetamide and 2-oxo-l-pyrrolidine derivatives having the formula II or pharmaceutically acceptable salts thereof,
  • X is -CA ! NR 5 R 6 or -CAOR 7 or -CA i -R 8 or CN;
  • a 1 and A 2 are independently oxygen, sulfur or -NR ⁇ ;
  • ⁇ - is hydrogen, alkyl, aryl or -CH 2 -R ⁇ a wherein R a is aryl, heterocycle, halogen, hydroxy, a-mino, nitro or cyano;
  • R ⁇ , R3 and R* are the same or different and each is independently hydrogen, halogen, hydroxy, thiol, amino, nitro, nitrooxy, cyano, azido, carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl, ester, ether, aryl, heterocycle, or an o y derivative, thio derivative, amino derivative, acyl derivative, sulfonyl derivative or sulfinyl derivative;
  • R-2a p3a g ⁇ p4a ⁇ Q th e same or different and each is independently hydrogen, halogen, alkyl, alkenyl, al nyl or aryl;
  • R5, R6, R ⁇ and R ⁇ are the same or different and each is independently hydrogen, hydroxy, alkyl, aryl, heterocycle or an oxy derivative;
  • R 8 is hydrogen, hydroxy, t-hiol, halogen, alkyl, aryl, heterocycle or a thio derivative; with the provisos that at least one of as R ⁇ , R ⁇ , R*, R ⁇ a , R ⁇ a and R* a is other than hydrogen; and that when the compound is a mixture of all possible isomers , X is -CONRSR ⁇ , A ⁇ is oxygen and R is hydrogen, methyl, ethyl or propyl then substitution on the pyrollidine ring is other than mono-, di-, or tri-methyl or mono- ethyl; and that when R 1 , R ⁇ , R*, R ⁇ a , R ⁇ a and R ⁇ a are each hydrogen, A 2 is oxygen and X is CONR 5 R 6 then R ⁇ is different from carboxy, ester, amido, substituted oxo- pyrrolidine, hydros, oxy derivative, amino, amino derivatives, methyl, naphthyl,
  • the present invention relates to the use of an active compound, as described above, for the manufacture of a medicament for preventing or treating an excitatory state during emergence from anaesthesia.
  • Anaesthesia may be induced by any suitable anaesthetic. Use in conjunction with anaesthesia induced by pentobarbital is preferred.
  • the present invention relates to a method of preventing or treating in a patient an excitatory state at the induction of or during emergence from anaesthesia by ad- ⁇ - ⁇ --i-mste-ring an effective dose of an active compound, as described above.
  • the present invention relates to a method of preventing or treating in a patient an excitatory state at the induction of or during emergence from anaesthesia by ad- ⁇ -i-mistering an effective dose of an active compound, as described above, wherein anaesthesia is or has been induced by pentobarbital.
  • the effective dose of an active compound, as described above, administered to the patient will typically lie between 3-300 mg per kg body weight., e.g. 150-300 mg per kg body weight for levetiracetam.
  • the effective dose of the active compound may be administered to the patient before induction of anaesthesia, during induction of anaesthesia simultaneously with the anaesthetic agent, during the resulting anaesthesia or during emergence from anaesthesia. If an excitatory state during induction of anaesthesia is to be prevented or treated, administration of the active compound takes place before or during induction of anaesthesia.
  • R 11 and R 12 are the same or different and each is independently amido, alkyl, alkenyl, alkynyl, acyl, ester, ether, aryl, aralkyl, heterocycle or an oxy derivative, thio derivative, acyl derivative, amino derivative, sulfonyl derivative, or sulflnyl derivative, each optionally substituted with any suitable group, including, but not limited to, one or more moieties selected from lower alkyl or other groups as described below as substituents for alkyl.
  • oxy derivative as used herein is defined as including -O-R * ⁇ groups wherein R * is as defined above except for "oxy derivative".
