MXPA02005071A - Compositions comprising s-tofisopam and use of these - Google Patents

Abstract

COMPOSITIONS FOR THE PREPARATION OF A MEDICAMENT FOR THE TREATMENT OR PREVENTION OF CONVULSIONS OR SEIZURES The present invention relates to compositions comprising S- tofisopam substantially free of R-tofisopam, and methods for treating or preventing convulsions and/or seizures comprising administration of the composition to subjects in need of treatment therefore. Also provided do compositions and methods for treating or preventing convulsions and/or seizures comprise administering S-tofisopam substantially free of R-tofisopam with another anti-convulsant.

Description

»\ COMPOSITIONS AND METHODS FOR THE TREATMENT OR PREVENTION OF CONVULSIONS OR ATTACKS This application claims the benefits of U.S. Provisional Application No. 60 / 292,026 filed May 18, 2001.

FIELD OF THE INVENTION The present invention relates to compositions and methods for treating or preventing seizures or attacks.

BACKGROUND OF THE INVENTION Tofisopam is 1- (3,4-dimethoxy-phenyl) -4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine, which may be represented by the formula: Tofisopam (racemic mixture) has been marketed under the names of Grandaxin® and Seriel®, "9 as an anxiolytic. Although tofisopam in a benzodiazepine, it differs structurally, from the classic benzodiazepines similar to diazepam, in that the nitrogen atoms in the ring structure are placed in 2,3 instead of in 1,4. Despite the structural similarity between classical 1,4-benzodiazepines and tofisopam, the difference in nitrogen position in the benzodiazepine ring confers pharmacological activity to tofisopam which is very different from classic benzodiazepines. A synthesis of tofisopam is described in U.S. Patent No. 3,736,315. Tofisopam has a chiral center at carbon C-5 and has, therefore, two enantiomers. In addition, each enantiomer of tofisopam can exist in two stable conformations based on the two configurations that can be assumed by the benzodiazepine ring containing nitrogen. The molecular structure and conformational properties of tofisopam have been determined by methods of X-ray crystallography, CD and NMR (Visy, J. and Simongi, M., Chirali ty 1: 211-215 (1989)). The diazepine ring 2,3 exists in two pot shaping classes. In the main conformers, (+) R and (-) S, the ethyl group attached to the center of asymmetry C-5 has an orientation quasi-equatorial, while in the shapers secondary, (-) R and (+) S, the ethyl group is placed in quasi-axial form. Therefore, racemic tofisopam can exist as four molecular species, that is: two enantiomers, each of which exists in two chiral conformations. The sign of optical rotation is reversed after inversion of the diazepine ring. In. crystal form, tofisopam exists only as the main conformations, being the tofisopam levorotatory of the absolute configuration (S) (Toth, G. et al., J. Heterocyclic Chem. 20: 709-713 (1983); Fogassy, E et al., In: Bio-Organic Heterocycles, Van der Pias, H. C, Ótvós, L., Simongi, M., eds. Budapest Amsterdam, Akademia, Kiado-Elsevier, 229: 233 (1984)). The absolute configuration of an asymmetric drug molecule can have profound effects on the efficacy of the drug. Fogassy et al. declares that a summary by Petocz et al. from a 1980 meeting, describes pharmacological tests in mice that exhibit distinct biological activity for the stereoisomers of tofisopam and includes the observation that the racemic tofisopam activity does not correspond to the sum of the activities of its enantiomers (Fogassy, E. et al. ., supra). However, Fogassy et al. does not describe the biological tests of the specific performance achieved by Petocz et al. In addition, a search of the prior art did not obtain this summary from Petocz et al. Therefore, there is currently no indication that Petocz et al. exists or refers to S-tofisopam and its unexpected properties. In addition, it has been reported that the binding of tofisopam enantiomers to human serum albumin is stereoselective and is affected by the interconversion of conformations (Simonyi, M. and Fitos, I., Biochem Pharmacology 32: 1911-1920 (1983)). Hungarian patent No. 178516 describes an attempt to separate the enantiomers of tofisopam and the observations with respect to the administration of the separated products in mice. Nevertheless, it is not reported on the purity of the separate products administered to the mice. In addition, the absolute configuration of the separated products is not reported and none of the tests in mice measured the anticonvulsive activity of the separated products. There have been two reports that tofisopam exhibits anticonvulsant activity in mice. In 1981, C. Ito argued that tofisopam can inhibit tryptamine-induced seizures in mice (Ito, C, Tokyo Med. College 39: 369-384 (1981); hereinafter, "Ito"). However, Ito's seizure reports do not support this conclusion. The administration of tofisopam, according to the tests described in Ito, seems to have no effect on the decrease in the incidence of seizures in mice (Table 6, Ito above). In addition, Ito did not test the anticonvulsant activity of S-Tofisopam practically free of R-tofisopam. In 1986, Pellow et al, reported that the administration of 100 mg / kg of tofisopam reduced the number of mice having seizures induced by the compound Ro 5-4864 (Pellow, S. and File, S., Drug Dev. Res. 7: 61-73 (1986)). However, Pellow et al. They also reported that all treated mice still suffered myoclonic jerks. In contrast, Pellow et al. reported that 25-50 mg / kg of tofisopam had preconvulsive activity in Tuck No. 1 mice when administered in combination with 3 mg / kg of picrotoxin or 30 mg / kg of pentylenetetrazole. Pellow et al. also reported that a dose of 10-50 mg / kg of tofisopam had no effect on the number or severity of seizures in Tuck No. 1 mice given 6 mg / kg of picrotoxin. Similarly, it was reported that, in Tuck No. 1 mice given 60 mg / kg of pentylenetetrazole, a dose of 10-25 mg / kg of tofisopam had no effect as an anticonvulsant. Pellow et al. did not test the anticonvulsant activity of S-tofisopam practically free of R-tofisopam. Numerous other reports, some of which were published after 1986, state that tofisopam has no anticonvulsant properties (Mennini et al *, Arch. Pharmaco ?, 32: 112-115 (1982); Saano, V., Med. Bio. 64: 201-206 (1986) Petocz, L., Acta Pharm., Hung 63: 79-82 (1993), Szego, J. et al., Acta Pharm. Hung 63: 91-98 (1993)). None of the studies tested the anticonvulsant activity of S-tofisopam practically free of its (R) enantiomer. It has been reported that tofisopam improves the actions of benzodiazepine anticonvulsants but not of phenytoin, sodium valproate or carbamazepine (Saano, V., Med. Biol. 64: 201-206 (1986)). For example, it was reported that the potentiating action of tofisopam is effective with diazepam against convulsions (Briley, M. Br. J. Pharmacol.82: 300P (1984); Mennini, T., Naugn-Schmiedeberg's Arch Pharmacol. : 112-115 (1982)) and against earthquakes (Saano, V., Pharmacol. Biochem. Behav., 17: 367-369 (1982); Saano, V., Med. Biol. 51: 49-53 (1983)) . None of these potentiation studies examined the effects of tofisopam enantiomers on the anticonvulsant activity of diazepam or other anticonvulsants.

