EA041317B1 - SYNERGETIC COMPOSITIONS CONTAINING (R)-DIMIRACETAM (1) AND (S)-DIMIRACETAM (2) IN A NON-RACEMIC RATIO - Google Patents

Description

Cross-reference to related application

This application claims priority to European Patent Application No. 17173760.4, filed May 31, 2017, which is hereby incorporated by reference in its entirety.

The technical field to which the invention belongs

The present invention relates to compositions and kits comprising (R)-3,6,7,7a-tetrahydro1H-pyrrolo[1,5-a]imidazole-2,5-dione ((R)-dimiracetam (1)) and ( S)-3,6,7,7a-tetrahydro-1H-pyrrolo[1,5a]imidazole-2,5-dione ((S)-dimiracetam (2)) in ratios within a range and their pharmaceutically acceptable solvates, or co-crystals, to pharmaceutical compositions containing said compositions, to their use as a medicament, and to the use of the compositions or pharmaceutical compositions or kits of the present invention for the treatment and/or prevention of a disease or disorder, generally and preferably selected from the following : peripheral sensory neuropathy, preferably peripheral neuropathic pain and other symptoms of peripheral sensory neuropathy; and neuropsychiatric pathological conditions such as seizure; depression or cognitive impairment; and motor neuron diseases such as amyotrophic lateral sclerosis.

State of the art

Glutamic acid is an excitatory neurotransmitter found in high amounts in the brain. The first indication of its role as an excitatory messenger came in the 1950s, when intravenous glutamate was found to cause convulsions. However, it was not until the 1970s and 1980s, when suitable pharmacological equipment first became available, that the complete glutamatergic neurotransmitter system, including biosynthetic and catabolic enzymes, cellular entry mechanisms, intracellular storage and release systems, and its cell surface and G protein-coupled receptors. With the help of which appeared only in the 1990s. molecular biology equipment, techniques were provided for the molecular identification and classification of glutamatergic ion channels, receptors, transporters, and the like.

Membrane-bound ion channels, driven by excitatory amino acids, glutamate and glycine, and also responsive to the xenobiotic compound, N-methyl-D-aspartate (NMDA), regulate the flow of divalent and monovalent cations into pre- and postsynaptic nerve cells (see publication Foster et al., Nature, 1987, 329:395-396; Mayer et al., Trends in Pharmacol. Sci. 1990, 11:254-260). They differ in molecular structure, electrophysiological, and pharmacological characteristics from glutamate-gated cation-conducting ion channels that respond to xenobiotic agents, kainate, or alpha-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA); and, similarly, they differ from receptors belonging to the family of glutamate-gated G protein-coupled receptors, the so-called metabotropic glutamate receptors.

The NMDA-selective glutamate-gated ion channel has a heterotetrameric structural basis: it consists of two obligatory GluN1 units and two variable GluN2 receptor subunits encoded by the GRIN1 gene and one of the four GRIN2 genes, respectively. One or both of the GluN2 subunits can theoretically be replaced by a GluN3A or GluN3B subunit. There are 8 splicing variants in the GRIN1 gene product, while there are 4 different GRIN2 genes (GRIN2A-D) encoding 4 different GluN2 subunits. The glycine binding site is in the GluN1 subunit and the glutamate binding site is in the GluN2 subunit (Paoletti P. et al., Nat. Rev. Neurosci. 2013; 14(6):383-400).

Many classes of positive and negative allosteric modulators of glutamate-gated ion channels have been described; they bind to glutamate-gated ion channels at the interface between subunits of ligand-binding domains (LDBs) of the respective ion channels, at a site that is different from the glutamate or glycine binding sites contained within the SLD (Sun et al., 2002; Jin et al., 2005; Hackos et al., 2016). Allosteric modulators have also been described (Wang et al., 2017) that bind to the transmembrane domain of a glutamate-gated NMDA-type ion channel, where an extremely conserved structural motif (the so-called Lurcher domain) restricts ion flow through a pore if the ion channel is in a closed or deactivated condition (Karakas and Furukawa, 2014; Lee et al., 2014; Ogden and Traynelis, 2013).