  • Non-limiting examples are alkoxy, alkenyloxy, alkynyloxy, acyloxy, oxyester, oxyamido, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy, arylsulfinyloxy, aryloxy, aralkoxy or heterocyclooxy such as pentyloxy, allyloxy, methoxy, ethoxy, phenoxy, benzyloxy, 2- naphthyloxy, 2-pyridyloxy, methylenedioxy, carbonate.
  • thio derivative as used herein, is defined as including -S-R * ⁇ groups wherein R ⁇ is as defined above except for "thio derivative".
  • Non-limiting examples are alkylthio, alkenylthio, alkynylthio and arylthio.
  • amino derivative as used herein, is defined as including -NHRI * or - NRHR 2 groups wherein R 1 ⁇ - and R 1 ⁇ are as defined above .
  • Non-limiting examples are mono- or di-alkyl-, alkenyl-, alkynyl- and arylamino or mixed a-mino.
  • acyl derivative as used herein, represents a radical derived from carboxylic acid and thus is defined as including groups of the formula RH-CO-, wherein Ri 1 is as defined above and may also be hydrogen.
  • Non-limiting examples are for yl, acetyl, propionyl, isobutyryl, valeryl, lauroyl, heptanedioyl, cyclohexanecarbonyl, crotonoyl, fumaroyl, acryloyl, benzoyl, naphthoyl, furoyl, nicotinoyl, 4-carboxybutanoyl, oxalyl, ethoxalyl, cysteinyl, oxamoyl.
  • sulfonyl derivative as used herein, is defined as including a group of the formula -SO2-R 1 1 . wherein R 1 1 is as defined above except for "sulfonyl derivative".
  • R 1 1 is as defined above except for "sulfonyl derivative”.
  • Non-limiting examples are alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl and arylsulfonyl.
  • sulflnyl derivative as used herein, is defined as including a group of the formula -SO-R 1 *, wherein R 1 1 is as defined above except for "sulflnyl derivative".
  • R 1 1 is as defined above except for "sulflnyl derivative”.
  • Non-limiting examples are alkylsulflnyl, alkenylsulflnyl, aLkynylsulflnyl and arylsulfinyl.
  • alkyl is defined as including saturated, monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof and containing 1-20 carbon atoms, preferably 1-6 carbon atoms for non-cyclic alkyl and 3-6 carbon atoms for cycloalkyl (in these two preferred cases, unless otherwise specified, "lower alkyl”).
  • Alkyl moieties may optionally be substituted by 1 to 5 substituents independently selected from the group consisting of halogen, hydroxy, thiol, --u-nino, nitro, cyano, thiocyanato, acyl, acyloxy, sulfonyl derivative, sulflnyl derivative, alkylamino, carboxy, ester, ether, amido, azido, cycloalkyl, sulfonic acid, sulfonamide, thio derivative, oxyester, oxyamido, heterocycle, vinyl, Cl-5-alkoxy, C6-10-aryloxy and C6-10-aryl.
  • Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, and 2,2,2-trimethylethyl each optionally substituted by at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino, nitro and cyano, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1, l-dimethyl-2,2-dibromoethyl, 1, l-dimethyl-2,2,2-trichloroethyl.
  • alkyl, alkenyl and alkynyl represent straight- or branched chains, Cl-12, preferably Cl-4-alkylene or C2-12-, preferably C2-4-alkenylene or -alkynylene moieties respectively.
  • Groups where branched derivatives are conventionally qualified by prefixes such as "n”, “sec”, “iso” and the like are in the n-form unless otherwise stated.
  • aryl as used herein, is defined as including an organic radical derived from an aromatic hydrocarbon consisting of 1-3 rings and containing 6-30 carbon atoms by removal of one hydrogen, such as phenyl and naphthyl each optionally substituted by 1 to 5 substituents independently selected from halogen, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulflnyl, alkylamino, carboxy, ester, ether, amido, azido, sulfonic acid, sulfonamide, alkylsulfonyl, alkylsulfinyl, alkylthio, oxyester, oxyamido, aryl, Cl-6-alkoxy, C6-10-aryloxy, Cl-6- alkyl, Cl-6-haloalkyl .
