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Valnoctamide Stereoisomers, a Method for Their Europäisches Patentamt *EP000966429B1* (19) European Patent Office Office européen des brevets (11) EP 0 966 429 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.7: C07C 233/05, A61K 31/16 of the grant of the patent: 04.06.2003 Bulletin 2003/23 (86) International application number: PCT/IL98/00015 (21) Application number: 98900346.2 (87) International publication number: (22) Date of filing: 14.01.1998 WO 98/030536 (16.07.1998 Gazette 1998/28) (54) VALNOCTAMIDE STEREOISOMERS, A METHOD FOR THEIR SYNTHESIS AND SEPARATION AND USES THEREOF VALNOCTAMID-STEREOISOMERE, EINE METHODE ZU IHRER HERSTELLUNG UND ABTRENNUNG UND IHRE ANWENDUNGEN STEREO-ISOMERES DU VALNOCTAMIDE, LEUR PROCEDE DE SYNTHESE ET DE SEPARATION, ET LEURS UTILISATIONS (84) Designated Contracting States: (56) References cited: AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC US-A- 3 056 726 NL PT SE • BAREL, SHIMON ET AL: "Stereoselective (30) Priority: 14.01.1997 IL 12000697 pharmacokinetic analysis of valnoctamide in healthy subjects and in patients with epilepsy" (43) Date of publication of application: CLIN. PHARMACOL. THER. (ST. LOUIS) (1997), 29.12.1999 Bulletin 1999/52 61(4), 442-449 CODEN: CLPTAT;ISSN: 0009-9236, XP002063383 (73) Proprietor: YISSUM RESEARCH DEVELOPMENT • PISANI, F. ET AL: COMPANY "Carbamazepine-valnoctamide interaction in OF THE HEBREW UNIVERSITY OF JERUSALEM epileptic patients: in vitro/in vivo correlation" Jerusalem 91042 (IL) EPILEPSIA (N. Y.) (1993), 34(5), 954-9 CODEN: EPILAK;ISSN: 0013-9580, XP002063379 cited in (72) Inventors: the application • BIALER, Meir • BIALER, M. ET AL: "Pharmacokinetics of a 96222 Jerusalem (IL) valpromide isomer, valnoctamide, in healthy • YAGEN, Boris subjects" EUR. J. CLIN. PHARMACOL. (1990), 96757 Jerusalem (IL) 38(3), 289-91 CODEN: EJCPAS;ISSN: 0031-6970, • SPIEGELSTEIN, Ofer XP002063380 cited in the application 90805 Mevasseret Zion (IL) • J. P.CHAMBON ET AL: "Valnoctamide: • ROEDER, Michael Pharmacological data suggesting an D-72810 Gomaringen (DE) antiepileptic activity" NEUROSCI. LETT. • SCHURIG, Volker [SUPPL], vol. 5, 1980, page S327 XP002063381 D-72076 Tubingen (DE) cited in the application (74) Representative: Remarks: Leson, Thomas Johannes Alois, Dipl.-Ing. et al The file contains technical information submitted Patentanwälte after the application was filed and not included in this Tiedtke-Bühling-Kinne & Partner, specification Bavariaring 4 80336 München (DE) Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 0 966 429 B1 Printed by Jouve, 75001 PARIS (FR) EP 0 966 429 B1 Description Field of the Invention 5 [0001] The present invention generally relates to the individual (2R)(3S) stereoisomer of the drug valnoctamide (a mixture of four stereoisomer kinds, VCD-valmethamide or 2-ethyl-3-methyl pentanamide) obtainable by the process defined in claim 1 useful in treatment of neurological and psychotic disorders such as different kinds of epilepsy and affective disorders, and useful as tranquilizers and to treat pain, and to pharmaceutical compositions containing, as an active ingredient, said stereoisomer. The present invention further relates to a method for stereoselective separation 10 and quantification of the four stereoisomers from a racemic mixture of VCD or plasma of patients treated with the racemic drug. The present invention further relates to a unique method for the synthesis of the individual stereoisomers (2S)(3S) and (2R)(3S). 15 Background of the Invention [0002] Epilepsy is an ancient disease which affects about 1% of the global population. Despite the progress in an- tiepileptic therapy, about 25% of the epileptic patients continue to suffer from uncontrolled seizures and medication toxicity. At present, there are four major epileptic drugs in use: phenobarbital, phenytoin, carbamazepine and valproic 20 acid. Valproic acid (VPA) is one of the major antiepileptic drugs. It has two major side effects, teratogenicity and hepatotoxicity, which have been associated with valproate therapy. Valnoctamide (VCD-valmethamide or 2-ethyl-3 methyl pentanamide) is an isomer of a valpromide (VPD) and is sold as an over- the-counter drug in several European countries. It has been available clinically for many decades and is 25 still used as a mild tranquilizer and occasionally as an antiepileptic drug (Chambon JP, Perio A, Neurosci. Lett [Suppl] 5: S327-S327, 1980). Valpromide (VPD) is used as an anticonvulsant and antipsychotic agent, and in humans it is a prodrug of valproic acid (VPA). VPD may also be useful in treatment of neurological disorders and psychotic or affective disorders such as convulsions and epilepsy, and useful as tranquilizers and to treat pain. Recently, interest in VCD was revived by the observation that this compound possesses marked anticonvulsant activity in animal models. 