Allosteric modulators of glutamate-gated ion channels hold promise for therapeutic applications and even applications in healthy individuals in various areas such as learning, memory, mood, attention, emotion, motor neuronal disease, peripheral sensory neuropathy, and pain perception (Cull-Candy S. et al. , Curr Opin Neurobiol 2001;11(3):327-35).

Compounds that modulate NMDA receptor function may be useful in the treatment of many neurological and psychiatric disorders, including but not limited to:

bipolar disorder (Martucci L. et al., Schizophrenia Res, 2006; 84(2-3):214-21),

- 1 041317 major depression (Li N. et al., Biol. Psychiatry. 2011; 69(8):754-61), treatment-resistant depression (Preskorn S. H. 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 postpartum depression (Weickert C.S. et al. Molecular Psychiatry (2013), 18, 1185-1192), seasonal affective disorder, etc.), Alzheimer's disease (Hanson J.E. et al., Neurobiol. Dis. 2015; 74:254-62; Li S. et al., J. Neurosci. 2011; 31(18): 6627-38) and other types of dementia (Orgogozo J. M. 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 K. R. et al., Clin. Exp. Pharmacol. Physiol. 2008; 35(11):1388-94), Huntington's chorea (Tang T. S. 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), cognitive impairment (Wang D. et al., 2014, Expert. Opin. Ther. Targets, 2014; 18(10):1121-30), head injury (Bullock M.R. et al. ., Ann NY Acad. Sci. 1999; 890:51-8), spinal cord injury, stroke (Yang Y. et al., J .Neurosurge. 2003; 98(2):397-403), epilepsy (Naspolini A.P. et al., Epilepsy Res. 2012 Jun; 100(1-2):12-9), movement disorders (e.g. dyskinesias) (Morissette M. et al. , Mov. Disord. 2006; 21(1):9-17), various neurodegenerative diseases (eg, amyotrophic lateral sclerosis (Fuller P.I. et al., Neurosci. Lett. 2006; 399(1-2):157-61) or neurodegeneration associated with bacterial or chronic infections), glaucoma (Naskar R. et al. Semin Ophthalmol. 1999 Sep; 14(3):152-8), pain (eg, chronic, cancer-induced, postoperative and neuropathic pain (Wu L.J. 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 autistic disorders (Won H. et al., Nature. 2012; 486(7402):261-5), memory and learning disorders (Tang, Y .P et al., Nature, 1999; 401(6748):63-9), obsessive-compulsive disorder (Arnold P.D. et al., Psychiatry Res. 2009; 172(2):136-9), attention deficit hyperactivity disorder (ADHD) (Dorval K.M. et al. , Genes Brain Behav. 2007;6(5):444-52),

PTSD (post-traumatic stress disorder) (Haller J. et al. Behav Pharmacol. 2011; 22(2):11321; Leaderbrand K. et al. Neurobiol. Learn Mem. 2014; 113:35-40), tinnitus (Guitton M. J., and Dudai Y., Neural Plast 2007; 80904; Hu S. S. et al., 2016; 273(2): 325332), sleep disorders (such as narcolepsy or excessive daytime sleepiness, patent WO 2009/058261 A1), vertigo 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), state anxiety, autoimmune disorders such as neuropsychiatric systemic lupus erythematosus (Kowal C. et al., Proc. Natl. Acad. Sci. U.S.A. drug or drug abuse) (Nagy J., 2004, Curr Drug Targets CNS Neurol Disord. 2004; 3(3):169-79; Shen H. et al., Proc. Natl. AcadSci. USA. 2011; 108(48):19407-12).

