Synergistic compositions comprising (r)-2-(2-oxopyrrolidin-1-yl)butanamide and (s)-2-(2-oxopyrrolidin-1-yl)butanamide in non-racemic ratio

Abstract

To provide a composition of the enantiomers of 2-(2-oxopyrrolidin-1- yl)butanamide and pharmaceutically acceptable solvates or co-crystals thereof in a certain ratio, a pharmaceutical composition comprising the composition, and its use as a medicament.SOLUTION: The present invention relates to a composition of the enantiomers of 2-(2-oxopyrrolidin-1- yl)butanamide and pharmaceutically acceptable solvates or co-crystals thereof in a certain ratio, a pharmaceutical composition comprising the composition, its use as a medicament and the use of the inventive compositions or pharmaceutical compositions in the treatment and / or prevention of a disease or a disorder typically and preferably selected from seizure-related disorders, peripheral sensory neuropathy, preferably peripheral neuropathic pain; seizure; depression; or cognitive impairment.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to compositions and kits comprising a range of ratios of (R)-2-(2-oxopyrrolidin-1-yl)butanamide and (S)-2-(2-oxopyrrolidin-1-yl)butanamide and pharma- ceutically acceptable solvates or co-crystals thereof, pharmaceutical compositions comprising said compositions, their use as medicaments, and the use of the composition or pharmaceutical composition or kit of the invention for the treatment and / or prevention of a central nervous system disease or disorder typically and preferably selected from seizure-related disorders, preferably wherein the disease is epilepsy. [Background technology]

[0002] Glutamate is an excitatory neurotransmitter ubiquitously present in the brain. Its role as an excitatory messenger was first indicated in the 1950s, when intravenous administration of glutamate was recognized to induce seizures. However, the detection of the entire glutamatergic neurotransmitter system, including its biosynthetic and degradative enzymes, cellular uptake mechanisms, intracellular storage and release systems, and its cell surface ion channels and G protein-coupled receptors, was not achieved until the 1970s, and it was not until the 1980s that suitable pharmacological tools were first identified. It was not until the 1990s that emerging molecular biology tools provided the means for the molecular identification and classification of glutamatergic ion channels, receptors, transporters, etc. Membrane-bound ion channels gated by the excitatory amino acids glutamate and glycine, and also responsive to the xenobiotic compound N-methyl-D-aspartate (NMDA), control the influx of both divalent and monovalent cations into presynaptic and postsynaptic neural cells (see Foster et al., Nature 1987, 329:395-396; Mayer et al., Trends in Pharmacol. Sci. 1990, 11:254-260). They are molecularly, electrophysiologically, and pharmacologically distinct from glutamate-gated cation-conducting ion channels that respond to the xenobiotic substances kainate or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), as well as distinct from a family of glutamate-gated G protein-coupled receptors, the so-called metabotropic glutamate receptors.

[0003] NMDA-preferring glutamate-gated ion channels have a heterotetrameric structure base of two essential GluN1 units and two variable GluN2 receptor subunits, each encoded by the GRIN1 gene and one of four GRIN2 genes. One or both GluN2 subunits can potentially be replaced by GluN3A or GluN3B subunits. The GRIN1 gene product has eight splice variants, while there are four different GRIN2 genes (GRIN2A-D) that code for four different GluN2 subunits. The glycine-binding site is present on the GluN1 subunit, and the glutamate-binding site is present on the GluN2 subunit (Paoletti P et al., Nat Rev Neurosci. 2013; 14(6):383-400). Compounds that modulate NMDA receptor function have been shown to be effective in treating bipolar disorder (Martucci L et al., Schizophrenia Res, 2006; 84(2-3):214-21), major depressive disorder (Li N et al., Biol Psychiatry. 2011; 69(8):754-61), treatment-resistant depression (Preskorn SH et al. J Clin Psychopharmacol. 2008; 28(6):631-7) and other mood disorders, including schizophrenia (Grimwood S et al., Neuroreport. 1999; 10(3):461-5), pre- and post-partum depression (Weickert CS et al. Molecular Psychiatry (2013) 18, 1185-1192), seasonal affective disorder, and others; Alzheimer's disease (Hanson JE et al., Neurobiol Dis. 2015; 74:254-62; Li S et al., J Neurosci. 2011; 31(18):6627-38) and other dementias (Orgogozo JM et al. Stroke 2002, 33: 1834-1839), Parkinson's disease (Duty S, CNS Drugs. 2012; 26(12):1017-32; Steece-Collier K et al., Exp Neurol. 2000; 163(1):239-43; Leaver KR et al. Clin Exp Pharmacol Physiol. 2008; 35(11):1388-94), Huntington's disease (Tang TS et al., Proc Natl Acad Sci USA. 2005; 102(7):2602-7; Li L et al., J Neurophysiol. 2004; 92(5):2738-46), multiple sclerosis (Grasselli G et al., Br J Pharmacol. 2013; 168(2):502-17), and cognitive impairment (Wang D et al. 2014, Expert Opin Ther Targets 2014; 18(10):1121-30), head trauma (Bullock MR et al., Ann NY Acad Sci. 1999; 890:51-8), spinal cord injury, stroke (Yang Y et al., J Neurosurg. 2003; 98(2):397-403), epilepsy (Naspolini AP et al., Epilepsy Res. 2012 Jun; 100(1-2):12-9), movement disorders (e.g., dyskinesia) (Morissette M et al., Mov Disord. 2006; 21(1):9-17), various neurodegenerative diseases (e.g., amyotrophic lateral sclerosis (Fuller PI et al., Neurosci Lett. 2006; 399(1-2):157-61) or associated with bacterial or chronic infection, glaucoma (Naskar R et al. Semin Ophthalmol. 1999 Sep; 14(3):152-8), pain (e.g., chronic, cancer, postoperative and neuropathic pain (Wu LJ and Zhuo M, Neurotherapeutics. 2009; 6(4):693-702), diabetic neuropathy, migraine (Peeters M et al., J Pharmacol Exp Ther. 2007; 321(2):564-72), cerebral ischemia (Yuan H et al., Neuron. 2015; 85(6):1305-18), encephalitis (Dalmau J. et al., Lancet Neurol. 2008; 7(12):1091-8), autism and autism spectrum disorders (Won H. et al., Nature. 2012; 486(7402):261-5), memory and learning disorders (Tang, YP et al., Neurotherapeutics. 2012; 10(1):109-11), and neuropathic pain (Wu LJ and Zhuo M, Neurotherapeutics. 2009; 10(1):109-11). al., Nature. 1999; 401(6748):63-9), obsessive-compulsive disorder (Arnold PD et al., Psychiatry Res. 2009; 172(2):136-9), attention-deficit hyperactivity disorder (ADHD) (Dorval KM et al., Genes Brain Behav. 2007; 6(5):444-52), Post-Traumatic Stress Disorder (PTSD) (Haller J et al. Behav Pharmacol.2011; 22(2):113-21; Leaderbrand K et al. Neurobiol Learn Mem. 2014; 113:35-40), tinnitus (Guitton MJ, and Dudai Y, Neural Plast.2007; 80904; Hu SS et al. 2016; 273(2): 325-332), sleep disorders (sleep disorders such as narcolepsy or excessive daytime sleepiness, WO 2009 / 058261), dizziness and nystagmus (Straube A. et al., Curr Opin Neurol. 2005; 18(1):11-4; Starck M et al. J Neurol. 1997 Jan; 244(1):9-16), anxiety, neuropsychiatric autoimmune disorders such as systemic lupus erythematosus (Kowal C et al. Proc. Natl. Acad. Sci. USA 2006; 103, 19854-19859), and addiction disorders (e.g., alcoholism, drug addiction) (Nagy J, 2004, Curr Drug Targets CNS Neurol Disord. 2004; 3(3):169-79.; Shen H et al., Proc Natl Acad Sci USA. 2011; 108(48):19407-12).

