2-oxo-1-pyrrolidine derivatives, processes for preparing them and their uses
AssigneeUcb, S.A.
InventorsEdmond Differding, Benoit Kenda, Benedicte 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.
Claims39
A compound having the formula I or a pharmaceutically acceptable salt thereof,
- 71
- wherein
- X is —CA1NR5R6 or —CA1OR7 or —CA1-R8 or CN;
- A1 and A2 are independently oxygen, sulfur or —NR9;
- R1 is hydrogen, alkyl, aryl or —CH2—R1a wherein R1a is aryl, heterocycle, halogen, hydroxy, amino, nitro or cyano;
- R2, R3 and R4 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 oxy derivative, thio derivative, amino derivative, acyl derivative, sulfonyl derivative or sulfinyl derivative;
- R2a, R3a and R4a are the same or different and each is independently hydrogen, halogen, alkyl, alkenyl, alkynyl or aryl;
- R5, R6, R7and R9 are the same or different and each is independently hydrogen, hydroxy, alkyl, aryl, heterocycle or an oxy derivative;
- and
- R8 is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle or a thio derivative;
- with the provisos that at least one of as R2, R3, R4, R2a, R3a and R4a 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 pyrrolidine ring is other than mono-, di-, or tri-methyl or mono-ethyl;
- and that when R1, R2, R4, R2a, R3a and R4a are each hydrogen, A2 is oxygen and x is —CONR5R6 then R3 is different from carboxy, ester, amido, substituted oxo-pyrrolidine, hydroxy, oxy derivative, amino, amino derivatives, methyl, naphthyl, phenyl optionally substituted by oxy derivatives or in the para position by an halogen atom.
A compound according to any preceding claim as a pure enantiomer.
A compound according to any preceding claim, which, when the carbon atom to which R1 is attached is asymmetric, is in the “S”-configuration.
A compound selected from those hereinbefore numbered 8, 9, 10, 22, 23, 27, 30, 31, 32, 33, 38, 40, 41, 43, 46, 47, 49, 64, 71, 72, 73, 75, 81, 83, 86, 87, 88, 92, 93, 95, 96, 98, 100, 103, 105, 110, 119, 127, 142, 146, 149, 151, 152,156, 157, 158, 159, 162, 163, 164, 165, 166, 169, 170, 171, 173, 174, 175, 176, 180, 181, 185, 187, 188, 195, 196, 197, 198, 200, 201, 204, 205, 207, 209, 211, 212, 213, 214, 215, 219, 221, 222, 223, 224, 225, 226, 228, 229, 234, 250, 251, 252, 264, 265, 267, 304, 306, 350, 351, AA 1, AA 2, AA 3, AA 4 and AA 5 or a pharmaceutically acceptable salt thereof.
(2S)-2-[(4S)-4-(2,2-difluorovinyl)-2-oxopyrrolidinyl]butanamide or a pharmaceutically acceptable salt thereof.
The (4R) and (4S) diastereoisomers of (2S)-2-[2-oxo-4-propylpyrrolidinyl]butanamide or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising an effective amount of a compound according to any preceding claim in combination with a pharmaceutically acceptable diluent or carrier.
The use of a compound according to any preceding claim for the manufacture of a medicament for the treatment of epilepsy, epileptogenesis, seizure disorders, convulsions and other neurological disorders including bipolar disorders, mania, depression, anxiety, migraine, trigeminal and other neuralgia, chronic pain, neuropathic pain, cerebral ischemia, cardiac arrhythmia, myotonia, cocaine abuse, stroke, myoclonus, essential tremor and other movement disorders, neonatal cerebral haemorrhage, amyotrophic lateral sclerosis, spasticity, Parkinson's disease and other degenerative diseases, bronchial asthma, asthmatic status and allergic bronchitis, asthmatic syndrome, bronchial hyperreactivity and bronchospastic syndromes as well as allergic and vasomotor rhinitis and rhinoconjunctivitis.
A method for treating epilepsy, epileptogenesis, seizure disorders, convulsions and other neurological disorders including bipolar disorders, mania, depression, anxiety, migraine, trigeminal and other neuralgia, chronic pain, neuropathic pain, cerebral ischemia, cardiac arrhythmia, myotonia, cocaine abuse, stroke, myoclonus, essential tremor and other movement disorders, neonatal cerebral haemorrhage, amyotrophic lateral sclerosis, spasticity, Parkinson's disease and other degenerative diseases, 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 any preceding claim.
Dependencies are inferred from the claim text.