Symptoms of peripheral sensory neuropathy, including one of the most prominent symptoms, peripheral neuropathic pain (Zilliox L.A., 2017), are frequently encountered clinical pathological conditions: the prevalence in the general population is estimated to be between 7 and 10% (van Hecke O. et al ., 2014). Painful peripheral neuropathy alone is estimated to affect approximately 10 million people in the United States. Peripheral sensory neuropathy is often resistant to treatment, and patients have little satisfaction with the results of their treatment. Several drugs have been shown to be effective in the treatment of peripheral sensory neuropathy associated with diabetic neuropathy and postherpetic neuralgia, and these drugs are often also used in the treatment of neuropathic pain associated with other pathological conditions. These therapies often lead to unwanted side effects, and discontinuation of treatment can be difficult. It is important to understand that peripheral sensory neuropathy affects many aspects of daily life and is associated with poor general health, poor quality of life, poor sleep, and increased anxiety and depression. In fact, the quality of life of people with chronic peripheral sensory neuropathy has been estimated to be as poor as that of patients with clinical depression, coronary artery disease, recent myocardial infarction, or poorly controlled diabetes mellitus (Smith B.H. et al., 2007).

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The American Academy of Neurology has published guidelines for the treatment of painful diabetic neuropathy (Bril V. et al., 2011), postherpetic neuralgia (Dubinsky R.M. et al., 2004), and trigeminal neuralgia (Gronseth G. et al., 2008). Several other practice guidelines for the treatment of neuropathic pain have also been published (Attal N. et al., 2010; Moulin D., et al., 2014).

Depending on the site of damage that causes symptoms, sensory neuropathy is usually divided into central and peripheral. Examples of pathological conditions associated with peripheral sensory neuropathy are diabetic neuropathy, human immunodeficiency virus-associated neuropathy, chemotherapy-induced peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, complex regional pain syndrome, compressive mononeuropathies, radiculoneuropathy, inflammatory neuropathies (acute and chronic inflammatory demyelinating polyneuropathy), post-traumatic neuropathy or neuropathy associated with the sensation of having an amputated limb.

Typically, peripheral sensory neuropathy has both positive and negative symptoms. Positive symptoms include tingling (pinching in the limbs), tingling, lightning or cutting sensations, aching, sharp, drawing or lightning symptoms, sharp or burning pain, or pain similar to electric shocks. Negative symptoms include numbness, deadness, or a feeling of wearing socks. Some specific features of peripheral sensory neuropathy include hyperalgesia (increased sensitivity to a common noxious stimulus); allodynia (pain when exposed to a stimulus that usually does not cause pain); hyperesthesia (increased sensitivity to a stimulus); paresthesia (abnormal sensitivity, provoked or spontaneous); dysesthesia (unpleasant abnormal sensitivity); hypesthesia (reduced pain in response to a normal painful stimulus); analgesia (loss of pain sensation) and anesthesia (loss of sensation). Positive signs or symptoms presumably characterize excessive activity in the sensory pathway due to a low threshold or increased excitability. Negative signs and symptoms are perceived as diminished or absent sensation and result from loss of sensory function.

Although some pharmacological agents have been found to be effective in treating the symptoms of peripheral sensory neuropathy (Finnerup N.B. et al., 2015), only a small number of patients suffering from neuropathic pain show a complete response to drug treatment. Most patients reasonably expect that treatment will make the pain bearable. In general, a 30% reduction in pain on an 11-point numerical rating scale is considered clinically important and represents moderate relief or significant improvement. In addition, it is also important to recognize and treat comorbidities such as anxiety and depression, and secondary treatment goals may include improving sleep, improving function, and improving overall quality of life. These goals can best be achieved if drug treatment is one component of an interdisciplinary approach to treatment.

The drugs approved by the US Food and Drug Administration for the treatment of neuropathic pain are carbamazepine, duloxetine, pregabalin, gabapentin, oral lidocaine, and oral capsaicin. Tramadol and opioid analgesics are effective for various types of neuropathic pain, but they are not generally recommended as first-line treatment due to concerns about its safety in long-term treatment. However, they are recommended as a first-line treatment for acute neuropathic pain, neuropathic pain due to cancer, and episodic exacerbations of severe neuropathic pain. The use of strong opioids (codeine, morphine, oxycodone and fentanyl) for the treatment of a variety of neuropathic pain is controversial and a public health concern due to the increasing number of deaths associated with prescription opioids. The high risk of overdose, dependence, and addiction that these medicines exhibit may outweigh the potential benefits.