  • Aryl radicals are preferably monocyclic containing 6-10 carbon atoms.
  • Preferred aryl groups are phenyl and naphthyl each optionally substituted by 1 to 5 substituents independently selected from halogen, nitro, amino, azido, Cl-6- alkoxy, Cl-6-alkylthio, Cl-6-alkyl, Cl-6-haloalkyl and phenyl.
  • halogen includes an atom of CI, Br, F, I.
  • hydroxy represents a group of the formula -OH.
  • thiol represents a group of the formula -SH.
  • cyano represents a group of the formula -CN.
  • nitro represents a group of the formula -NO2.
  • nitrooxy represents a group of the formula -ON02-
  • amino represents a group of the formula -NH2.
  • sulfonic acid represents a group of the formula - SO3H.
  • sulfonamide represents a group of the formula -S0 2 NH 2 .
  • ester as used herein is defined as including a group of formula -
  • ether is defined as including a group selected from Cl-50- straight or branched alkyl, or C2-50- straight or branched alkenyl or alkynyl groups or a combination of the same, interrupted by one or more oxygen atoms.
  • amido is defined as including a group of formula -CONH2 or - CONHR 1 1 or -CONR 1 1 R 12 wherein R 1 1 and R 12 are as defined above.
  • heterocycle as used herein is defined as including an aromatic or non aromatic cyclic alkyl, alkenyl, or alkynyl moiety as defined above, having at least one O, S and/or N atom interrupting the carbocyclic ring structure and optionally, one of the carbon of the carbocyclic ring structure may be replaced by a carbonyl.
  • Non-limiting examples of aromatic heterocycles are pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetra-zolyl, quinazolinyl, quinolizinyl, naphthyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, pyrazolyl, indolyl, indolizinyl, purinyl, isoindolyl, carbazolyl, thiazolyl, 1,2,4-thiadiazolyl, thieno(2,3-b)furanyl, furopyranyl, benzofuranyl, benzoxepinyl, isooxazolyl, oxazolyl, thianthrenyl, benzothiazolyl, or benzo
  • Non-l- ⁇ -niting examples of non aromatic heterocycles are tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl, morpholino , morpholinyl, l-oxaspiro(4.5)dec-2-yl, pyrrolidinyl, 2-oxo-pyrrolidinyl, sugar moieties (i.e.
  • heterocycle also includes bicyclic, tricyclic and tetracyclic, spiro groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or another monocyclic heterocyclic ring or where a monocyclic heterocyclic group is bridged by an alkylene group, such as quinuclidinyl, 7- azabicyclo(2.2. l)heptanyl, 7-oxabicyclo(2.2. l)heptanyl, 8-azabicyclo(3.2. l)octanyl.
  • X are -COO R 7 or -CONR 5 R 6 , wherein R 5 , R 6 and R 7 are preferably hydrogen, Cl-4 -alkyl, phenyl or alkylphenyl.
  • X is carboxy or -CONR ⁇ R ⁇ , wherein R 5 and R 6 are preferably hydrogen, Cl-4 -alkyl, phenyl or alkylphenyl, especially -CONH2.
  • R 5 and R 6 are preferably hydrogen, Cl-4 -alkyl, phenyl or alkylphenyl, especially -CONH2.
  • a 1 and A 2 are each oxygen.
  • R 1 is hydrogen, alkyl, especially Cl-12 alkyl, particularly lower alkyl or aryl especially phenyl.
  • R* groups are 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 such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1, 1 -dimethyl-2, 2-dibromoethyl, 1 , l-dimethyl-2,2,2-trichloroethyl.
  • Ri as ethyl is especially preferred.
  • R 2 and R 2 are independently hydrogen, halogen or alkyl, especially lower alkyl.
  • R 2 and R 2a groups are independently 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 such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, l,l-dimethyl-2, 2-dibromoethyl, 1 , 1 -dimethyl-2 , 2 , 2-trichloroethyl.
  • R 2 and R 2a are hydrogen.