[0004] Recent human clinical studies have identified NMDA-type glutamate-gated ion channels as novel targets of great interest for the treatment of depression (Singh JB et al., Biol Psychiatry 2016; 80(6):424-431; Preskorn SH et al. J Clin Psychopharmacol 2008; 28(6):631-7). These studies were performed using the known NMDA receptor antagonists ketamine and CP-101606 and showed a significant reduction in depression assessment scores in patients with treatment-refractory depression. Although the efficacy was remarkable, the side effects of using these NDMA receptor antagonists were troublesome.

[0005] NMDA-modulating small molecule agonist and antagonist compounds have been developed for potential therapeutic use. However, many of them have very narrow therapeutic index and undesirable side effects, including hallucinations, ataxia, irrational behavior, and significant toxicity, all of which limit their effectiveness and / or safety. Moreover, more than 50% of depressed patients do not experience a satisfactory therapeutic response to known administered drugs. In most cases, more than 2 weeks of drug therapy are required before meaningful improvement is observed, as is evident in open-label studies of pharmacological treatment of depression (Rush et al, Am. J. Psychiatry 2006, 163:1905). A seizure is a single occurrence of uncontrolled electrical activity in the brain, usually for a short period of time. It can cause a number of signs and symptoms, such as convulsions, impaired thinking, loss of consciousness, and / or other symptoms. Usually, seizures are considered a symptom of a disease. Epilepsy, for example, is a chronic disease of recurrent unprovoked seizures and is a type of seizure disorder. In epilepsy, a convulsion is a sudden, violent, and irregular movement of the limbs, usually caused by involuntary muscle contractions associated with epilepsy and / or poisoning.

[0006] A seizure disorder is a medical condition characterized by episodes of uncontrolled electrical activity in the brain, thus resulting in symptoms including two or more types of seizures. Seizure-related disorders are distinguished from one another by their underlying causes and their own set of symptoms due to the affected area in the brain. Generalized seizures result in loss of consciousness. When motor symptoms are involved, for example, grand mal seizures (also called tonic-clonic grand mal seizures with muscle spasms or convulsions), signs and symptoms are evident from muscle stiffening (tonic), relaxing muscles (atonic), muscles causing brief sporadic jerks of the body or limbs (myoclonic), and repetitive shaking or spasms of the body (clonic). When non-motor or absence-like symptoms are involved in generalized seizures, the symptoms can include spatial fixation with occasional eye blinking, and lack of awareness of objects or things going on around the patient. Partial or focal seizures do not cause loss of consciousness or confusion for several minutes. The patient is aware of twitching or altered sensations. The patient may be dismayed for several minutes.

[0007] Seizures of unknown onset involve unclassified symptoms and may share suspicious features of generalized or focal seizures. For example, simple partial seizure disorders vary from person to person depending on the area of ​​the brain affected. Childhood benign rolandic epilepsy causes tongue twitching, which can interfere with speech and cause drooling. Catamenial epilepsy refers to seizures that occur in relation to the menstrual cycle. Atonic seizures cause symptoms such as falling that are not usually associated with loss of consciousness. Absence seizures cause a brief loss of consciousness with few or no symptoms. Clonic seizures cause rhythmic spasms that affect both sides of the body at the same time. Tonic seizures cause muscle stiffening. Febrile seizures usually occur in children between the ages of 6 months and 5 years. Other symptoms of seizure disorders can include convulsions, eye blinking, sudden loss of muscle tone, sudden head bending or screaming, unexpected falls to the ground, changes in taste or smell, tongue biting, or eye rolling. These examples illustrate the complexity of seizure disorders and their symptoms. Although pharmacotherapy is effective for the majority of patients with seizure-related symptoms, significant unmet medical needs and treatment challenges remain. These include drug-resistant epilepsy, adverse reactions, drug interactions, the need for better identification of epilepsy syndromes, and the lack of antiepileptic drugs that can prevent the development of epilepsy and its comorbidities. Many newer second-generation antiseizure drugs cause fewer drug interactions and are better tolerated than older agents, but they have not proven to be more effective or reduced the prevalence of drug-resistant epilepsy.

[0008] Thus, there remains an urgent and important medical need to develop new orally effective therapeutic agents for the prevention and treatment of seizure-related disorders. The S-enantiomer of 2-(2-oxopyrrolidin-1-yl)butanamide (S-etiracetam, or levetiracetam, or L059) has been marketed as Keppra® for the treatment of partial onset, myoclonic, or tonic-clonic seizures, and epilepsy. The pharmacology of racemic etiracetam has also been reported, for example, by Sara et al. Psychopharmacology (Berl). 1980;68(3):235-41 and Van Aken et al. in Acta Anaesthesiol Belg. 1980;31 Suppl:21-8. The R-enantiomer of etiracetam appears to be less potent than the S-enantiomer (Gower et al., Eur J Pharmacol. 1992 Nov 10;222(2-3):193-203); Verloes R, et al., Effects of nootropic drugs in a scopolamine-induced amnesia model in mice. Psychopharmacology (Berl). 1988;95(2):226-30). The in vitro and in vivo potencies of the individual enantiomers were compared within a single publication, and the in vivo potency of racemic etiracetam was described separately. The S-enantiomer of etiracetam appears to be more potent than the R-enantiomer or racemate. Available data seem to suggest that the vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam (Lynch et al., Proc Natl Acad Sci US A. 2004 Jun 29;101(26):9861-6) and that AMPA-type glutamate-gated ion channels may play a role in the mechanism of action of leviracetam (Carunchio et al., Epilepsia. 2007 Apr;48(4):654-62).

[0009] In European Patent No. 0165919, the R-enantiomer of 2-(2-oxopyrrolidin-1-yl)butanamide (R-etiracetam, or L060) was claimed to be 10 times more potent than racemic etiracetam upon subcutaneous injection in the electric shock-induced amnesia model in rats. Dimiracetam is a (RS)-3,6,7,7a-tetrahydro-1H-pyrrolo[1,2-a]imidazole-2,5-dione, which is a negative allosteric modulator of spinal NMDA-type glutamate receptors in rat spinal synaptosome preparations (Fariello RG, et al. Neuropharmacology. 2014, 81:85-94) and is orally active in rat models of neuropathic pain, depression, and cognitive impairment (Pinza M, et al. J Med Chem 1993, 36(26):4214-20). The inventors have surprisingly found that non-racemic mixtures of R and S-dimiracetam lead to activity superior to that of the single enantiomers and racemate. This finding is the basis of co-pending international application PCT / EP2018 / 064125, which is incorporated herein by reference in its entirety. Summary of the Invention

[0010] It has now been surprisingly and unexpectedly found that compositions of the (R)- and (S)-enantiomers of 2-(2-oxopyrrolidin-1-yl)butanamide having an enantiomeric excess (ee) of the (S)-enantiomer of 20% or more and 67% or less can exhibit higher pharmacological potency than the corresponding individual enantiomers or than the racemate, particularly in several rat models of seizure-related disorders. Thus, these compositions of the (R)- and (S)-enantiomers of 2-(2-oxopyrrolidin-1-yl)butanamide provide synergistic effects that could not be predicted based on the potency of the individual enantiomers or the racemate. Thus, compositions of the invention having an enantiomeric excess of certain (S)-2-(2-oxopyrrolidin-1-yl)butanamides are much more efficient than the corresponding racemic mixtures in reducing the severity and frequency of seizures in an electrical stimulation-induced seizure kindling model, in reducing peripheral neuropathic pain in the paw-pressure test after administration of sodium monoiodoacetate, or in preventing oxaliplatin-induced peripheral neuropathic pain, or in improving cognitive function.