Thus, there remains an urgent and important need in medicine to develop new orally effective drugs for the treatment of peripheral sensory neuropathy and peripheral neuropathic pain that are toxicologically beneficial and potentially non-addictive and non-addictive.

In addition, there remains an important need in medicine to develop new orally effective drugs for the treatment of neuropsychiatric diseases, such as those described in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5); and for the treatment of motor neuron diseases such as amyotrophic lateral sclerosis.

Dimiracetam (2,5-dioxohexahydro-1H-pyrrolo[1,2-a]imidazole (IUPAC name): (RS)-3,6,7,7a-tetrahydro-1H-pyrrolo [1,5a]imidazole-2,5-dione) is a bicyclic derivative of 2-pyrrolidinone and is a nootropic representative of the racemate group:

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AU 2012/201853 discloses the use of dimiracetam or a pharmaceutically acceptable solvate thereof, alone or together with other active ingredients, for the preparation of a medicament useful for the treatment and/or prevention of chronic pain.

WO 93/09120 describes certain processes for the preparation of fused imidazole derivatives, and in particular for the preparation of chiral fused imidazole derivatives.

US 5200406 describes that dimiracetam may be useful for restoring learning ability and treating memory difficulties. One example of a disease treated with dimiracetam is Alzheimer's disease.

Dimiracetam was originally developed for use as a cognitive enhancer and has been shown to improve learning and memory in rats (Pinza M. et al., 1993; EP 335483). In studies using healthy human volunteers and a single dose (Torchio L. et al., 1995), dimiracetam improves some indicators of temporary cognitive impairment caused by scopolamine injection compared with placebo. Other medical uses of dimiracetam have been described, including in particular its general efficacy in rodent models of neuropathic pain. The efficacy of dimiracetam for the treatment of neuropathic pain of other origins has been described in established models of neuropathic pain caused by nerve injury, chemotherapy, or monoiodoacetate (MIA)-induced osteoarthritis (Fariello R. et al., 2014); Di Cesare Mannelli L. et al., 2015a; Di Cesare Mannelli L. et al., 2015b; WO2008/125674; EP 2857017 B1, US 2010/0125096; WO 2012/055057). Chemotherapy-induced symptoms of neurotoxicity respond to dimiracetam regardless of the chemotherapeutic agent used: all models using dideoxycytidine (ddC), oxaliplatin, vincristine, paclitaxel, and sorafenib showed a response to dimiracetam exposure; and dimiracetam has been shown to be effective not only in treating but also in preventing the symptoms resulting from the administration of these chemotherapeutic agents. One oral administration of dimiracetam can completely, however temporarily, bring hyperalgesia and allodynia to a level corresponding to that of healthy control subjects. With repeated twice-daily oral administration, maximum exposure is sustained and no signs of tachyphylaxis or tolerance are observed, despite dose reduction and an increase in the interval between doses to ensure once-daily oral administration. In addition, the effects of dimiracetam are targeted to a specific disease: in a model of unilateral chronic lesion with stenosis (CHS), in which rats develop peripheral neuropathic pain in one hind limb in which the sciatic nerve has been surgically ligated, but does not develop in the other limb, who underwent sham surgery, oral administration of a single dose of dimiracetam reduces the pain response only in the limb with a ligated nerve and does not affect the algesia or allodynia in the limb, which was subjected to sham surgery; this profile differs markedly from exposure to, for example, opiates, which in this model affect both limbs (Christensen D. et al., 1998).

The mechanism of the pharmacological action of dimiracetam was studied using preparations of hippocampal and spinal cord synaptosomes. This study is designed to pharmacologically model the physiological process of glutamate-induced glutamate release; its sensitivity to pH, Zn2 ⁺ , and ifenprodil suggests the involvement of an NMDA receptor isoform containing pH-sensitive GluN1 and GluN2A subunits (Fariello et al., 2014). Inhibition of glutamate signaling is a well-known basis for the prevention or treatment of neuropathic pain (Latremoliere and Woolf, 2009). In the spinal cord, at the junction where peripheral sensory afferents form the first and only synaptic connection with the interneurons of the central nervous system (Marieb, Wilhelm and Mallat, 2017), glutamate-induced release of glutamate is a component of activated or sensitized signaling that results from damaged peripheral nerve (Latremolier and Woolf, 2009).

