"2-Oxo-1-Pyrrolidine Derivative and Its Pharmaceutical Uses"
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(19) & (11) EP 1 452 524 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 207/27 (2006.01) A61K 31/4015 (2006.01) 14.10.2009 Bulletin 2009/42 A61P 25/08 (2006.01) (21) Application number: 04007878.4 (22) Date of filing: 21.02.2001 (54) "2-oxo-1-pyrrolidine derivative and its pharmaceutical uses" "2-Oxo-1-Pyrrolidinderivate und ihre pharmazeutische Verwendung" "Dérivé de 2-oxo-1-pyrrolidine et ses applications pharmaceutique" (84) Designated Contracting States: • Talaga, Patrice AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU 1170 Watermael-Boitsfort (BE) MC NL PT SE TR (74) Representative: UCB (30) Priority: 23.02.2000 GB 0004297 Intellectual Property c/o UCB S.A. (43) Date of publication of application: Intellectual Property Department 01.09.2004 Bulletin 2004/36 Allée de la Recherche 60 1070 Brussels (BE) (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: (56) References cited: 01925354.1 / 1 265 862 WO-A-99/13911 GB-A- 1 309 692 (73) Proprietor: UCB Pharma, S.A. • PROUS: "LEVETIRACETAM" DRUGS OF THE 1170 Brussels (BE) FUTURE, BARCELONA, ES, vol. 19, no. 2, 1994, pages 111-113, XP000908882 ISSN: 0377-8282 (72) Inventors: • FISCHER W ET AL: "Die Wirksamkeit von • Differding, Edmond Piracetam, Meclofenoxat und Vinpocetin in 1348 Ottignies-Louvain-La-Neuve (BE) verschiedenen Krampfmodellen bei der Maus" • Kenda, Benoît PHARMAZIE, VEB VERLAG VOLK UND 5080 Emines (BE) GESUNDHEIT. BERLIN, DD, vol. 46, no. 5, 1991, • Lallemand, Bénédicte pages 359-360, XP002173100 ISSN: 0031-7144 4950 Waimes (BE) • GLOZMAN ET AL: "synthesis and anticonvulsive • Matagne, Alain activity od 4-phenyl-2-pyrrolidinone-1-a cetic 6280 Gerpinnes (BE) acid amides" CHEMICAL ABSTRACTS + • Michel, Philippe INDEXES, AMERICAN CHEMICAL SOCIETY. 1650 Beersel (BE) COLUMBUS, US, vol. 95, no. 3, 1981, page 661, • Pasau, Patrick XP002173104 ISSN: 0009-2258 1450 Chastre (BE) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 452 524 B1 Printed by Jouve, 75001 PARIS (FR) EP 1 452 524 B1 Description [0001] The present invention concerns a compound selected from the (4R) and (4S) diastereoisomers of (2S)-2-[2- oxo-4-propylpyrrolidinyl]butanamide or a pharmaceutically acceptable salt thereof. 5 [0002] European Patent No. 0 162 036 B1 discloses the compound (S)-α-ethyl-2-oxo-1-pyrrolidine acetamide, which is known under the International Nonproprietary Name of levetiracetam. [0003] Levetiracetam, a laevorotary compound, is disclosed as a protective agent for the treatment and prevention of hypoxic and ischemic type aggressions of the central nervous system. This compound is also effective in the treatment of epilepsy, a therapeutic indication for which it has been demonstrated that its dextrorotatory enantiomer (R)-α-ethyl- 10 2-oxo-1-pyrrolidine acetamide, also known from European Patent No. 0 165 919 B1, completely lacks activity (A.J. GOWER et al., Eur. J. Pharmacol., 222, (1992), 193-203). [0004] Racemic α-ethyl-2-oxo-1-pyrrolidine acetamide and analogs thereof are known from British Patent No. 1 309 692. US Patent No. 3 459 738 discloses derivatives of 2-oxo-1-pyrrolidine acetamide. European Patent No. 0 645 139 B1 discloses the anxiolytic activity of levetiracetam. PCT Application No. PCT/EP00/11808 discloses the use of leveti- 15 racetam for the curative and/or prophylactic treatment of bipolar disorders, migraine, chronic or neuropathic pain as well as combinations of levetiracetam with at least one compound inducing neural inhibition mediated by GABAA receptors. [0005] It has now surprisingly been found that certain analogs of levetiracetam, particulary those bearing further substitution in the pyrrolidone ring, demonstrate markedly improved therapeutic properties. [0006] In one aspect, the invention therefore provides a compound selected from the (4R) and (4S) diastereoisomers 20 of (2S)-2-[2-oxo-4-propylpyrrolidinyl]butanamide or a pharmaceutically acceptable salt thereof. In particular the present invention relates to compound (2S)-2-[(4R)-2-oxo-4-propylpyrrolidinyl] butanamide [0007] The "pharmaceutically acceptable salts" according to the invention include therapeutically active, non-toxic base and acid salt forms which the compounds according to the present invention are able to form. [0008] Compounds according to the