SUMMARY OF THE INVENTION An object of this invention is to provide new compositions and methods for treating and preventing seizures and attacks. The present invention provides a composition comprising a therapeutically effective amount of S-tofisopam substantially free of its (R) -enantiomer and a pharmaceutically acceptable carrier. A composition comprising a prodrug or pharmaceutically acceptable salt of S-tofisopam virtually free of R-tofisopam is also contemplated. Preferably, the amount of S-tofisopam or the pharmaceutically acceptable salt thereof is 80% or more by weight of the total weight of tofisopam. More preferably, the amount of S-tofisopam or the pharmaceutically acceptable salt thereof is 85% or more by weight of the total weight of tofisopam. More preferably, the amount of S-tofisopam or the pharmaceutically acceptable salt thereof is 90% or more by weight of the total weight of tofisopam. More preferably, the amount of S-tofisopam or the pharmaceutically acceptable salt thereof is 95% or more by weight of the total weight of tofisopam. Most preferably, the amount of S-tofisopam or the pharmaceutically acceptable salt thereof is 99% or more by weight of the total weight of tofisopam. In one aspect of the invention, the conformation of S-tofisopam is 80% (-) and 20% (+). The present invention also provides compositions comprising practically S-tofisopam free from its enantiomer (R), and one or more other anticonvulsants. In accordance with a modality, the other anticonvulsant is selected from the group consisting of: phenytoin, mephenytoin, ethotoin, phenobarbital, mephobarbital, primidone, carbamazepine, ethosuximide, methsuximide, fensuximide, valproic acid, trimethadione, parametadione, phenacemide, acetazolamide, progabide, diazepam, lorazepam, clonazepam , clorazepate and nitrazepam. In a preferred embodiment, the other anticonvulsant is a 1,4-benzodiazepine. In yet another preferred embodiment, the other anticonvulsant is diazepam, lorazepam, clonazepam, clorazepate or nitrazepam. In one embodiment, the pharmaceutical composition is a controlled release pharmaceutical composition. The present invention provides methods for treating seizures or attacks, comprising administering to a subject in need of treatment thereof, a therapeutically effective amount of S-tofisopam practically free of R-tofisopam which is sufficient to mitigate seizures. or attacks. Another embodiment of the invention relates to methods for preventing seizures or seizures in a subject at risk of developing seizures or seizures and which comprises administering to the subject a therapeutically effective amount of S-tofisopam practically free from its P150 enantiomer (R), which is sufficient to prevent seizures or attacks. The administration of a prodrug or a pharmaceutically acceptable salt of S-tofisopam is also contemplated in accordance with the methods of this invention. In another embodiment of this invention, the subject in need of treatment is suffering from seizures or seizures caused by an alteration or condition selected from the group consisting of: epilepsy, acquired immunodeficiency syndrome (AIDS), Parkinson's disease, Alzheimer's disease , other neurodegenerative diseases, among which are: Huntington's chorea, schizophrenia, obsessive-compulsive disorders, tinnitus, neuralgia, trigeminal neuralgia, amyotrophic lateral sclerosis (ALS), tics (for example, Gille de la Tourette syndrome), post-traumatic epilepsy, alcohol use, alcohol withdrawal, intoxication or withdrawal of barbiturates, brain injury or illness, brain tumor, asphyxia, drug abuse, electric shock, fever (especially in young children), head trauma, heart disease, stroke of heat, arterial hypertension, meningitis, poisoning, cerebral embolism, toxemia of pregnancy, related uremia with kidney failure, poisonous bites and stings, withdrawal of benzodiazepines, febrile seizures and afebrile infantile convulsions.