In hippocampal synaptosome preparations, dimiracetam is an ineffective inhibitor, having an IC ₅₀ value for inhibiting NMDA and glycine induced release of [ ³ H]-O-aspartate preloaded into the synaptosome preparation of about 3 μM. However, in synaptosome preparations of the spinal cord, dimiracetam is much more effective, with an IC ₅₀ value for inhibition of NMDA- and glycine-induced [ ³ H]-O-aspartate release of approximately 20 nM (Fariello R. et al., 2014).

The ability of dimiracetam to block glutamate-induced glutamate release in the spinal cord underlies its usefulness in the prevention or treatment of peripheral sensory neuropathies; other brain mechanisms may underlie its efficacy in treating depression in rats (Fariello et al., 2011; WO 2015/010217) and its efficacy in rat and human models of scopolamine-induced cognitive impairment (Pinza et al. .,

1993).

Dimiracetam is a chiral compound containing one stereocenter, but it has been used in clinical studies as a racemic mixture of its (R)- and (S)-enantiomers. This was carried out despite the fact that (R)-dimiracetam is the more active enantiomer (WO 2008/125674), since the dimiracetam racemate was found to be even more effective than either of the individual enantiomers. For example, oral administration of a single dose of (R)-dimiracetam to 2',3'-dideoxycytidine (ddC, zalcitabine) pre-treated rats resulted in an incomplete effective response, whereas administration of the (S)-enantiomer resulted in a less effective response than administration of an appropriate dose of the (R)-enantiomer. On the other hand, administration of racemic dimiracetam resulted in an excellent response compared to administration of (R)- or (S)-dimiracetam alone (WO 2008/125674). This order of magnitude increase in the efficacy of (S)-, (R)- and racemic dimiracetam is also observed with dimiracetam in reversing MIA-induced hyperalgesia (WO 2008/125674).

Brief summary of the invention

According to the invention, unexpectedly and unexpectedly, it was found that compositions containing the (R)- and (S)-enantiomers of dimiracetam, having an enantiomeric excess (EI) of (R)-dimiracetam (1) greater than or equal to 30% and less than or equal to 60% , have a higher pharmacological efficacy than the corresponding single enantiomers or even than the racemate, and thus provide a synergistic effect that could not be predicted based on the effectiveness of individual enantiomers or the racemate. These compositions preferably inhibit NMDA and glycine induced release of [ ³ H]-D-aspartic acid from rat spinal cord synaptosomes by at least about 40%, preferably at least about 45%, at a concentration of about 10 nM.

Thus, according to the invention, unexpectedly and unexpectedly, it was found that the preferred composition of the present invention, having an enantiomeric excess of (R)-dimiracetam equal to 33% (corresponding to the ratio of dimiracetam (R):(S) enantiomers of 2:1) , inhibited NMDA and glycine-induced release of [ ³ H]-D-aspartic acid from rat spinal cord synaptosomes by about 50% at a concentration of 10 nM (FIG. 1A, Table 1). Another preferred composition of the present invention, having an enantiomeric excess of (R)-dimiracetam of 50% (corresponding to a dimiracetam (R):(S) enantiomeric ratio of 3:1), inhibits NMDA- and glycine-induced release of [ ³ H ]-D-aspartic acid from rat spinal cord synaptosomes even by 52% at a concentration of 1 nM (Fig. 1B, Table 1). In comparison, racemic dimiracetam inhibits NMDA and glycine-induced release of [ ³ H]-D-aspartic acid from rat spinal cord synaptosomes by 36% at a concentration of 10 nM, corresponding to a calculated IC ₅₀ value of 15 nM (Fig. 1B; Table 1); the calculated IC ₅₀ value for (R)-dimiracetam is 123 nM (FIG. 1D), and the calculated IC ₅₀ value for (S)-dimiracetam is 418 nM (FIG. 1E).