[0011] Thus, the compositions of the present invention of (S)-2-(2-oxopyrrolidin-1-yl)butanamide represented by formula (I) and (R)-2-(2-oxopyrrolidin-1-yl)butanamide represented by formula (II), having an enantiomeric excess (ee) of the (S)-enantiomer of 20% or more and 67% or less (preferably 50% or less), respectively, are pharmacologically more effective at a given dose than the pure enantiomers alone or the racemic mixture of these compounds. The term racemic refers to a 1:1 mixture by mass of (R)- and (S)-enantiomers, and thus the mixture has an enantiomeric excess (ee) of 0%. Thus, the effect associated with the present invention is a synergistic effect resulting from a specific range of ratios between (S)-2-(2-oxopyrrolidin-1-yl)butanamide and (R)-2-(2-oxopyrrolidin-1-yl)butanamide, which are surprisingly represented by formulas (I) and (II), respectively. The compositions of the present invention are beneficial and can be used in the treatment and / or prevention of seizure-related disorders.

[0012] In a first aspect, the present invention provides a compound of formula (I) (sometimes referred to herein as (S)-2-(2-oxopyrrolidin-1-yl)butanamide) and a compound of formula (II) (sometimes referred to herein as (R)-2-(2-oxopyrrolidin-1-yl)butanamide): [ka] and / or a pharma- ceutically acceptable solvate or cocrystal thereof, The present invention provides a composition, wherein the enantiomeric excess (ee) of the compound of formula (I) is 20% or more and 67% or less (preferably 50% or less). In another aspect, the present invention provides a pharmaceutical composition comprising a composition of the present invention and a pharma- ceutically acceptable carrier. In yet another embodiment, the present invention provides a kit of parts comprising a compound of formula (I) and a compound of formula (II) and instructions for combining the compound of formula (I) and the compound of formula (II) to obtain an enantiomeric excess (ee) of said compound of formula (I) of 20% or more and 67% or less (preferably 50% or less). In this embodiment, the same preferred ranges of the enantiomeric excess (ee) of said compound of formula (I) and the enantiomeric ratio of the compound of formula (I) to the compound of formula (II) apply as described herein for the composition.

[0013] In yet another aspect, the present invention provides a composition of the invention or a pharmaceutical composition of the invention or a kit of the invention for use as a medicament. In yet another aspect, the present invention provides the composition of the present invention or the pharmaceutical composition of the present invention or the kit of the present invention for the treatment and / or prevention of a seizure-related disorder. In yet another aspect, the present invention provides a method for the treatment and / or prevention of a seizure-related disorder. In yet another aspect, the present invention provides the use of a composition of the invention or a pharmaceutical composition of the invention or a kit of the invention in the manufacture of a medicament for the treatment and / or prevention of a seizure-related disorder. In yet another aspect, the invention provides an article of manufacture comprising a composition of the invention or a pharmaceutical composition of the invention, a container or package, and written instructions, such as a package insert, and directions for administration. Further aspects and embodiments of the present invention will become apparent as the specification proceeds. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The term "about" when used to characterize enantiomeric excess means ±4% with reference to a given numerical value, unless otherwise indicated. In each of the embodiments of the present invention, "about" can be omitted. The term "preferably" is used to describe features or embodiments that are not required by the present invention, but which may result in an improved technical effect, and are therefore desirable, but not essential. Some compounds are described herein by reference to their structural formula and / or their chemical name, such as IUPAC name. In the event of a discrepancy between the structural formula and the chemical name, the present invention expressly relates to the compound referred to by both the structural formula and the chemical name. For numerical values ​​described herein, unless otherwise specified, the last decimal place of the numerical value preferably indicates its precision. Thus, unless other tolerances are given, the maximum allowable range is preferably ascertained by applying rounding rules to the last decimal place. Thus, a value of 2.5 preferably includes the range 2.45 to 2.54.

[0015] The term "treatment" of a disorder or disease as used herein is well known in the art. "Treatment" of a disorder or disease means that the disorder or disease is suspected or diagnosed in a patient / subject. A patient / subject suspected of suffering from a disorder or disease typically exhibits certain clinical and / or pathological symptoms that a person skilled in the art can easily attribute to a particular pathological condition (i.e., diagnose the disorder or disease). "Treatment" of a disorder or disease can, for example, lead to the cessation of the progression of the disorder or disease (e.g., no worsening of symptoms) or the slowing of the progression of the disorder or disease (if the cessation of progression is only transient). "Treatment" of a disorder or disease can also lead to a partial response (e.g., improvement of symptoms) or a complete response (e.g., disappearance of symptoms) of the subject / patient suffering from the disorder or disease. Thus, "treatment" of a disorder or disease can also refer to the improvement of the disorder or disease, for example, lead to the cessation of the progression of the disorder or disease or the slowing of the progression of the disorder or disease. Such a partial or complete response may be followed by a relapse. It should be understood that subjects / patients may respond to a wide range of treatments (such as the exemplary responses described above). Treatment of a disorder or disease includes, inter alia, curative treatment (preferably leading to a complete response, and even a cure, of the disorder or disease) and symptomatic treatment (including symptomatic relief).

[0016] The term "prevention" of a disorder or disease as used herein is also well known in the art. For example, a patient / subject suspected of being susceptible to a disorder or disease may benefit from the prevention of the disorder or disease in particular. The subject / patient may undergo a given medical treatment known to carry a risk of developing an undesirable effect, such as the development of peripheral neuropathy symptoms associated with cancer chemotherapy. The subject / patient may have susceptibility or predisposition or risk factors for the disorder or disease, including but not limited to a genetic predisposition. Such predisposition may be determined by standard methods or assays, for example using genetic markers or phenotypic indicators. It should be understood that the patient / subject has not been or cannot be diagnosed with a disorder or disease that can be prevented according to the present invention (e.g., the patient / subject does not exhibit any clinical or pathological symptoms). Thus, the term "prevention" includes the use of the aqueous pharmaceutical composition of the present invention before any clinical and / or pathological symptoms are diagnosed or determined or can be diagnosed or determined by the attending physician.

[0017] The present invention relates to a composition comprising (S)-2-(2-oxopyrrolidin-1-yl)butanamide of formula (I) and (R)-2-(2-oxopyrrolidin-1-yl)butanamide of formula (II) in a certain ratio. It should be understood that the term "composition" does not require that the pure compound of formula (I) and the pure compound of formula (II) must be mixed. They can be formulated together or separately and administered simultaneously or subsequently, provided that the ratio of the compound of formula (I) and the compound of formula (II) obtained in the treated subject is as required by the present invention. Preferably, the composition of the invention is a mixture of a compound of formula (I) and a compound of formula (II), however, the composition of the invention can also include a combination of one or more articles comprising a compound of formula (I) and one or more articles comprising a compound of formula (II), or a combination of one or more articles comprising a compound of formula (I) and a mixture of a compound of formula (I) and a compound of formula (II), e.g., about a 1:1 mixture of a compound of formula (I) and a compound of formula (II).

[0018] Furthermore, the 2-(2-oxopyrrolidin-1-yl)butanamide contained in the composition of the present invention must be present in the entire range of the ratio of the compound of formula (I) to the compound of formula (II) required in the present invention, or the entire range expressed as the enantiomeric excess of the compound of formula (I). In other words, it is contrary to the spirit of the present invention to theoretically divide a composition containing equal amounts of the compound of formula (I) and the compound of formula (II) into a component containing an excess amount of the compound of formula (I) and another component containing an excess amount of the compound of formula (II). Therefore, regardless of the physical form of the composition of the present invention, the composition as a whole must satisfy the requirements regarding the range of the ratio of the compound of formula (I) to the compound of formula (II) required in the present invention, or the range expressed as the enantiomeric excess of the compound of formula (I). It should be understood that the ratio of the compound of formula (I) to the compound of formula (II), alternatively expressed as the enantiomeric excess of the compound of formula (I), is based on a statistically meaningful number of 2-(2-oxopyrrolidin-1-yl)butanamide molecules, typically greater than 1000 molecules. In the present invention, the relative amounts of the compound of formula (I) to the compound of formula (II) are expressed by the ratio of the compound of formula (I) to the compound of formula (II), or by the enantiomeric excess of the compound of formula (I).