P150 In a preferred embodiment, the subject is suffering from seizures or seizures caused by epilepsy. The present invention also provides methods for treating or preventing seizures or attacks and comprising the administration, to a subject in need of treatment thereof, of a therapeutically effective amount of S-tofisopam, a prodrug or salt thereof, practically free of R -tofisopam together or sequentially z-with one or more other anticonvulsants. The other anticonvulsant can be selected from the group consisting of: phenytoin, mephenytoin, ethotoin, phenobarbital, mephobarbital, primidone, carbamazepine, ethosuximide, methsuximide, phensuximide, valproic acid, trimethadione, parametadione, phenazemide, acetazolamide, progabide, diazepam, lorazepam, clonazepam, clorazepate and nitrazepam.

In one embodiment, the other anticonvulsant is a benzodiazepine. In a preferred embodiment, the other anticonvulsant is a 1,4-benzodiazepine. In yet another preferred embodiment, the other anticonvulsant is diazepam, lorazepam, clonazepam, clorazepate or nitrazepam.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 graphically illustrates the dose-dependent effect of tofisopam on picrotoxin-induced attacks in male NSA mice.

P150 Figure 2 graphically illustrates the dose-dependent effect of S-tofisopam on picrotoxin-induced attacks in male NSA mice. Figure 3 graphically illustrates the dose-dependent anticonvulsant effect of racemic tofisopam on picrotoxin-induced attacks in male NSA mice. Figure 4 graphically illustrates the dose-dependent anticonvulsant effect of diazepam on picrotoxin-induced attacks in male NSA mice. Figure 5 graphically illustrates the anticonvulsant effect of R-tofisopam on picrotoxin-induced attacks in male NSA mice. Figure 6 illustrates graphically the dose-dependent anticonvulsant effect of S-tofisopam on picrotoxin-induced attacks in male NSA mice.