  • R 3a , R 4 and R 4a are independently hydrogen, alkyl, especially methyl or ethyl or aryl especially phenyl or aralkyl, especially benzyl.
  • R 3a , R 4 and R 4a groups are independently 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 such as trifluoromethyl, trichloromethyl, 2,2, 2-trichloroethyl, 1 , 1 -dimethyl-2 , 2-dibromoethyl, 1 , 1 -dimethyl-2, 2, 2-trichloroethyl.
  • R 4 and R 4a are hydrogen.
  • R 3a is particularly hydrogen or alkyl, especially lower alkyl and is most preferably hydrogen.
  • R 3 is hydrogen, Cl-12-alkyl, especially Cl-6-alkyl, each optionally substituted by one or more substituents selected from hydroxy, halogen, cyano, thiocyanato or alkoxy and attached to the ring either directly or via a thio, sulflnyl, sulfonyl, carbonyl or oxycarbonyl group and optionally, a Cl-4-alkylene bridge, particularly methylene; C2-6-alkenyl or -alkynyl, especially C2-3-alkenyl or -alkynyl each optionally substituted by one or more halogens; azido; cyano; amido; carboxy; triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl,
  • R 3 is Cl-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, Cl-6-alkyl, Cl-6 haloalkyl, Cl-6-alkoxy, amino, azido, phenyl and nitro and each attached to the ring either directly or via a sulfonyloxy and optionally additionally a Cl-4-alkylene bridge, particularly methylene.
  • substituents selected from halogen,
  • R 3 groups are 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 such as trifluoromethyl, trichloromethyl, 2,2, 2-trichloroethyl, 1 , 1 -dimethyl-2 , 2-dibromoethyl, 1 , 1 -dimethyl-2 , 2, 2-trichloroethyl.
  • R3 is especially Cl-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, Cl-6-alkyl, Cl-6 haloalkyl or azido.
  • R 3 groups are Cl-6 alkyl and C2-6 haloalkenyl.
  • R ⁇ and R ⁇ are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl, especially hydrogen or methyl.
  • R ⁇ and R ⁇ are hydrogen.
  • R 7 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso or tert-butyl, 2,2,2-trimethylethyl, methoxy, ethoxy, phenyl, benzyl or the same substituted by at least one halogen atom such as trifluoromethyl, chlorophenyl.
  • R 7 is hydrogen, methyl or ethyl especially hydrogen.
  • R 8 is 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 such as trifluoromethyl, chlorobenzyl.
  • R 8 is hydrogen or methyl.
  • Combinations of one or more of these preferred compound groups are especially preferred.
  • a particular group of compounds of formula II comprises those wherein, A2 is oxygen;
  • X is -CONR 5 R 6 or -COOR 7 or -CO-R 8 or CN;
  • R! is hydrogen or alkyl, aryl, , halogen, hydroxy, amino, nitro, cyano;
  • R 2 , R 3 , R 4 are the same or different and each is independently hydrogen or halogen, hydroxy, amino, nitro, cyano, acyl, acyloxy, a sulfonyl derivative, a sulflnyl derivative, an amino derivative, carboxy, ester, ether, amido, sulfonic acid, sulfonamide, alkoxycarbonyl, a thio derivative, alkyl, alkoxy, oxyester, oxyamido, aryl, an oxy derivative, heterocycle, vinyl and R 3 may additionally represent C2-5 alkenyl, C2-5 alkynyl or azido each optionally substituted by one or more halogen, cyano, thiocyano, azido, , cyclopropyl, acyl and/or phenyl; or phen
  • R 2a , R 3a and R 4a are hydrogen
  • R5, R6, R 7 are the same or different and each is independently hydrogen, hydroxy, alkyl, aryl, heterocycle or oxy derivative;
  • R 8 is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle, alkylthio or thio derivative.
  • R is preferably methyl, ethyl, propyl, isopropyl, butyl, or isobutyl; most preferably methyl, ethyl or n-propyl.
