Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
1999-07-13
2002-07-09
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S215000, C564S134000, C564S142000, C564S143000, C514S629000, C514S923000
Reexamination Certificate
active
06417399
ABSTRACT:
FIELD OF THE INVENTION
The present invention generally relates to the individual stereoisomers of the drug valnoctamide (a mixture of four stereoisomer kinds, VCD-valmethamide or 2-ethyl-3-methyl pentanamide) 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, these stereoisomers. The present invention further relates to a method for stereoselective separation 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.
BACKGROUND OF THE INVENTION
Epilepsy is an ancient disease which affects about 1% of the global population. Despite the progress in antiepileptic 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 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 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 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. 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 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 VCD in humans was performed This characterization clearly demonstrates that VCD pharmacokinetics is stereoselective, with one isomer exhibiting a much higher clearance and a shorter half-life compared with the other stereoisomers. 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.
The present invention relates to the stereoisomers of valnoctamide which are 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 stereoselective 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.
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 chromatography-mass spectrometry (GC-MS) assay which allows specific and sensitive quantitation of valnoctamide stereoisomers in human plasma. This method is the only one available for investigating the pharmacokinetics and pharmacodynamics of valnoctamide stereoisomers in plasma samples, investigations 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.
SUMMARY OF THE INVENTION
The present invention relates to stereoisomers of valnoctamide (one of four isomers of valnoctamide) 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 stereoisomers or a stereoisomer of valnoctamide, useful as anticonvulsant drugs or tranquilizers.
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 a rate of 8° C./minute until 100° C., holding for a minute then reaching final temperature of 250° C. at a rate of 4° 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 separated on a chiral stationary phase column, preferably consisting of octakis (3-O-butanoyl-2,6-di-o-pentyl)-&ggr;-cyclodextin chemically linked via a 6-mono-octamethylene spacer to a dimethylpolysiloxane and being coated on a fused silica capillary column of 25 m×250 &mgr;m coated by 0.25 &mgr;m octakis (3-O-butanoyl-2,6-di-o-pentyl)-&ggr;-cyclodextrin.
The present invention further relates to a method of 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 a rate of 8° C./minute until 100° C., holding for a minute, then reaching final temperature of 250° C. at a rate of 4° 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 of 20cm/sec and the GC carrier gas is helium. Following, the isomers are separated on a chiral stationary phase column, preferably consisting of octakis (3-O-butanoyl-2,6-di-o- pentyl)-&ggr;-cyclodextrin chemically linked via a 6-mono-octamethylene spacer to a dimethyl polysiloxane and being coated with a fused silica capillary column of 25m X 250 &mgr;m coated with 0.25 &mgr;m octakis (3-O-butanoyl-2,6-di-o-pentyl)-&ggr;-cyclodextrin.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to stereoisomers of the drug, valnoctamide (VCD-valmethamide or 2-ethyl-3-methyl pentanamide), 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, these stereoisomers. VCD, as compared with the well-known antiepileptic drug VPA, is retained in the body for a relatively long period and the plasma levels of its corresponding acid (VCA) are much lower than those of the parent d
Bialer Meir
Roeder Michael
Schurig Volker
Spiegelstein Ofer
Yagen Boris
Kumar Shailendra
Lowe Hauptman & Gilman & Berner LLP
Yissum Research Development Company of the Hebrew University of
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