present invention and their salts can be in the form of a solvate, which is included 25 within the scope of the present invention. Such solvates include for example hydrates, alcoholates and the like. [0009] Compounds according to the present invention and some of their intermediates have at least one stereogenic center in their structure. This 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. [0010] With respect to the present invention reference to a compound or compounds is intended to encompass that 30 compound in each of its possible isomeric forms and mixtures thereof unless the particular isomeric form is referred to specifically. [0011] The invention also includes within its scope pro-drug forms of the compounds according to the present invention. [0012] The term "prodrug" as used herein includes compound forms which are rapidly transformed in vivo to the parent compound according to the invention, for example, by hydrolysis in blood. Prodrugs are compounds bearing groups 35 which are removed by biotransformation prior to exhibiting their pharmacological action. Such groups include moieties which are readily cleaved in vivo from the compound bearing it, which compound after cleavage remains or becomes pharmacologically active. Metabolically cleavable groups form a class of groups well known to practitioners of the art. They include, but are not limited to such groups as alkanoyl (i.e. acetyl, propionyl, butyryl, and the like), unsubstituted and substituted carbocyclic aroyl (such as benzoyl , substituted benzoyl and 1- and 2-naphthoyl), alkoxycarbonyl (such 40 as ethoxycarbonyl), trialklysilyl (such as trimethyl- and triethylsilyl), monoesters formed with dicarboxylic acids (such as succinyl), phosphate, sulfate, sulfonate, sulfonyl, sulfinyl and the like. The compounds bearing the metabolically cleavable groups have the advantage that they may exhibit improved bioavailability as a result of enhanced solubility and/or rate of absorption conferred upon the parent compound by virtue of the presence of the metabolically cleavable group. T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery System", Vol. 14 of the A.C.S. Symposium Series; "Bioreversible 45 Carriers in Drug Design", ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. [0013] The compounds according to their invention can be prepared analogously to conventional methods as under- stood by the person skilled in the art of synthetic organic chemistry. [0014] The following process description sets forth certain synthesis routes in an illustrative manner. Other alternative and/or analogous methods will be readily apparent to those skilled in this art. As used herein in connection with substituent 50 meanings, "=" means "is" and "≠" means "is other than". [0015] It has now been found that compounds according to the present invention and their pharmaceutically acceptable salts are useful in a variety of pharmaceutical indications. [0016] For example, the compounds according to the invention are useful for the treatment of epilepsy, epileptogenesis, seizure disorders and convulsions. 55 [0017] These compounds may also be used for the treatment of 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, ne- onatal cerebral haemorrhage, amyotrophic lateral sclerosis, spasticity, Parkinson’s disease and other degenerative 2 EP 1 452 524 B1 diseases. [0018] In addition the compounds according to the invention may be used in the treatment of bronchial asthma, asthmatic status and allergic bronchitis, asthmatic syndrome, bronchial hyperreactivity and bronchospastic syndromes as well as allergic and vasomotor rhinitis and rhinoconjunctivitis. 5 [0019] Thus, the present invention, in a further aspect, concerns the use of a compound according to the present inventionor a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of neuro- logical and other disorders such as mentioned above. [0020] In particular, the present invention concerns the use of a compound acccording to the present invention or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of epilepsy, bipolar 10 disorders, chronic pain or neuropathic pain, migraine, bronchial-, asthmatic- or allergic conditions. [0021] The activity and properties of the active compounds, oral availability and stability in vitro or in vivo can vary significantly among the optical isomers of the disclosed compounds. [0022]