  • R 2 and R 4 are preferably independently hydrogen or halogen or methyl, ethyl, propyl, isopropyl, butyl, isobutyl; and, most preferably, are each hydrogen.
  • R 3 is preferably Cl-5 alkyl, C2-5 alkenyl, C2 - C5 alkynyl, cyclopropyl, azido, each optionally substituded 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 phen
  • a further particular group of compounds of formula II comprises those wherein, X is -CA I NH2, -CA i NHCHa or -CA 1 N(CH 3 ) 2 ; R 1 is alkyl or phenyl;
  • R 3 is alkyl, alkenyl, alkynyl, cyano, isothiocyanato, ether, carboxyl, amido, aryl, heterocycle; or R 3 is CH2R 10 wherein R 10 is hydrogen, cycloalkyl, oxyester, oxyalkylsulfonyl, oxyarylsufonyl, aminoalkylsulfonyl, aminoarylsulfonyl, nitrooxy, cyano, isothiocyanato, azido, alkylthio, arylthio, alkylsulfinyl, alkylsulfonyl, heterocycle, aryloxy, alkoxy or trifluoroethyl; R 3a is hydrogen, alkyl or aryl (especially with the proviso that when R 3a is hydrogen, R 3 other than methyl); or R 3 R 3a form a cycloalkyl; and R 2 , R 2 , R 4 and
  • R 1 is preferably alkyl especially Cl-12- more particularly Cl-6-alkyl and is most preferably ethyl;
  • R 2 , R 2a , R 3a and R 4a are preferably hydrogen
  • R 3 is preferably selected from hydrogen; Cl-12-alkyl, especially Cl-6-alkyl, each optionally substituted by one or more substituents selected from hydroxy, halogen, cyano, thiocyanato or alkoxy and attached to the ring either directly or via a thio, sulflnyl, sulfonyl, carbonyl or oxycarbonyl group and optionally additionally a Cl-4- alkylene bridge, particularly methylene; C2-6-alkenyl or -alkynyl, especially C2-3- alkenyl or -alkynyl, each optionally substituted by one or more halogens; azido; cyano; amido; carboxy; triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidiny
  • R 3 a is preferably hydrogen or Cl-4-alkyl
  • R 4 and R 4a are preferably, independently hydrogen, Cl-4-alkyl, phenyl or benzyl.
  • a further group of compounds of formula II comprises those in racemic form wherein, when X is -CONR ⁇ R ⁇ and R 1 is hydrogen, methyl, ethyl or propyl, then substitution on the pyrrolidine ring is other than mono-, di-, or tri-methyl or mono-ethyl.
  • a further group of compound of formula II comprises those in racemic form wherein, when X is -CONR 5 R 6 and R 1 is hydrogen or Cl-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.
  • a further particular group of compounds of formula II (Compounds IE) comprises those wherein, X is -CA 1 NH 2 ;
  • R 1 is H
  • R 3 is azidomethyl, iodomethyl, ethyl optionally substituted by 1 to 5 halogen atoms, n-propyl optionally substituted by 1 to 5 halogen atoms, vinyl optionally subsituted by one or two methyl, and/or 1 to 3 halogen atoms, acetylene optionally substituted by
  • R 3a is hydrogen or halogen, preferably fluorine; and R 2 , R 2a , R 4 and R 4a are each hydrogen; as their racemates or in enantiomerically enriched form, preferably the pure enantiomers.
  • a further particular group of compounds of formula II (Compounds IF) comprises those wherein,
  • X is -CA 1 NH 2 ;
  • R 1 is H
  • R 3 is Cl-6-alkyl, C2-6-alkenyl or C2-6-alkynyl optionally substituted by azido, oxynitro, 1 to 6 halogen atoms;
  • R 3a is hydrogen or halogen, preferably fluorine; and R 2 , R 2a , R 4 and R 4a are each hydrogen; as their racemates or in enantiomerically enriched form, preferably the pure enantiomers.
  • compositions of formula II include therapeutically active, non-toxic base and acid salt forms which the compounds of formula II are able to form.