[0019] It should be understood that the "ratio" of the compound of formula (I) to the compound of formula (II) used herein refers to the mass ratio of the compound of formula (I) to the compound of formula (II) unless otherwise specified. When the solvate of the compound of formula (I) and / or the compound of formula (II) is used, the solvent is to be ignored in this calculation. In other words, the "ratio of the compound of formula (I) to the compound of formula (II)" is calculated as follows: TIFF2025020146000002.tif20156

[0020] As known by those skilled in the art, the ratio of compounds that differ only in chirality, such as in the case of compounds of formula (I) and formula (II), can be determined in several ways known in the art, including, but not limited to, chromatography using a chiral support, polarimetry of the rotation of polarized light, nuclear magnetic resonance spectroscopy using a chiral shift reagent, or derivatization of the compound using a chiral compound such as Mosher's acid followed by chromatography or nuclear magnetic resonance spectroscopy. Furthermore, enantiomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and direct fractional crystallization of racemates by chiral cocrystallization techniques that exploit the formation of specific hydrogen bonding interactions present in the cocrystal (see Springuel GR, et al., 2012; and U.S. Patent No. 6,570,036). Useful cocrystallization partners include enantiomers of mandelic acid, malic acid, tartaric acid and their derivatives, or enantiomers can be prepared by asymmetric synthesis. (See, for example, Eliel and Wilen, 1994.) The ratio of compounds of formula (I) to compounds of formula (II) (sometimes referred to as chiral purity) of compositions of the invention, such as non-racemic mixtures, is typically and preferably determined by chiral HPLC (see the Examples for details) and is represented by the equation: ee=(A S -A R ) / (A S +A R )×100% and express it as the enantiomeric excess (ee). S is the peak area of ​​the compound of formula (I) in the HPLC chromatogram of the sample solution, and A R is the peak area of ​​the compound of formula (II) in the HPLC chromatogram of the sample solution. In this regard, although chiral "purity" is mentioned above, it is recognized that the gist of the present invention is not to achieve a high chiral purity of the compound of formula (I) or the compound of formula (II). Rather, the gist of the present invention is that a certain range of ratios between the compound of formula (I) and the compound of formula (II) will cause a synergistic effect in particular. In contrast to cases where the purity of a compound is merely to be improved, i.e., where the objective is known, i.e., to obtain one particular compound, ideally with 100% purity, the present invention is based on a previously unknown ratio of two compounds, i.e., the compound of formula (I) and the compound of formula (II).

[0021] The term "pharmaceutically acceptable" indicates that the compound or composition, typically and preferably a solvate, cocrystal or carrier, typically and preferably when used in a formulation or typically and preferably when used to treat an animal, preferably a human, must be chemically or toxicologically compatible with other ingredients, typically and preferably a composition of the present invention. Preferably, the term "pharmaceutically acceptable" indicates that the compound or composition, typically and preferably a solvate, cocrystal or carrier, typically and preferably when used in a formulation or typically and preferably when used to treat an animal, preferably a human, must be chemically and toxicologically compatible with other ingredients, typically and preferably a composition of the present invention. Pharmaceutical compositions are described in "Remington: The Science and Practice of Pharmacy", Pharmaceutical Press, 22 nd It is recognized that the compositions may be formulated by techniques known to those skilled in the art, such as those published in the "Preparation of Intracranial and Non-Intracranial Agents" edition.

[0022] "Solvate" refers to an association or complex of one or more solvent molecules with the (S)-enantiomer of formula (I) or the (R)-enantiomer of formula (II). Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex where the solvent molecule is water.

[0023] "Co-crystal" refers to a crystal structure that includes at least two different compounds that are solid in their pure form under ambient conditions. The at least two different compounds can include a compound of formula (I) and / or a compound of formula (II) and / or any other component of the composition or excipient of the pharmaceutical composition. Co-crystals are made from neutral molecular species, and all species remain neutral after crystallization. Moreover, typically and preferably, they are crystalline homogeneous phase materials in which two or more building compounds are present in a defined stoichiometric ratio. In this regard, see Wang Y and Chen A, 2013; and Springuel GR, et al., 2012; and U.S. Patent No. 6,570,036. It should be understood that the compound of formula (I) and / or the compound of formula (II) can be in the form of any polymorph. Various co-crystals and techniques for preparing such co-crystals are described in RSC Drug Discovery, Pharmaceutical Salts and Co-crystals, published in 2012 by the Royal Society of Chemistry and edited by Johan Wouters and Luc Quere, in particular in chapters 15 and 16. Preferred examples of co-crystal formers are those disclosed in Table 16.1 of this reference. Even more preferred co-crystals include co-crystals of α-hydroxy acids, α-keto acids and / or α-keto amides with the compounds of formula (I) and (II) in the (R) to (S) ratios disclosed herein.Examples of α-hydroxy acids include atrolactic acid, benzilic acid, 4-chloromandelic acid, citric acid, 3,4-dihydroxymandelic acid, ethyl pyruvate, galacturonic acid, gluconolactone, glucuronic acid, glucuronolactone, glycolic acid, 2-hydroxybutanoic acid, 2-hydroxypentanoic acid, 2-hydroxyhexanoic acid, 2-hydroxyheptanoic acid, 2-hydroxyoctanoic acid, 2-hydroxynonanoic acid, 2-hydroxydecanoic acid, 2-hydroxyundecanoic acid, 4-hydroxymandelic acid, 3-hydroxybutanoic acid, 4 ... These include hydroxy-4-methoxymandelic acid, 4-hydroxy-3-methoxymandelic acid, α-hydroxyarachidonic acid, α-hydroxybutyric acid, α-hydroxyisobutyric acid, α-hydroxylauric acid, α-hydroxymyristic acid, α-hydroxypalmitic acid, α-hydroxystearic acid, 3-(2'-hydroxyphenyl)lactic acid, 3-(4'-hydroxyphenyl)lactic acid, lactic acid, malic acid, mandelic acid, methyllactic acid, methylpyruvate, mucic acid, α-phenylacetic acid, α-phenylpyruvic acid, pyruvic acid, saccharic acid, tartaric acid, and tartronic acid. Examples of α-keto acids include 2-ketoethanoic acid (glyoxylic acid), methyl 2-ketoethanoate, 2-ketopropanoic acid (pyruvic acid), methyl 2-ketopropanoate (methylpyruvate), ethyl 2-ketopropanoate (ethylpyruvate), propyl 2-ketopropanoate (propylpyruvate), 2-phenyl-2-ketoethanoic acid (benzoylformic acid), methyl 2-phenyl-2-ketoethanoate (methyl benzoylformate), ethyl 2-phenyl Examples of α-ketoamides include methyl 3-phenyl-2-ketopropanoate (ethyl benzoylformate), 3-phenyl-2-ketopropanoate (phenylpyruvic acid), methyl 3-phenyl-2-ketopropanoate (methylphenylpyruvate), ethyl 3-phenyl-2-ketopropanoate (ethylphenylpyruvate), 2-ketobutanoic acid, 2-ketopentanoic acid, 2-ketohexanoic acid, 2-ketoheptanoic acid, 2-ketooctanoic acid, 2-ketododecanoic acid and methyl 2-ketooctanoate. Examples of α-ketoamides include any compound that can be obtained by reacting any one of the above examples of α-keto acids with a primary or secondary amine.