DETAILED DESCRIPTION OF THE INVENTION A composition according to this invention comprises S-tofisopam practically free of its (R) -enantiomer. The term "substantially free of its (R) -enantiomer", as used herein, means that the composition comprises at least 80% or more by weight of S-tofisopam and 20% by weight or less of R-tofisopam in terms of P150 Total weight of tofisopam. In a preferred embodiment, the composition comprises at least 85% or more by weight of S-tofisopam and 15% by weight or less of R-tofisopam in terms of total weight of tofisopam. In a more preferred mode, the composition comprises at least 90% or more by weight of S-tofisopam and 10% by weight or less of R-tofisopam in terms of the total weight of tofisopam. In yet another more preferred embodiment, the composition comprises at least 95% or more by weight of S-tofisopam and 5% or less of R-tofisopam in terms of total weight of tofisopam. In the most preferred embodiment, the composition comprises at least 99% or more by weight of S-tofisopam and 1% or less of R-tofisopam in terms of total weight of tofisopam. In one modality, the confirmation of S-tofisopam is 80% (-) and 20% (+). Tofisopam can be synthesized according to methods known in the art. For example, a method for synthesizing is described in U.S. Patent Nos. 3,736,315 and 4,423,044, the teachings of which are incorporated herein by reference. The (S) enantiomer of tofisopam can be obtained by the methods described herein (Example 1 or 3). The compositions of the present invention comprise S-tofisopam, practically free of R-tofisopam or a prodrug of a pharmaceutically acceptable salt of the P150 same, as the active ingredient, and may also contain a pharmaceutically acceptable carrier and, optionally, other therapeutic ingredients. In one embodiment, the composn of the present invention comprises S-tofisopam and one or more other anticonvulsants. The other anticonvulsant can be, for example: phenytoin, mephenytoin, ethotoin, phenobarbital, mephobarbital, primidone, carbamazepine, ethosuximide, methsuximide, phensuximide, valproic acid, trimethadione, parametadione, phenacemide, acetazolamide, progabide, diazepam, lorazepam, clonazepam, clorazepate and Nitrazepam In another embodiment, the composn of this invention comprises S-tofisopam and a benzodiazepine. In yet another embodiment, the composn of this invention comprises S-tofisopam and a 1,4-benzodiazepine. In still another embodiment, the composn of this invention comprises S-tofisopan and an anticonvulsant selected from the group consisting of diazepam, lorazepam, clonazepam, clorazepate or nitrazepam. Prodrugs according to this invention are inactive derivatives of S-tofisopam that are metabolized in vivo to the active agent in the body. The prodrugs useful according to this invention are those that have practically the same or better therapeutic value than S-tofisopam for the treatment and prevention of P150 seizures or attacks. For example, a prodrug useful in accordance with this invention can improve the penetration of the drug through the biological membranes, which leads to improved drug absorption, to prolong the duration of the action of the drug, for example, to the release slowing of the original drug from the prodrug and / or decreasing the metabolism of the first step of the drug; to direct the action of the drug; to improve the aqueous solubility and the stability of the drug (for example, in intravenous preparations, ophthalmic drops, etc.); to improve topical administration of the drug (e.g., dermal and ocular administration of the drug); improve the enzymatic and / or chemical stability of the drugs (for example, peptides) or decrease the side effects due to the drug. Methods for making prodrugs are known in the art (eg, Balant, LP, Eur. J. Drug Metab, Pharmacokinet., 15: 143-153 (1990) and Bundgaard, H., Drugs of the Future 16: 443-458. (1991), incorporated herein by reference). The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Because S-tofisopam is basic, salts can be prepared from pharmaceutically acceptable non-toxic acids, P150 among which inorganic and organic acids are included. These acids include: malic acid, acetic acid, benzenesulfonic acid (besylate), benzoic acid, camphor sulfonic acid, citric acid, ether sulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic and the like. The hydrobromic, hydrochloric, maleic, phosphoric and sulfuric acids are particularly preferred. . The composns according to this invention can be prepared for oral, rectal or transdermal use, for example for use in a patch. Alternatively, the composns may be prepared for sublingual or parenteral administration (including subcutaneous, intramuscular, intrathecal, and intravenous administration). The most appropriate route of administration in any given case will depend on the nature and severity of the condn being treated. According to a preferred aspect of this invention, the route of administration is oral. According to another preferred aspect of this invention, the route of administration is rectal, intramuscular, intranasal or intravenous. According to another preferred aspect of the invention, the route of administration is intraperitoneal or subcutaneous The composition can be presented in a unit dosage form and prepared by any of the elements known in the pharmacy art. In practical use, the S-tofisopam or the prodrug or salt thereof, practically free of R-tofisopam, can be combined as the active ingredient in a mixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration, for example, oral or parenteral administration (including infusions or intravenous injections). For example, carriers according to this invention include: starches, sugars, microcrystalline cellulose, stabilizers, diluents, granulating agents, lubricants, binders, and fillers and disintegrants. The compositions for oral dosage form can include any of the usual pharmaceutical media, for example: water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, for example suspensions, elixirs and solutions, or aerosols. The compositions of the present invention can also be formulated to provide a slow release and controlled by the active ingredient therein, for example hydropropylmethyl cellulose in various proportions to provide the desired release profile, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes and / or microspheres. In general, a controlled release preparation is a composition capable of releasing the active ingredient at the rate required to maintain a constant pharmacological activity for a desirable period of time. These dosage forms can provide for the delivery of a drug to the body for a predetermined period of time and thus maintain drug levels in the therapeutic range for longer periods of time than other uncontrolled formulations. For example, U.S. Patent No. 5,674,533 discloses controlled release compositions in liquid dosage forms for the administration of moguistein, a potent peripheral antitussive. U.S. Patent No. 5,059,595 describes the controlled release of active agents through the use of a gastro-resistant tablet for the therapy of organic mental disorders. U.S. Patent No. 5,591,767 describes a transdermal depot patch fluid for the controlled administration of ketorolac, a non-steroidal anti-inflammatory agent with potent analgesic properties. U.S. Patent No. 5,120,548 discloses a device for the administration of a controlled release drug comprising swellable polymers. U.S. Patent No. 5,073,543 discloses controlled release formulations containing a trophic factor trapped by a ganglioside liposome vehicle. U.S. Patent No. 5,639,476 discloses a solid, stable, controlled release formulation having a coating derived from an aqueous dispersion of a hydrophobic acrylic polymer. These patents are incorporated herein by reference. Biodegradable microparticles can be used in the controlled release formulations of this invention. For example, U.S. Patent No. 5,354,566 discloses a controlled release powder containing the active ingredient. U.S. Patent No. 5,733,566 describes the use of polymeric microparticles that release antiparasitic compositions. These patents are incorporated herein by reference. The controlled release of the active ingredient can be stimulated by means of various inducers, P150 example pH, temperature, enzymes, water or other compounds or physiological conditions. There are several mechanisms of drug release. For example, in one embodiment, the controlled release component can swell and form porous openings large enough to release the active ingredient after administration to a patient. The term "controlled release component" in the context of the present invention is defined herein as a compound or compounds, for example polymers, polymer matrices, gels, permeable membranes, liposomes and / or microspheres that facilitate the controlled release of the active ingredient. (for example, S-tofisopam or salt thereof) in the pharmaceutical composition. In another embodiment, the controlled release component is biodegradable, induced by exposure to the aqueous environment, pH, temperature or enzymes in the body. In another embodiment, sol-gels may be used, wherein the active ingredient is incorporated into a sol-gel matrix which is a solid at room temperature. This matrix is implanted in a patient, preferably a mammal, with a temperature high enough to induce gel formation of the sol-gel matrix, thus releasing the active ingredient within the patient. Pharmaceutical stabilizers can also be used to stabilize compositions containing P1504 S-tofisopam or prodrug or salts thereof; acceptable stabilizers include unrestricted L-cysteine hydrochloride, glycine hydrochloride, malic acid, sodium metabisulfite, citric acid, tartaric acid and L-cysteine