  • the acid addition salt form of a compound of formula II that occurs in its free form as a base can be obtained by treating the free base with an appropriate acid such as an inorganic acid, for example, a hydrohalic such as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like; or an organic acid, such as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like.
  • an appropriate acid such as an inorganic acid, for example, a hydrohalic such as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like
  • an organic acid such as, for example,
  • the compounds of formula II conta-ming acidic protons may be converted into their therapeutically active, non-toxic base addition salt forms, e.g. metal or ai-nine salts, by treatment with appropriate organic and inorganic bases.
  • Appropriate base salt forms include, for example, ammonium salts, alkali and earth alkaline metal salts, e.g. lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • salt forms can be converted into the free forms by treatment with an appropriate base or acid.
  • Compounds of the formula II and their salts can be in the form of a solvate, which is included within the scope of the present invention.
  • Such solvates include for example hydrates, alcoholates and the like.
  • stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondance with the rules described in Pure Appl. Chem., 45 (1976) 11-30.
  • the invention also relates to all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds of formula II or mixtures thereof (including all possible mixtures of stereoisomers). Furthermore certain compounds of formula II which contain alkenyl groups may exist as Z (zusammen) or E (entitch) isomers. In each instance, the invention includes both mixture and separate individual isomers.
  • the preferred active compounds of formula II are the following : (2S)-2-[(4S)-4- (2,2-difluorovinyl)-2-oxopyrrolidinyl]butanamide ; (2S)-2-[(4R)-2-oxo-4- propylpyrrolidinyl]butanamide ; and (2S)-2-[(4S)-2-oxo-4- propylpyrrolidinyl]butanamide.
  • the present invention concerns also a pharmaceutical composition for preventing or treating an excitatory state at the induction of or during emergence from anaesthesia comprising a therapeutically effective amount of an active compound as described above and a pharmaceutically acceptable carrier.
  • compositions comprising the active compound can, for example, be administered orally or parenterally, i.e., intravenously, intramuscularly, subcutaneously or intrathecally.
  • Pharmaceutical compositions which can be used for oral administration can be solids or liquids and can, for example, be in the form of tablets, pills, dragees, gelatin capsules, solutions, syrups, and the like.
  • the active compound can be used mixed with an inert diluent or a non-toxic pharmaceutically acceptable vehicle such as starch or lactose, for example.
  • these pharmaceutical compositions can also contain a binder such as microcrystalline cellulose, gum tragacanth or gelatine, a disintegrant such as alginic acid, a lubricant such as magnesium stearate, a glidant such as colloidal silicon dioxide, a sweetener such as sucrose or saccharin, or colouring agents or a flavouring agent such as peppermint or methyl salicylate.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatine
  • a disintegrant such as alginic acid
  • a lubricant such as magnesium stearate
  • a glidant such as colloidal silicon dioxide
  • a sweetener such as sucrose or saccharin
  • colouring agents or a flavouring agent such as peppermint or methyl salicylate.
  • They
  • compositions which can be used for parenteral administration are in the pharmaceutical forms which are known for this mode of administration and are in the form of aqueous or oily solutions or suspensions generally contained in ampoules, disposable syringes, glass or plastics vials or infusion containers.
  • these solutions or suspensions can optionally also contain a sterile diluent such as water for injection, a physiologic saline solution, oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol, antioxidants such as ascorbic acid or sodium bisulphite, chelating agents such as ethylene diamine-tetra-acetic acid, buffers such as acetates, citrates or phosphates and agents for adjusting the osmolarity, such as sodium chloride or dextrose.
  • a sterile diluent such as water for injection, a physiologic saline solution, oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol, antioxidants such as ascorbic acid or sodium bisulphite, chelating agents such as ethylene diamine-tetra-acetic acid, buffers such as acetate
  • compositions for oral administration are prepared using methods which are routinely used by pharmacists.
  • the percentage of active material in the pharmaceutical compositions can fall within a wide range of concentrations and depends on a variety of factors such as the patient's sex, age, weight and medical condition, as well as on the method of administration.