[0024] In a first aspect, the present invention provides a compound of formula (I) and a compound of formula (II) [ka] and / or a pharma- ceutically acceptable solvate or cocrystal thereof, The present invention provides a composition in which the enantiomeric excess (ee) of the compound of formula (I) is 20% or more and 50% or less. The enantiomeric excess (ee) of the compound of formula (I) can be higher than 50% and 67% or less. Therefore, in the present invention, the enantiomeric excess (ee) of the compound of formula (I) is 20% or more and 67% or less. Preferably, the enantiomeric excess (ee) of the compound of formula (I) is 20% or more and 50% or less.

[0025] Typically, non-solvated or non-co-crystallized compositions are preferred. More preferred are non-solvated and non-co-crystallized compositions. Thus, in another aspect, the present invention provides a composition comprising a compound of formula (I) and a compound of formula (II) in an enantiomeric excess (ee) of the compound of formula (I) of greater than or equal to 20% and less than or equal to 50%. More preferably, said enantiomeric excess (ee) of the compound of formula (I) is greater than or equal to 20% and less than or equal to about 40%. Even more preferably, said enantiomeric excess (ee) of the compound of formula (I) is greater than or equal to 20% and less than or equal to 35%.

[0026] The enantiomeric excess (ee) of the compound of formula (I) is preferably 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38% or 40% or more, whereas the enantiomeric excess (ee) of the compound of formula (I) can be preferably 48%, 46%, 44%, 42%, 40%, 38%, 36%, 34%, 32% or 30% or less. Examples of suitable preferred ranges of enantiomeric excess (ee) of compounds of formula (I) include 20% to 48%, 20% to 46%, 20% to 44%, 20% to 42%, 20% to 40%, 20% to 38%, 20% to 36%, 20% to 34%, 20% to 32%, 20% to 30%, 30% to 50%, 30% to 48%, 30% to 46%, 30% to 44%, 30% to 42%, 30% to 40%, 40% to 50%, 25% to 45%, 25% to 40%, 25% to 35%, 35% to 50%, 35% to 45%, 35% to 40%, and the like. Other preferred upper limits of the enantiomeric excess (ee) of the compound of formula (I) include 65%, 62%, 60%, 58%, 56%, 54%, 52% and 50%. As known to those skilled in the art, instead of the enantiomeric excess, the ratio of the compound of formula (I) to the compound of formula (II) can be referred to. The preferred range of the ratio of the compound of formula (I) to the compound of formula (II) is 1.5:1 to 3.0:1, preferably 1.5:1 to 2.3:1, more preferably 1.5:1 to 2.0:1. Another preferred range of the ratio of the compound of formula (I) to the compound of formula (II) is 1.5:1 to 5.0:1, preferably 2:1 to 4:1, more preferably 2:1 to 3.3:1, more preferably 2:1 or 3:1.

[0027] In another aspect, the present invention provides a pharmaceutical composition comprising a composition of the present invention and a pharma- ceutically acceptable carrier. In another embodiment, the present invention provides a kit of parts comprising a compound of formula (I) and a compound of formula (II) and instructions for combining the compound of formula (I) and the compound of formula (II) to obtain an enantiomeric excess (ee) of the compound of formula (I) of 20% or more and 67% or less (preferably 50% or less). In the following, whenever the use of the composition of the present invention is described, it should be understood that a kit according to the present invention can be used instead. Those skilled in the art will understand that the components of the kit can be combined before administration, which is preferred, or the components of the kit can be administered separately. In the latter case, the components of the kit should typically be administered within a time range of at most 30 minutes to achieve the effect of the present invention. In yet another aspect, the present invention provides a composition of the invention or a pharmaceutical composition of the invention or a kit of the invention for use as a medicament.

[0028] In yet another aspect, the present invention provides a composition of the present invention or a pharmaceutical composition of the present invention or a kit of the present invention for use in the treatment or prevention of seizure-related disorders. A wide variety of neurological and psychiatric conditions and disorders may have seizures or related seizure-like neurological phenomena as their etiology. Simply put, seizures or related seizure-like neurological phenomena are single, separate clinical events that occur due to excessive discharges from a collection of neurons or a group of seizure-susceptible neurons through a process called "ictogenesis". Thus, ictogenic seizures may only be a symptom of the disease. However, epilepsy and other similar seizure-related disorders are dynamic and often progressive diseases with a maturation process characterized by a complex and poorly understood series of pathological transformations. In addition, the use of the compounds and compositions of the present invention is typically and preferably intended for psychiatric diseases or disorders selected from depression and treatment-resistant depression, bipolar disorder, post-traumatic stress disorder, obsessive-compulsive disorder, autism spectrum disorder, schizophrenia, and anxiety; peripheral sensory neuropathy symptoms, preferably peripheral neuropathic pain and cold allodynia, fibromyalgia, irritable bowel syndrome, migraine, and cluster headache, and other acute and chronic central hypersensitivity disorders; and motor neuron disorders, such as spinal muscular atrophy, amyotrophic lateral sclerosis, Parkinson's dystonia, and Huntington's dystonia.Other examples of psychiatric diseases or disorders are described in the following examples.Therefore, the compounds and compositions of the present invention can also be used:

[0029] a) for the prevention or treatment of positive symptoms of peripheral neuropathy, including cold sensitivity, tingling, burning, or tingling sensations, such as those associated with chemotherapy, bacterial growth inhibitory therapy, viral infections and treatments, postherpetic neuralgia, osteonecrosis, trigeminal neuralgia, or diabetic peripheral neuropathy, including primary allodynia, secondary allodynia, or other pain or discomfort associated with sensitization of the spinal cord or higher brain structures or neuronal pathways; b) for the prevention or treatment of pain, including bone and joint pain, osteonecrosis pain, repetitive motion pain, dental pain, dysmenorrhea pain, cancer pain, myofascial pain, surgical pain, perioperative pain, and postoperative pain syndromes such as post-mastectomy syndrome, post-thoracotomy syndrome, or stump pain, as well as pain associated with angina, neuroma pain, complex regional pain syndrome, chronic pelvic pain, and chronic low back pain; c) For the prevention or treatment of inflammatory pain such as osteoarthritis, rheumatoid arthritis, rheumatic diseases, chronic arthritic pain and associated neuralgia, tendonitis and gout; d) For the prevention or treatment of neuropathic pain such as chemotherapy-induced pain, post-traumatic injury pain, contusion pain, painful traumatic mononeuropathy, painful polyneuropathy, spinal cord injury, low back pain, pain caused by nerve compression or entrapment, sacral pain, trigeminal neuralgia, migraine, post-herpetic neuralgia, phantom limb pain, post-herpetic pain, diabetic neuropathy, central pain syndromes caused by lesions at any level of the peripheral nervous system;

[0030] e) For the prevention or treatment of neuropsychiatric disorders. Examples of neuropsychiatric disorders include schizophrenia, psychoses including schizophrenia, schizophreniform disorders, schizoaffective disorders, delusional disorders, brief psychotic disorders, substance-related disorders, paranoid schizophrenia, disorganized schizophrenia, catatonic or difficult to type schizophrenia, substance-induced psychotic disorders, substance-related disorders and addictive behaviors; f) Obesity associated with excessive food intake, bulimia nervosa or other eating disorders; g) Brain damage occurring after stroke, cerebral edema, cerebral ischemia, cerebral hemorrhage, neurodegenerative diseases, cardiac bypass surgery and transplantation, perinatal hypoxia, cardiac arrest, and hypoglycemic brain injury; h) Sleep disorders such as insomnia, narcolepsy, or restless legs disorder; i) Affective disorders, anxiety disorders such as panic attacks, panic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder; j) Mood disorders such as depression, anhedonia, unipolar depression, bipolar disorder, psychotic depression; k) substance addiction, drug dependence, substance tolerance, dependence or withdrawal including to alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics;