dihydrochloride. Dosage forms according to the invention include tablets, coated tablets, tablets, capsules (for example, hard gelatin capsules), troches, dragees, dispersions, suspensions, solutions, patches, pills, coated pills and the like, among the that sustained release formulations well known in the art • are included. Refer, for example, to Introduction to Pharmaceutical Dosage Forms, 1985, Ansel H.C., Lea and Febiger, Philadelphia, PA; Remington's Pharmaceutical Sciences, 1995, Mack Publ. Co., Easton, PA. For example, the compositions of the present invention, suitable for oral administration, may be presented as discontinuous units, such as soft gelatin capsules, wafers, tablets, pills or aerosol sprays each containing a predetermined amount of active ingredient. Alternatively, the compositions of the present invention may be in the form of a powder or granules or as a solution or suspension in an aqueous liquid, a non-aqueous liquid, an oil in water emulsion or a P150 liquid emulsion of water in oil. These compositions can be prepared by any of the pharmaceutical methods but all methods include the step of bringing the active ingredient into association with the carrier. A preferred solid oral preparation is tablets. An oral, solid, most preferred preparation is coated tablets. If desired, the tablets can be coated by standard aqueous or non-aqueous techniques. In general, the compositions can be prepared by uniformly and intimately admixing the active ingredient or prodrug with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient, in a free-flowing form, for example a powder or granules, optionally mixed with one or more of a binder, filler, stabilizer, lubricant, inert diluent and / or surface active or dispersion. The molded tablets can be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. In one modality, each tablet contains between P150 approximately 10 mg and 100 mg of the active ingredient or prodrug and each wafer or capsule contains approximately between 10 mg and 300 mg of the active ingredient or prodrug. In another embodiment, the tablet, wafer or capsule contains one of four dosages: between about 10 mg and 50 mg, between about 100 mg and 150 mg of the active ingredient or prodrug. In the case where the composition comprises an anticonvulsant other than S-tofisopam, the salt or prodrug thereof, the other anticonvulsant may be present in an amount less than, greater than or equal to the amount of S-tofisopam, salt or prodrug thereof. same, as physically permitted by pharmaceutical techniques. In a preferred embodiment, the subject to be treated in accordance with the methods of the invention is a mammal. In another preferred embodiment, the subject to be treated according to the methods of this invention is a human. Seizures, according to this invention, are involuntary muscle contractions caused by abnormal neuronal activity that results in the contortion of the body and / or limbs. The attacks, according to this invention, are transient changes in behavior, induced by the rhythmic, synchronous and disordered activations of the neurons. The P150 Unpredictable occurrences of seizures are commonly associated with epilepsy. The two main types of epileptic seizures are partial seizures and generalized seizures. The partial attacks, as mentioned here, are characterized as those that affect neurons limited to a part of a cerebral hemisphere. Partial attacks may or may not be accompanied by deterioration of consciousness. Generalized attacks, as mentioned here, include those in which both hemispheres are involved and consciousness, usually deteriorates. The generalized attacks include absence attacks, myoclonic attacks, clonic attacks, tonic attacks, tonic-clonic attacks and atonic attacks (Dreifuss et al., Classification of Epileptic Seizures and the Epilepsies and Drugs of Choice for Their Treatment, p.1-9 , in: Antiepileptic Drugs: Pharmacology and Therapeutics, Eds. MJ Eadie and FJE Vajda; ilder et al., Classification of Epileptic Seuzures, pp. 1-13, In: Seuzure Disorders, A Pharmacological Approach to Treatment, Raven Press, New York (1981)). Pseudoepileptic or non-epileptic seizures can be caused by a definable medical cause, for example, cardiovascular disease, which includes arrhythmias, aortic stenosis and orthostatic hypotension; Toxic or metabolic alterations, including P150 hypoglycaemia and drug toxicity, or sleep disturbances. Non-epileptic seizures can also be induced by psychiatric conditions, for example, hysteria or schizophrenia. Seizures or attacks can be the result of specific disorders or conditions, for example: epilepsy, acquired immunodeficiency syndrome (AIDS), Parkinson's disease, Alzheimer's disease, other neurodegenerative diseases, including: Huntington's chorea, schizophrenia, obsessive-compulsive disorders, tinnitus, neuralgia, trigeminal neuralgia, amyotrophic lateral sclerosis (ALS), tics (for example, Gille de la Tourette syndrome), post-traumatic epilepsy, alcohol use, alcohol withdrawal, intoxication or withdrawal of barbiturates, brain injury or illness, brain tumor, asphyxia, drug abuse, electric shock, fever (especially in young children), head trauma, heart disease, heat stroke, high blood pressure, meningitis, poisoning, stroke, toxemia of pregnancy, uremia related to kidney failure, poisonous bites and stings, withdrawal of benzodiazepines, convulsions febrile and afebrile infantile convulsions. The magnitude of a therapeutic or prophylactic dose of the active ingredient (for example from S- P150 tofisopam or salt thereof) or the prodrug of S-tofisopam and, if desired, another anticonvulsant to treat or prevent seizures or attacks, will vary with the severity of the patient's distress and the route of administration. The dose and frequency of the dose will also vary according to the age, weight and response of the individual patient. In general, the recommended daily dose range for the conditions described herein may fall within the range of between about 10 mg and 1200 mg per day, generally divided equally in doses administered one to four times a day. A daily dose can vary between 50 mg and 600 mg per day, usually divided equally, in a dosage of one to four times a day. Alternatively, a daily dose range may be between 100 mg and 400 mg per day, usually divided equally, in a dosage of two to four times a day. It may be necessary to use dosages outside these ranges in some cases and adjust the amounts of S-tofisopam, the salt or prodrug thereof, administered alone or in combination with other anticonvulsants. The treating physician will know how to increase, decrease or interrupt the treatment based on the patient's response. The various terms described above, such as for example "therapeutically effective amount", are encompassed by the P150 scheme of dose frequency and dosage amounts described in the above. To be used in the treatment or prevention of seizures or seizures, the physician will generally prescribe the period of treatment and dose frequency of S-tofisopam, practically free of R-tofisopam, on a patient-by-patient basis. In general, the treatment or prevention of seizures or attacks with S-tofisopam, prodrug or salt thereof virtually free of R-tofisopan, however, can be carried out for as long a period as necessary, either in a single session uninterrupted or in discontinuous sessions. For example, therapy can be carried out for a period of 4 to 18 weeks. According to the methods of this invention, the S-tofisopam, the salt or prodrug thereof may be administered alone or in combination with one or more other anticonvulsants to treat or prevent seizures or seizures, including shaking (ie, clonic activity). The other anticonvulsant may be selected from the group consisting, unrestricted, of: phenytoin, mephenytoin, ethotoin, phenobarbital, mephobarbital, primidone, carbamazepine, ethosuximide, methsuximide, phensuximide, valproic acid, trimethadione, parametadione, phenazemide, acetazolamide, progabide, P150 diazepam, lorazepam, clonazepam, clorazepate and nitrazepam. The other anticonvulsant may be included in the composition comprising S-tofisopam, the salt or prodrug thereof. Alternatively, the other anticonvulsant may be administered concurrently with the composition comprising S-tofisopam, the salt or prodrug thereof or, at any time during the treatment of the subject, with the composition. In accordance with one aspect of the invention, S-tofisopam is administered together with at least one other benzodiazepine to treat or prevent seizures or attacks. In another aspect of the invention, S-tofisopam is administered together with at least one other 1,4-benzodiazepine. In yet another aspect of the invention, S-tofisopam is administered together with diazepam, lorazepam, clonazepam, clorazepate or nitrazepam to treat or prevent seizures or seizures. Any suitable route of administration can be used to provide the subject of this invention, an effective dosage of S-tofisopam practically free of R-tofisopam. For example, oral, rectal, parenteral, transdermal, subcutaneous, sublingual, intranasal, intramuscular, intraperitoneal, intrathecal, and the like may be employed, as appropriate. Throughout this specification, it will be understood that the word "comprise" or its variations, P150 as "comprises" or "comprising" implies the inclusion of a declared integer or a group of integers, but not the exclusion of any other integer or group of integers. U.S. Provisional Application No. 60 / 292,026 filed May 8, 2001, is hereby incorporated herein by reference in its entirety. The present invention is illustrated with the following examples. However, it should be noted that these examples are for illustrative purposes only and will not be construed as limiting the invention in any way.