30 Both VCD and VPD are three times more potent as anticonvulsants than VPA. In addition, VPD, unlike VPA, has not been found to be teratogenic in animals possibly because it contains a carboxamide moiety instead of a carboxylic acid. However, in humans VPD acts as a prodrug to VPA and therefore its superiority over VPA in animal models does not have clinical implications. Unlike VPD, VCD acts as a drug on its own in both animals and humans and undergoes only slow and very little 35 transformation to its corresponding (less active) valnoctic acid (VCA). Based on its anticonvulsant potency, metabolic stability and lack of teratogenicity, VCD was viewed as having potential to become a new antiepileptic drug. It was recently found, however, that VCD is an inhibitor of the enzyme epoxide hydrolase. This inhibition was regarded as a drawback to the development of racemic VCD as a new antiepileptic drug. In the present invention, for the first time, characterization of the pharmacokinetics (PK) of the four stereoisomers of 40 VCD in humans was performed. This characterization clearly demonstrates that VCD pharmacokinetics is stereose- lective, with one isomer exhibiting a much higher clearance and a shorter half-life compared with the other stereoi- somers. Stereoselective pharmacokinetics has been demonstrated previously with different drugs, such as verapamil and mephenytoin, but this is the first time that PK stereoselectivity has been shown for an amide of an aliphatic short- chain fatty acid. 45 [0003] The present invention relates to the (2R)(3S) stereoisomer of valnoctamide obtainable by the process defined in claim 1 useful in treatment of neurological and psychotic disorders such as different kinds of epilepsy and affective disorders, and useful as tranquilizers and to treat pain. The present invention further relates to a method for stereose- lective separation and quantification of the four stereoisomers from a racemic mixture of VCD and to a method for the synthesis of the 2S, 3S and 2R,3S VCD stereoisomers. 50 [0004] The stereoisomers have all of the benefits, and more, of the racemic drug of valnoctamide, but do not have any of its drawbacks, making them preferable for use in the treatment of convulsions and epilepsy and as an active ingredient in pharmaceutical compositions for the treatment of the latter. The present invention further relates to a method for separating the four stereoisomers of racemic valnoctamide. This method is a new stereoselective gas chroinatography-mass spectrometry (GC-MS) assay which allows specific and 55 sensitive quantitation of valnoctamide stereoisomers in human plasma. This method is the only one available for in- vestigating the pharmacokinetics and pharmacodynamics of valnoctamide stereoisomers in plasma samples, investi- gations which may have important practical implications for the development of a new anticonvulsant drug for humans. The present invention further relates to a unique method for the synthesis of the individual stereoisomers (2S) (3S) 2 EP 0 966 429 B1 and (2R) (3S). Summary of the Invention 5 [0005] The present invention relates to the (2R)(3S) stereoisomer of valnoctamide (one of four isomers of valnocta- mide) obtainable by the process defined in claim 1 useful in treatment of neurological and psychotic disorders such as different kinds of epilepsy and affective disorders, and useful as tranquilizers and to treat pain, and to pharmaceutical compositions, containing as an active ingredient at least the (2R)(3S) stereoisomer of valnoctamide obtainable by the process defined in claim 1, useful as anticonvulsant drugs or tranquilizers. 10 The present invention further relates to a method for separating valnoctamide isomers comprising subjecting a mixture of racemic valnoctamide to gas chromatography preferably with oven temperature programming conditions; 50°C for 1 minute, increasing at and of 80°C / minute until 100°C, holding for a minute then reaching final temperature of 250°C at a rate of 40°C / minute, the injector temperature is 240°C and the GC-MS transfer line temperature is 250°C; inlet pressure is 5 psi with a linear flow rate 20 cm / second and the GC carrier gas is helium. Following, the isomers are 15 separated on a chiral stationary phase column, preferably consisting of octakis (3-O-butanoyl-2,6-di-o-pentyl)-γ-cyclo- dextrin chemically linked via a 6-mono-octamethylene spacer to a dimethylpolysiloxane and being coated on a fused silica capillary column of 25 m x 250µm coated by 0.25 µm octakis (3-O-butanoyl-2,6-di-o-pentyl)-γ-cyclodextrin. The present invention farther relates to a method for the stereoselective synthesis of the valnoctamide stereoisomers (2S,3S) and (2R,3S) comprising; 20 (a) synthesizing (3S)-methyl valeric acid from L-isoleucine; (b) subsequently synthesizing of (3S)-methyl valeroyl chlorid; and (c) subsequently synthesizing (2S,3S) valnoctic acid or subsequently synthesizing (2R,3S) valnoctic acid; (d) subsiquently synthesizing (2S,3S) valnoctamide or (2R,3S) valnoctamid.
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