[0031] l) Impairments in cognitive function, such as age-related cognitive decline or cognitive impairment, such as Alzheimer's disease, ischemia, trauma, vascular problems or stroke, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, chemotherapy, perinatal hypoxia, other medical conditions or different types of dementia associated with substance abuse; m) Parkinson's disease, including drug-induced parkinsonism, or postencephalitic parkinsonism; n) Attention deficit disorders, including Attention Deficit Hyperactivity Disorder (ADHD), Obsessive-Compulsive Disorder, phobias, Post-Traumatic Stress Disorder, Autism and Autism Spectrum Disorders, and Impulse Control Disorders; o) tinnitus, presbycusis; p) To enhance learning and memory; q) for the prevention or treatment of hereditary or sporadic motor neuron disorders, examples of which include amyotrophic lateral sclerosis, primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, Friedreich's ataxia, and fragile X syndrome; r) for the prevention or treatment of movement disorders, examples of which include dystonia, chorea including Huntington's disease, Parkinson's-associated dystonia, Creutzfeldt-Jakob disease, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, and basal ganglia calcification; s) Due to akinesia, such as akinetic rigidity syndrome, t) Drug-induced parkinsonism such as neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and drug-induced postural tremors including rest, postural and intention tremors, chorea (such as Sydenham's chorea, Huntington's disease, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea and hemiballismus), generalized or focal myocardial infarction, for dyskinesias such as tics (including simple tics, complex tics and symptomatic tics), and dystonias (including generalized dystonias such as idiopathic dystonia, drug-induced dystonia, symptomatic dystonia and paroxysmal dystonia, and focal dystonias such as blepharospasm, oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia, dystonic writer's cramp and hemiplegic dystonia), muscle spasms, and disorders associated with muscle spasms or weakness, including tremors; u) as well as for urinary incontinence, multiple system atrophy, tuberous sclerosis, olivo-ponto-cerebellar atrophy, cerebral palsy, drug-induced optic neuritis, ischemic retinopathy, diabetic retinopathy, glaucoma, spasticity, myoclonus, and dyskinesias associated with Tourette's syndrome.

[0032] Additionally, the compositions of the present invention can be used, for example, in non-therapeutic applications, to enhance learning and memory in healthy subjects. In yet another aspect, the present invention provides a method for the treatment and / or prevention of a disease or disorder, typically and preferably selected among seizure-related disorders, said method comprising the step of administering a composition of the present invention or a pharmaceutical composition of the present invention or a kit of the present invention.

[0033] Part of the present invention is also to provide a method of treatment of a disease or disorder, in which a therapeutically effective amount of the composition of the present invention or the pharmaceutical composition of the present invention or the kit of the present invention is administered to an animal, preferably a human, in need thereof. Herein, the term "therapeutically effective amount" refers to an amount sufficient to modulate one or more of the symptoms of the condition or disease to be treated, preferably between 10 mg and 3000 mg per administration, administered once a day, twice a day or three times a day by the oral route. Furthermore, part of the present invention is also to provide a method of prevention of a disease or disorder, in which a therapeutically effective amount of the composition of the present invention or the pharmaceutical composition of the present invention or the kit of the present invention is administered to an animal, preferably a human, reasonably expected to be in need thereof. Herein, the term "therapeutically effective amount" refers to an amount sufficient to modulate one or more of the expected symptoms of the condition or disease to be avoided, preferably between 10 mg and 3000 mg per administration, administered once a day, twice a day or three times a day by the oral route.

[0034] In yet another aspect, the present invention provides the use of the composition of the invention or the pharmaceutical composition of the invention or the kit of the invention in the manufacture of a medicament for use in the treatment and / or prevention of a disease or disorder, wherein the disease or disorder is typically and preferably selected from seizure-related disorders. It is even more preferred that the composition or pharmaceutical composition or kit is administered in conjunction with at least one anti-seizure drug, and said administration of said composition or pharmaceutical composition with said at least one anti-seizure drug is in parallel, simultaneous, sequential or separate administration. Non-limiting examples of such anti-seizure drugs are selected from the group consisting of eslicarbazepine, lacosamide, rufinamide, pregabalin, stiripentol, oxcarbazepine, tiagabine, fosphenytoin, topiramate, gabapentin, felbamate, lamotrigine, zonisamide, and vigabatrin.

[0035] The composition or pharmaceutical composition or kit is preferably used in conjunction with at least one anti-seizure drug, said anti-seizure drug being preferably selected from eslicarbazepine, lacosamide, rufinamide, pregabalin, stiripentol, oxcarbazepine, tiagabine, fosphenytoin, topiramate, gabapentin, felbamate, lamotrigine, zonisamide, and vigabatrin. The disease or disorder is preferably stroke. The dosage will depend on the route of administration, the severity of the disease, the age and mass of the patient or subject, and other factors normally considered by the attending physician when determining the individual regimen and dosage level for a particular patient or subject. The composition or pharmaceutical composition of the present invention can be administered by any route, including oral, intramuscular, subcutaneous, topical, transdermal, intranasal, intravenous, sublingual or rectal administration.Typically and preferably, the pharmaceutical composition of the present invention is administered by oral route in a single dose unit once a day, twice a day or three times a day, most preferably once a day or twice a day.In the most preferred embodiment, the composition or pharmaceutical composition of the present invention is administered twice a day. Typically and preferably, the oral dose of the composition or pharmaceutical composition of the present invention is between 10 mg and 3000 mg per administration, more preferably between 20 mg and 2000 mg per administration, even more preferably between 50 mg and 1000 mg per administration. Typically and preferably, the composition or pharmaceutical composition is orally administered twice daily at a dose between 10 mg and 3000 mg per administration, more preferably between 20 mg and 2000 mg per administration, even more preferably between 50 mg and 1000 mg per administration.

[0036] The pharmaceutical composition of the present invention can be prepared by mixing suitably selected pharma- ceutically acceptable excipients, vehicles, adjuvants, additives, surfactants, desiccants or diluents known to those skilled in the art, and can be suitably adapted for oral, parenteral or topical administration.Typically and preferably, the pharmaceutical composition of the present invention is administered in the form of tablets, capsules, sachets, powders, granules, pellets, oral or parenteral solutions, suspensions, suppositories, ointments, creams, lotions, gels, pastes, and / or can comprise liposomes, micelles and / or microspheres. The pharmaceutically acceptable carrier of the pharmaceutical composition of the present invention is, without limitation, any pharmaceutically acceptable excipient, vehicle, adjuvant, additive, surfactant, desiccant or diluent.Suitable pharmaceutically acceptable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter.The pharmaceutically acceptable carrier of the present invention can be solid, semi-solid or liquid.

[0037] Tablets, capsules or sachets for oral administration are usually provided in dose units and may contain conventional excipients such as binders, fillers, diluents, tablet formers, lubricants, detergents, disintegrants, colorants, flavors and wetting agents. Tablets may be coated according to methods well known in the art. Suitable fillers preferably include or are cellulose, mannitol, lactose and similar agents. Suitable disintegrants preferably include or are starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate. Suitable lubricants preferably include or are magnesium stearate, for example. Suitable wetting agents preferably include or are sodium lauryl sulfate. These oral solid compositions may be prepared by conventional mixing, filling or tableting methods. Mixing operations may be repeated to disperse the active agent in compositions containing large amounts of fillers. These operations are conventional.

[0038] Oral liquid compositions can be provided in the form of, for example, aqueous solutions, emulsions, syrups or elixirs, or in the form of dry products that are reconstituted with water or suitable liquid carriers when used. Liquid compositions can contain conventional additives, such as suspending agents, for example, sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan monooleate or acacia; non-aqueous carriers (which can contain edible oils), for example, almond oil, fractionated coconut oil, oily esters such as glycerol esters, propylene glycol or ethyl alcohol; preservatives, for example, methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavors or coloring agents. Oral preparations can include or be formulated as conventional preparations, such as tablets or granules. For parenteral administration, liquid dosage units can be prepared that contain the composition of the present invention and a sterile carrier. The oral formulation may further comprise a taste-masking component to optimize the taste perception of the oral formulation. Examples of such taste-masking components may be citrus, licorice, mint, grape, blackcurrant or eucalyptus based flavorants known to those skilled in the art. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and sterilising by filtration before filling into a suitable vial or ampoule and sealing.