EXAMPLE 1 Resolution of S-tofisopam The enantiomers of tofisopam were resolved by chiral chromatography. For example, tofisopam (42.8 mg dissolved in acetonitrile) was loaded onto a Chirobiotic V column (ASTEC, hippany, New Jersey). Elution of the compounds with MTBE / ACN 90/10 (volume / volume), 40 ml / min, was monitored at 310 nm, trajectory of 2 mm. The R (+) enantiomer was the first compound to elute from the column. The tofisopam R (-) ("A"), tofisopam S (- / +) ("B" and "B") and residual tofisopam R (+) ("A") was coeluted and collected in a subsequent fraction .

P1504 The S (-) enantiomer was isolated from fraction 2 by the following protocol. Fraction 2 was dried, redissolved in 1 ml of acetonitrile and loaded onto a chirobiotic V-column. Peak B and B 'was recycled by passing over a column V chirobiotic twice more (MTBE / ACN 90/10 (v / v), 40 ml / min monitored at 310 nm, trajectory of 2 mm). A peak containing tofisopam S (-) was collected from the third recycle, dried and stored for use in biological examinations. The final preparations of tofisopam R and S were examined with respect to the enantiomeric purity by two distinct groups. One group reported that the final preparation of R-tofisopam was 98% pure (ie, with an enantiomeric excess of 96%) and that that of S-tofisopam was 95% pure (ie, with an enantiomeric excess of 90%) . The second group reported that R-tofisopam was more than 97.5% pure (ie, with an enantiomeric excess of> 95%) and that S-tofisopam was 87% pure (ie, with an enantiomeric excess of 74%). ), as determined by analytical chromatography. Analytical evaluations of the starting material and the final preparations of tofisopam R and S, as carried out by the second group, were carried out using Chiral Tech OD GH 060 (Daicel) columns (hexane / lPA 90/10, 25 ° C, detection at 310 nm). We believe that the results of the analysis of the purity of P150 tofisopam R and S obtained by the second group were correct. The second group was also the group that tested the enantiomeric purity of the tofisopam R and S obtained as described in Example 3 below.