  • the quantity of active product in compositions for oral administration is at least 0.5% by weight and can be up to 80% by weight with respect to the composition weight.
  • active material and active product as used by the Applicant mean levetiracetam alone or combined with at least one other pharmaceutically active compound for use in these pathologies.
  • the quantity of active material present is at least 0.5% by weight and can be up to 33% by weight with respect to the composition weight.
  • the dosage unit is in the range 1 mg to 400 mg of active product.
  • levetiracetam significantly counteracts an excitatory state at the induction of anaesthesia without having any significant effect per se on spontaneous locomotor activity.
  • the mean level of locomotor activity is maintained to a level comparable to the level of control animals.
  • Levetiracetam thus has an advantage in enabling the practitioner to adapt the doses to the patient more easily, without the risk of inducing side effects of underactivity due to overdosing.
  • the high margin of safety of levetiracetam for other indications see A. J. Gower et al., Eur. J. Pharmacol., 22, p 193-203 (1992) - W. L ⁇ scher and D. H ⁇ nack, Eur. J. Pharmacol., 232, p 147-158 (1993) - H. Klitgaard, A. Matagne, J. Gobert, E. W ⁇ lfert, Eur. J.
  • EXAMPLE Comparison of the effects of levetiracetam and valproate on an excitatory state induced by pentobarbital
  • the hyperactivity and over excitement induced by pentobarbital, under some conditions, in rodents can be considered to mimic one of the unwanted side-effects of the drug observed in certain patients during induction of or emergence from anaesthesia.
  • a sub-hypnotic dose of 20 mg/kg pentobarbital (NEMBUTAL®) is employed in mice and their locomotor activity observed as proposed by Vetulani et al., Pharmacology Biochemistry & Behavior, vol. 33, 1989: 927-929.
  • the locomotor activity was evaluated during 10 minutes in an apparatus (activity cage, UGO BASILE®) constructed in grey perspex (35 x 23 x 24 cm high) and situated in a quiet room.
  • the cage floor was made up of 30 evenly spaced stainless steel bars (3 mm in diameter), which were insulated from each other (spaced 11 mm apart). The odd bars were earthed. The even bars were active and wired in four sets.
  • the "bridges" the animal made or broke with its paws, linked or disconnected one or more active bars with earth, thereby producing random configurations, which changed as the animal moved. These changes in configuration were converted into pulses by four solid state resistance detectors. An electronic counter summed up the pulses and printed the results at intervals of 10 minutes.
  • NEMBUTAL® 20 mg/kg was administered intraperitoneally (i.p.) 30 minutes before testing.
  • Drugs were injected in a total volume of 10 ml/kg. Control animals received the same volume of a saline solution (0.9 %).
  • the control groups received two injections of the vehicle (saline solution) (saline + saline group).
  • the experimental groups received an injection of pentobarbital and an injection of vehicle (pentobarbital + saline group) or levetiracetam (pentobarbital + levetiracetam groups) or sodium valproate (pentobarbital + valproate groups).
  • pentobarbital + saline group an injection of pentobarbital and an injection of vehicle
  • pentobarbital + saline group or levetiracetam
  • pentobarbital + valproate groups pentobarbital + valproate groups.
  • the effects of each of levetiracetam and sodium valproate alone on locomotor activity were also evaluated.
  • the mice were placed in the center of the activity cage and the experimenter started the system for a recording of 10 minutes.
  • Levetiracetam significantly counteracted this hyperactivity without having any significant effect per se on spontaneous locomotor activity.
  • the mean level of locomotor activity was maintained to a level comparable to the level of control animals.
  • Sodium valproate another antiepileptic drug, also decreased the pentobarbital-induced locomotor hyperactivity.
  • the level of locomotor activity was already below the level of the control animals. When given alone, this dose increased the spontaneous locomotor activity of normal mice.