[0039] Adjuvants such as local anesthetics, preservatives and buffers can be added to the pharmaceutical composition.In order to enhance stability, the composition can be frozen after being filled into a vial and water can be removed under vacuum.In order to promote uniform distribution of the composition of the present invention, surfactants or humectants can be advantageously included in the pharmaceutical composition. Topical formulations preferably include or are ointments, creams, lotions, gels, gums, solutions, pastes, or may include liposomes, micelles or microspheres. The subject that can be treated by the composition or pharmaceutical composition of the present invention is human and animal.Preferred animal is domestic animal, including but not limited to guinea pig, rabbit, horse, donkey, camel, cow, sheep, goat, pig, cat, dog and parrot.More preferred subject is mammal, and even more preferred is human. In yet another aspect, the invention provides an article of manufacture comprising a composition of the invention or a pharmaceutical composition of the invention or a kit of the invention, a container or package, and written instructions, such as a package insert, and directions for administration.

[0040] It is further envisaged that compositions of compounds of formula (I) or compounds of formula (II) and racetams such as aniracetam, brivaracetam, sevaracetam, coluracetam, dimiracetam, doriracetam, dupracetam, fasoracetam, imracetam, methylphenylpiracetam, nebracetam, nefiracetam, omberacetam (noopept), oxiracetam, phenylpiracetam, phenylpiracetam hydrazide, piracetam, pramiracetam, rolipram, rolziracetam and / or seletracetam can also be used to prepare synergistic mixtures and compositions, particularly when the ratio of the enantiomers of the compounds of formula (I) or compounds of formula (II) and the racetam or other racetams is selected within the ranges disclosed herein for mixtures of compounds of formula (I) and compounds of formula (II). It is further envisaged that compositions of compounds of formula (I) or compounds of formula (II) with other compounds such as those disclosed in U.S. Pat. No. 7,544,705 or U.S. Pat. No. 8,334,286 can also be used to prepare synergistic mixtures and compositions, particularly when the ratio of compounds of formula (I) or compounds of formula (II) and dimiracetam-like compounds or enantiomers of dimiracetam-like compounds is selected within the ranges disclosed herein for mixtures of compounds of formula (I) and compounds of formula (II). Non-patent references cited herein are abbreviated by first author and year of publication. Full citations are listed below. TIFF2025020146000004.tif179170 TIFF2025020146000005.tif238170 TIFF2025020146000006.tif237170 TIFF2025020146000007.tif192170 EXAMPLES

[0041] The examples of the present invention are merely illustrative and not limiting. Racemic 2-(2-oxopyrrolidin-1-yl)butanamide and samples of the individual enantiomers of formula (I) and (II) can be synthesized using commercially available starting materials, such as those purchased from Sigma-Aldrich. These commercially available supplies can be used as received from the supplier without further purification, using preparative synthesis methods and techniques well known to those skilled in the art.

[0042] Example 1 Synthesis of 2-(2-oxopyrrolidin-1-yl)butanamide (R)-2-(2-oxopyrrolidin-1-yl)butanamide, (S)-2-(2-oxopyrrolidin-1-yl)butanamide, and racemic mixtures of 2-(2-oxopyrrolidin-1-yl)butanamide were prepared according to the methods described in European Patent No. 0165919 and U.S. Patent No. 6,784,197. The enantiomeric excess of the (R)- and (S)-enantiomers was greater than or equal to 96% for each enantiomer when used separately to prepare the compositions of the invention. To achieve the desired enantiomeric excess of 20% or more ee (excess (S)) and 50% or less ee (excess (S)), as well as other desired specific compositions according to the invention, several methods known to those skilled in the art can be applied. For example, said compositions were prepared by mixing the individual enantiomers or by mixing the racemate of 2-(2-oxopyrrolidin-1-yl)butanamide with the respective amount of the (S)-enantiomer. Furthermore, starting from racemic 2-(2-oxopyrrolidin-1-yl)butanamide, part or all of the (R)-enantiomer can be removed by preparative chiral column chromatography.

[0043] Example 2 Pentylenetetrazol-induced seizure model in mice This study assessed the dose-response relationship of the protective effect of levetiracetam in a published mouse model (Gower et al. (Eur. J. Pharmacol. 222, 1992, 193-203)) of tonic-clonic convulsions kindled by a once-daily injection of pentylenetetrazole (PTZ). Furthermore, at a fixed dose, the protective effect of levetiracetam was compared with that exhibited by racemic etiracetam or by two mixtures of levetiracetam and etiracetam. The two mixtures tested differed in the ratio of the R enantiomer of etiracetam in the mixture (i.e., 1-to-3 R-to-S-etiracetam and 1-to-5 R-to-S-etiracetam).

[0044] animal Male CD1 adult mice (Envigo, Italy, weight 20-25 g on arrival) were used. Cages were brought into the laboratory the day before the experiment for acclimatization. Each treatment group consisted of 15 mice. Mice were fed a standard laboratory diet. Food and water were available ad libitum. Room temperature and relative humidity were kept constant at 22 ± 2 °C and 55 ± 15%, respectively, and a 12-h light and 12-h dark cycle was maintained. Drugs Levetiracetam (batch P102-14050, supplied by Astatech), etiracetam (supplied by Shaanxi Swiden Biotech Co., Ltd., catalog number E932970), or a mixture of 1 part levetiracetam and 1 part etiracetam (1-to-3 R-to-S-etiracetam) or 1 part levetiracetam and 0.5 part etiracetam (1-to-5 R-to-S-etiracetam) were dissolved in 1% carboxymethylcellulose (CMC) solution at a formulation strength of 55 mg / mL and administered orally once per day. Compounds were administered daily on days 1-11, 60 minutes prior to PTZ (55 mg / kg intraperitoneally). PTZ was dissolved in saline. Seizures developed within approximately 20 minutes in vehicle-treated mice after intraperitoneal injection.

[0045] PTZ-induced kindling test The study was performed according to Gower et al. (Eur. J. Pharmacol. 222, 1992, 193-203). Separate groups of male mice were orally administered levetiracetam (10, 30, or 60 mg / kg po); etiracetam (30 mg / kg po); or 1-vs-3 R-vs-S-etiracetam (30 mg / kg po); or 1-vs-5 R-vs-S-etiracetam (30 mg / kg po); or oral vehicle once daily for 11 consecutive days, 60 minutes before administration of PTZ (pentylenetetrazole, 55.0 mg / kg ip). Immediately after PTZ injection, the mice were placed in individual cages and observed for tonic and clonic seizures. statistical analysis Chi-square tests were used to test for significance between two measures of behavioral outcomes. Data were analyzed with the Social Science Statistics Program. P values ​​≤ 0.05 were considered significant (link https: / / www.socscistatistics.com / tests / chisquare / default2.aspx).

[0046] result The results are summarized in Tables 1 and 2 below. [Table 1]

[0047] [Table 2]

[0048] A single daily injection of PTZ (55 mg / kg i.p.) caused a gradual increase in the percentage of vehicle control-treated mice with tonic or clonic convulsions, increasing from less than 25% on day 1 to 100% on day 11 (Table 1). Pretreatment with levetiracetam (10, 30 or 60 mg / kg orally) led to a dose-dependent reduction in this phenomenon. Statistical significance of the percentage of mice exhibiting seizures compared to the vehicle-treated group was only reached at a dose of 60 mg / kg orally from day 8 to day 11 of treatment (Table 1). The strength of the effect of levetiracetam was such that after oral administration of 60 mg / kg, the incidence of clonic convulsions did not exceed 20% in the first 6 days and reached a maximum of 40% after 11 days of kindling. At the lower dose of levetiracetam tested (10 mg / kg po), all mice showed tonic or clonic convulsions at the end of treatment. A moderate reduction in the effect was observed at the 30 mg / kg po dose (Table 1).