EXAMPLE 2 Evaluation of tofisopam and its enantiomers as anticonvulsants. Picrotoxin was used as the convulsive agent and diazepam, an established anticonvulsant, was used as a control. Anticonvulsant activity against picrotoxin-induced attacks was considered evidence of clinical antiepileptic potential and the reason for further evaluation of an anticonvulsant profile of the test compound (Swinyard, EA et al., General principles: experimental detection, quantification and evaluation of anticonvulsants. In: Antiepileptic Drugs, DM Woodbury et al., Eds Raven Press, New York (1990) pp. 111-126). Male NSA mice weighing approximately -25 g were injected intraperitoneally (ip) with several doses (8-10 animals / dose) of diazepam, tofisopam, R-tofisopam of Example 1 or S-tofisopam of Example 1, 15 minutes before the injection of picrotoxin . Picrotoxin (5 mg / kg, Sigma Chem. Co., St. Louis, Missouri, P150 E.U.A.) was dissolved in saline and administered subcutaneously to induce seizures. In addition, picrotoxin alone was administered to seven animals as a control. All test drugs were dissolved in dimethylsulfoxide (DMSO). Both S-tofisopam and R-tofisopam showed a yellow color when dissolved in DMSO. After the injection of picrotoxin, the mice were placed in a Plexiglas cage for 30 minutes for observation. The onset of seizures was defined as the presence of a single episode of clinical or tonic activity (including myoclonic jerks) during the 30-minute observation period. The vehicle DMSO for the drug had no effect on the attack activity at the concentration used. Euthanasia was immediately applied to the animals after the observation period by inhalation of C02. The ED50 values (the dose of test compound at which half of the animals were protected against picrotoxin-induced attacks) and their confidence limits of 95% were calculated by the Litchfield and Wilcoxon method (J. Pharmacol. Exp. Ther 96: 99-113 (1949)). The results of these experiments are summarized in Table 1 below. The effect of tofisopam on induced attacks P150 by picrotoxin in NSA mice is shown in Figure 1. The racemic tofisopam produced a dose-dependent inhibition (expressed as percent protection) of picrotoxin-induced attacks in mice when administered intraperitoneally. The ED50 value (95% confidence limits) was 37.8 (28.2-50.8) mg / kg. R-tofisopam did not inhibit seizures induced by picrotoxin at either 20 or 50 mg / kg. On the other hand, the (S) enantiomer exhibited anticonvulsant activity with approximately 60% protection at 40 mg / kg (see Figure 2). An estimate of ED50 (95% confidence limits) of S-tofisopam was 35 (28-43) mg / kg.

Table 1 Summary of ED50 anticonvulsant values for tested compounds These data indicate that both S-tofisopam and P150 the racemic have intrinsic anticonvulsant activity against picrotoxin-induced attacks in NSA mice. In contrast, the (R) enantiomer of tofisopam did not show anticonvulsant activity.

EXAMPLE 3 Preparation of enantiomers of tofisopam The diastereomeric salts of tofisopam were prepared using the following procedure: (1) 3.0 g of racemic tofisopam were first dissolved in 10 ml of chloroform, after which, 10 ml of distilled water were added to the racemate dissolved (solution A). (2) In a separate vessel, 1.5 g of D or L-dibenzoyl tartaric acid (DBTA) was dissolved in 20 ml of chloroform (molar ratio of 0.56 from "DBTA to tofisopam) (solution B). The mixture was stirred and heated to 45 ° C until the dissolution was complete. DB- (L) -TA was used (characterized by negative optical rotation) to purify R-tofisopam, while DB- (D) -TA (characterized by positive optical rotation) was used to purify S-tofisopam. (3) Solutions A and B were mixed and stirred until precipitation was complete. the mixture was then cooled to 5 ° C to improve the yield. The solids were filtered, washed three times with 4 ml of cold chloroform and dried.

P150 To dissociate the diastereomeric salts of tofisopam and recover the resolved tofisopam, the dried material was suspended (4) in 50 ml of 0.5M NaOH and then stirred for 2 hours with 10 ml of chloroform. (5) The aqueous phase was separated and discarded, and the chloroform layer was evaporated to dryness. (6) The solids were then triturated with 50 ml of 5% acetic acid until the gummy paste became granular. (7) The resulting solids were filtered and dried. (8) The pH of the filtrate was raised by at least 10 using solid sodium hydroxide granules and stirring for one hour. The solids were then filtered and dried. The production of S-tofisopam with an enantiomeric purity of 96% (that is, an enantiomeric excess of 92%) required four cycles of enrichment of the resolution procedure, in which the solids obtained at the end of the previous procedure were redissolved and they repeated steps 1-8. The final preparation of R-tofisopam and S-tofisopam was 95.6% pure (ie, with an enantiomeric excess of 91.2%) and 96% pure (ie, with an enantiomeric excess of 92%), respectively, as determined by analytical chromatography.