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Abstract

La présente invention concerne l'utilisation de dérivés de 2-oxo-1-pyrrolidone, en particulier (S)-(-)-?-éthyl-2-oxo-1-pyrrolidineacétamide, destinés à la préparation de médicaments efficaces pour la prévention ou le traitement d'un état d'excitation à l'anesthésie ou à la réanimation.
PCT/EP2003/004982 2002-05-14 2003-05-13 Utilisation de derives de 2-oxo-1-pyrrolidone pour la preparation d'un medicament WO2003094913A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007012439A1 (fr) * 2005-07-26 2007-02-01 Ucb Pharma, S.A. Compositions pharmaceutiques a base de levetiracetam et leur methode de preparation
US20100240728A1 (en) * 2006-06-08 2010-09-23 Ucb Pharma, S.A. Co-Crystals of Pyrrolidinones
US8957226B2 (en) * 2005-09-15 2015-02-17 Ucb Pharma S.A. 2-oxo-1-pyrrolidine derivatives, processes for preparing them and their uses

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4696943A (en) * 1984-05-15 1987-09-29 U C B Societe Anonyme (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide
WO2001039779A1 (fr) * 1999-12-01 2001-06-07 Ucb, S.A. Derive de pyrrolidine acetamide seul ou combine pour traiter des affections du snc
WO2001062726A2 (fr) * 2000-02-23 2001-08-30 Ucb, S.A. Derives de 2-oxo-1-pyrrolidine, procedes de preparation et utilisations desdits derives

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4696943A (en) * 1984-05-15 1987-09-29 U C B Societe Anonyme (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide
WO2001039779A1 (fr) * 1999-12-01 2001-06-07 Ucb, S.A. Derive de pyrrolidine acetamide seul ou combine pour traiter des affections du snc
WO2001062726A2 (fr) * 2000-02-23 2001-08-30 Ucb, S.A. Derives de 2-oxo-1-pyrrolidine, procedes de preparation et utilisations desdits derives

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GALLINAT J ET AL: "[Piracetam in anesthesia for prevention of postoperative delirium]", ANASTHESIOLOGIE, INTENSIVMEDIZIN, NOTFALLMEDIZIN, SCHMERZTHERAPIE: AINS. GERMANY SEP 1999, vol. 34, no. 9, September 1999 (1999-09-01), pages 520 - 527, XP008010004, ISSN: 0939-2661 *
GOULIAEV ALEX HAAHR ET AL: "Piracetam and other structurally related nootropics.", BRAIN RESEARCH REVIEWS, vol. 19, no. 2, 1994, pages 180 - 222, XP001122842, ISSN: 0165-0173 *
ZAFFIRI O ET AL: "[Personal experience with the use of piracetam (Nootropil) in anesthesiology]", MINERVA ANESTESIOLOGICA. ITALY MAR 1977, vol. 43, no. 3, March 1977 (1977-03-01), pages 201 - 202, XP008010009, ISSN: 0375-9393 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007012439A1 (fr) * 2005-07-26 2007-02-01 Ucb Pharma, S.A. Compositions pharmaceutiques a base de levetiracetam et leur methode de preparation
EA014961B1 (ru) * 2005-07-26 2011-04-29 Юсб Фарма С.А. Фармацевтические композиции, включающие леветирацетам, и способы их получения
US8802142B2 (en) 2005-07-26 2014-08-12 Ucb Pharma, S.A. Pharmaceutical compositions comprising levetiracetam and process for their preparation
US8957226B2 (en) * 2005-09-15 2015-02-17 Ucb Pharma S.A. 2-oxo-1-pyrrolidine derivatives, processes for preparing them and their uses
US20100240728A1 (en) * 2006-06-08 2010-09-23 Ucb Pharma, S.A. Co-Crystals of Pyrrolidinones
US8211936B2 (en) * 2006-06-08 2012-07-03 Ucb Pharma, S.A. Co-crystals of pyrrolidinones
US8642641B2 (en) 2006-06-08 2014-02-04 Ucb Pharma, S.A. Co-crystals of pyrrolidinones

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