[0049] In a subsequent sequence of experiments, the antiepileptic effects of levetiracetam at 30 mg / kg orally were compared with those of racemic etiracetam (30 mg / kg orally) and the 1-vs-3 R-vs-S etiracetam and 1-vs-5 S-vs-R etiracetam mixtures (Table 2). 1-vs-3 R-vs-S-etiracetam administered orally at 30 mg / kg was more effective than levetiracetam. The percentage of mice exhibiting tonic / clonic convulsions was smaller than that of the levetiracetam group, and this effect was statistically significant starting from day 8 through day 11. With 1-vs-5 R-vs-S-etiracetam, the percentage of mice exhibiting tonic or clonic seizures on day 11 was 67% (Table 2), numerically smaller than that of the levetiracetam-treated group. conclusion The PTZ kindling mouse seizure model showed a dose-response effect of oral levetiracetam, consistent with previously published data. At a comparison of 30 mg / kg oral doses, levetiracetam was moderately effective, and racemic etiracetam at 30 mg / kg oral doses was ineffective. Notably, the 1-vs-3 R-vs-S-etiracetam and 1-vs-5 R-vs-S-etiracetam mixtures were more effective than levetiracetam itself. For the 1-vs-3 R-vs-S-etiracetam mixture, this difference achieved statistical significance with levetiracetam as late as days 8-11.

[0050] Example 3 Efficacy of novel compositions in seizure models The associated anti-seizure efficacy of the novel compositions is evaluated in a kindling model of temporal lobe epilepsy as described in Loscher W et al., J. Pharm. Exp. Ther., 284:474-479, 1998. Electrode implantation. For kindling experiments, rats were anesthetized with chloral hydrate (360 mg / kg i.p.) and stereotaxically implanted with one bipolar electrode in the right basolateral amygdala according to the surgical technique described in the atlas of Paxinos and Watson (1986). The coordinates for electrode implantation are AP-2.2, L-4.8, V-8.5. All coordinates are measured from bregma. A skull screw serves as a neutral reference electrode. The electrode assembly is bonded to the skull by dental acrylic cement.

[0051] Kindling development experiments. Four groups of 8 rats each are implanted with kindling electrodes as described above. Two weeks after implantation, the initial (prekindling) electrical sensitivity (ADT) of the stimulated area is determined in each rat using the ascending staircase technique. The initial current intensity is 10 μA, and the current intensity is increased by about 20% of the previous current at 1-minute intervals until an after-discharge of at least 3 seconds is elicited. The next morning, chronic treatment is started and the animals are stimulated with a suprathreshold current of 500 μA 1 hour after each intraperitoneal injection of the test compound. Group I receives an intraperitoneal injection of vehicle (saline), group II receives an intraperitoneal injection of 13 mg / kg levetiracetam, group III receives an intraperitoneal injection of 27 mg / kg levetiracetam, and group IV receives an intraperitoneal injection of 54 mg / kg levetiracetam. Vehicle or drug is injected once a day, 5 days a week (excluding weekends). After 21 injections, treatment and amygdala stimulation are terminated. After a 5-day washout period, further 500 μA amygdala stimulation is performed until all animals show 10 stage 5 seizures. After each stimulation, seizure severity, seizure duration and after-discharge duration are recorded as follows. Seizure severity is classified according to Racine (1972): 1, immobility, eye closure, vibrissa twitching, sniffing, facial clonus; 2, head nodding associated with more severe facial clonus; 3, clonus of one forelimb; 4, rearing often accompanied by bilateral forelimb clonus; 5, rearing with loss of balance and falling with generalized clonic seizures. Seizure duration is the duration of limbic (stages 1-2) and / or motor seizures (stages 3-5). Limbic seizure activity (low amplitude after-discharge and immobility associated with episodic facial clonus or head nodding) that often occurs after the end of the motor seizure is not included in seizure duration. Afterdischarge time is the total time of an amygdala EEG spike with an amplitude at least twice that of the prestimulus recording and a frequency greater than 1 / sec.

[0052] One week after the final stage 5 seizure, postkindling ADT is determined in each group as described above for prekindling ADT. Based on the experimental results of Examples 1 and 2, it can be seen that the effect of the claimed ratio of S:R-enantiomers of 2-(2-oxopyrrolidin-1-yl)butanamide leads to increased anti-seizure efficacy compared to either the racemate of 2-(2-oxopyrrolidin-1-yl)butanamide or the individual enantiomers of 2-(2-oxopyrrolidin-1-yl)butanamide.

[0053] All patents, publications, and abstracts cited above are incorporated herein by reference in their entirety. Various embodiments of the invention have been described as realizations of various objects of the invention. It should be recognized that these embodiments are merely illustrative of the principles of the invention. Numerous modifications and variations thereof will be readily apparent to those skilled in the art without departing from the spirit and scope of the invention as defined in the following claims.

Claims

1. A compound of formula (I) and a compound of formula (II), 【Chemistry 1】 and / or a pharma- ceutically acceptable solvate or cocrystal thereof, A composition, wherein the enantiomeric excess (ee) of the compound of formula (I) is 20% or more and 67% or less.

2. 2. The composition of claim 1, wherein the enantiomeric excess (ee) of the compound of formula (I) is greater than or equal to 20% and less than or equal to 50%.

3. 3. The composition according to claim 1 or 2, wherein the enantiomeric excess (ee) of the compound of formula (I) is greater than or equal to 20% and less than or equal to 40%.

4. The composition of any one of claims 1 to 3, wherein the compound of formula (I) and / or its pharma- ceutically acceptable solvate or co-crystal and the compound of formula (II) and / or its pharma- ceutically acceptable solvate or co-crystal are packaged separately.

5. 2. The composition of claim 1, wherein the composition is a non-racemic mixture of 2-(2-oxopyrrolidin-1-yl)butanamide and a pharma- ceutically acceptable solvate or co-crystal thereof, wherein the non-racemic mixture comprises the compound of formula (I) in an enantiomeric excess (ee) of the compound of formula (I) of greater than or equal to 20% and less than or equal to 67% relative to the compound of formula (II).

6. A pharmaceutical composition comprising the composition of any one of claims 1 to 5 and a pharma- ceutically acceptable carrier.

7. A kit of parts comprising a compound of formula (I) and a compound of formula (II) and instructions for combining the compound of formula (I) and the compound of formula (II) to obtain an enantiomeric excess (ee) of the compound of formula (I) of greater than or equal to 20% and less than or equal to 67%.

8. A composition according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 6 or a kit of parts according to claim 7 for use as a medicament.

9. 9. The composition or pharmaceutical composition or kit according to claim 8, for use in the treatment and / or prevention of a disease, injury or disorder, wherein the disease, injury or disorder is selected from seizure-related disorders.

10. 10. The composition or pharmaceutical composition or kit for use according to claim 9, wherein the composition or pharmaceutical composition is to be administered orally twice daily at a dose between 10 mg and 3000 mg per administration, more preferably between 20 mg and 2000 mg per administration, even more preferably between 50 mg and 1000 mg per administration.

11. a compound of formula (I) and a compound of formula (II), or Compounds of formula (I) and racemates of compounds of formulas (I) and (II) 7. A method for preparing a composition according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 6, comprising combining:

12. Use of a compound of formula (I) and / or a compound of formula (II) and / or a racemate of the compounds of formula (I) and (II) in the preparation of a composition according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 6 or a kit according to claim 7.

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