P150 EXAMPLE 4 Evaluation of tofisopam and its enantiomers as anticonvulsants The preparations of the enantiomers of tofisopam of Example 3, as well as of racemic diazepam and tofisopam were tested using the picrotoxin-induced seizure test, as described in Example 2. The results of these experiments are summarized in Table 2 below. The racemic tofisopam produced a dose-dependent inhibition of picrotoxin-induced attacks in mice with an ED50 value (95% confidence limits) of 51.4 (26.8-98.5) mg / kg (see Figure 3). Diazepam also produced a dose-dependent anticonvulsant activity with an ED50 value (95% confidence limits) of 0.45 (0.27-0.77) mg / kg (see Figure 4). The effect of R-tofisopam on picrotoxin-induced attacks in mice is shown in Figure 5. Although R-tofisopam exhibits anticonvulsant activity at doses of 32 mg / kg and 64 mg / kg, no additional increase in protection was observed at 90 mg / kg. In addition, at a dose of 128 mg / kg of R-tofisopam, no protection against picrotoxin-induced attacks was observed. The ED50 value could not be calculated because none of the doses produced at P150 less 50% protection against attacks induced by picrotoxin and also due to the inverted U shape of the dose response curve (Figure 5). S-tofisopam showed dose-dependent anticonvulsant activity with an ED50 value (95% confidence limits) of 15.1 (7.6-30.1) mg / kg (see Figure 6).

Table 2 Summary of ED5Q anticonvulsant values for tested compounds These data indicate that both the thofisopan S and the racemic have intrinsic anticonvulsant activity, therefore, they support the conclusions of the study described in Example 2. In addition, these results demonstrated that highly pure S-tofisopam exhibits anticonvulsant activity significantly greater than the composed of racemate.

P150

Claims (27)

1. CLAIMS! A composition comprising a therapeutically effective amount of S-tofisopam, a prodrug or a pharmaceutically acceptable salt thereof, substantially free of its (R) -enantiomer, with a pharmaceutically acceptable carrier.
2. The composition according to claim 1, wherein the amount of S-tofisopam or a prodrug or a pharmaceutically acceptable salt thereof is 85% or more by weight of the total weight of tofisopam.
3. 3. The composition according to claim 1, wherein the amount of S-tofisopam or a prodrug or a pharmaceutically acceptable salt thereof is 90% or more by weight of the total weight of tofisopam.
4. 4. The composition according to claim 1, wherein the amount of S-tofisopam or a prodrug or a pharmaceutically acceptable salt thereof is 95% or more by weight of the total weight of tofisopam.
5. The composition according to claim 1, wherein the amount of S-tofisopam or a prodrug or a pharmaceutically acceptable salt thereof is 99% or more by weight of the total weight of tofisopam.
6. 6. The composition according to claim 1, wherein the conformation of S-tofisopam is 80% (-) and 20% (+). P150
7. 7. The composition according to claim 1, further comprising another anticonvulsant.
8. 8. The composition according to claim 7, wherein the other anticonvulsant is a benzodiazepine.
9. The composition according to claim 7, wherein the other anticonvulsant is a 1,4-benzodiazepine.
10. The composition according to claim 7, wherein the other anticonvulsant is selected from the group consisting of diazepam, lorazepam, clonazepam, clorazepate and nitrazepam.
11. The composition according to claim 1, wherein the composition is a controlled release pharmaceutical composition.
12. 12. A method for treating seizures or seizures and comprising administering to a subject in need of treatment thereof a therapeutically effective amount of the composition of claim 1.
13. 13. A method for preventing seizures or seizures in a subject that is at risk of developing seizures or attacks and comprising administering to the subject a therapeutically effective amount of the composition of claim 1.
14. 14. The method according to claim 12 or 13, wherein the subject is a human.
15. 15. The method according to claim 12 or 13, P150 wherein the amount of S-tofisopam or a prodrug or a pharmaceutically acceptable salt thereof is 90% or more by weight of the total weight of tofisopam.
16. The method according to claim 12 or 13, wherein the amount of S-tofisopam or a prodrug or a pharmaceutically acceptable salt thereof is 95% or more by weight of the total weight of tofisopam.
17. The method according to claim 12 or 13, wherein the amount of S-tofisopam or a prodrug or a pharmaceutically acceptable salt thereof is 99% or more by weight of the total weight of tofisopam.
18. 18. The method according to claim 12 or 13, wherein the composition of claim 1 is administered together or sequentially with another anticonvulsant.
19. 19. The method according to claim 18, wherein the other anticonvulsant is a benzodiazepine.
20. The method according to claim 18, wherein the other anticonvulsant is a 1,4-benzodiazepine.
21. The method according to claim 18, wherein the other anticonvulsant is selected from the group consisting of diazepam, lorazepam, clonazepam, clorazepate and nitrazepam.
22. 22. The method according to claim 12 or 13, wherein the composition is administered via P1504 intraperitoneal, subcutaneous, intranasal, intramuscular, intrathecal, sublingual, rectal, by intravenous infusion, transdermally or orally as a tablet, a capsule or a liquid suspension.
23. 23. The method according to claim 12 or 13, wherein the administered amount of S-tofisopam, prodrug or a pharmaceutically acceptable salt thereof is about 10 mg to 1200 mg.
24. 24. The method according to claim 23, wherein the administered amount of S-tofisopam, prodrug or a pharmaceutically acceptable salt thereof is about 50 mg to 600 mg.
25. 25. The method according to claim 23, wherein the administered amount of S-tofisopam, prodrug or a pharmaceutically acceptable salt thereof is about 100 mg to 400 mg.
26. 26. The method according to claim 12 or 13, wherein the amount is administered in 1 to 4 doses per day.
27. 27. The method according to claim 26, wherein the amount is administered in 1 to 2 doses per day. P1504