These unexpected results have been confirmed in other rat models of peripheral neuropathic pain, such as the MIA-induced knee arthritis model or the oxaliplatin-induced neuropathic pain model. Thus, the compositions of the present invention, having an enantiomeric excess of (R)-dimiracetam, are much more effective in reducing peripheral neuropathic pain in the paw pressure test after administration of sodium monoiodoacetate (MIA; Fig. 2) or in preventing oxaliplatin-induced peripheral pain. neuropathic pain (Fig. 3) than racemic mixtures of dimiracetam. Compositions of the present invention having an enantiomeric excess of (R)-dimiracetam are also much more effective than compositions containing an excess of the (S)-enantiomer of dimiracetam (FIG. 2).

Therefore, the compositions of the present invention containing the (R)- and (S)-enantiomers of dimiracetam, having an enantiomeric excess (EI) of (R)-dimiracetam greater than or equal to 30% and less than or equal to 60%, are pharmacologically more effective in given dose than pure single enantiomers or racemic dimiracetam. The term racemic dimiracetam means a mixture of (R)- and (S)-enantiomers in a 1:1 weight ratio, which thus has an enantiomeric excess (EI) of (R)-dimiracetam equal to 0%. Thus, the effect according to the present invention is a synergistic effect, which unexpectedly arises due to the use of a certain range of ratios of (R)-dimiracetam and (S)-dimiracetam.

Since the concentration-time dependences in the plasma of rats after oral administration of (R)- or (S)-dimiracetam are the same and (R)- and (S)-enantiomers do not turn into each other

- 5 041317 friend in vivo (Fig. 4A and 4B, respectively), the behavior of the compositions proposed in the present invention containing enantiomers, is not explained by the pharmacokinetics or metabolism of the enantiomers. The fact that the (R)- and (S)-enantiomers are both effective separately (although with different potency) and that, when combined at the appropriate ratio, their pharmacological potency is higher than that of the racemate, shows that they have such the same mechanism of pharmacological action as racemic dimiracetam, and are applicable for the treatment of the same diseases. Therefore, the compositions of the present invention are useful and can be used to treat and/or prevent a large number of the diseases and disorders described in the detailed description section. The diseases or disorders are usually and preferably selected from the following: peripheral sensory neuropathy, preferably peripheral neuropathic pain and other symptoms of peripheral sensory neuropathy; and neuropsychiatric pathological conditions such as seizure; depression or cognitive impairments; and motor neuronal diseases such as amyotrophic lateral sclerosis. More preferably, if the disease or disorder is usually selected from among the following: peripheral sensory neuropathy, preferably peripheral neuropathic pain; seizure; depression or cognitive impairment.

The first object of the present invention is a composition containing (R)-3,6,7,7a-tetrahydro-1H-pyrrolo[1,5-a]imidazole-2,5-dione ((R)-dimiracetam (1)) and (S)-3,6,7,7a-tetrahydro-1H-pyrrolo[1,5-a]imidazole-2,5-dione ((S)-dimiracetam (2)):

and/or pharmaceutically acceptable solvates or co-crystals thereof, wherein the enantiomeric excess (EI) of said (R)-dimiracetam (1) is greater than or equal to 30% and less than or equal to 60%.

One specific example of such a composition of the present invention is a non-racemic mixture of 3,6,7,7a-tetrahydro-1H-pyrrolo[1,5-a]imidazole-2,5-dione (dimiracetam) and pharmaceutically acceptable solvates or co-crystals, wherein said non-racemic mixture contains (R)-3,6,7,7a-tetrahydro-1H-pyrrolo[1,5-a]imidazole-2,5-dione ((R)-dimiracetam (1)) and (S)-3,6,7,7a-tetrahydro-1H-pyrrolo[1,5-a]imidazole-2,5-dione ((S)-dimiracetam (2)) at enantiomeric excess (EI) (R) -dimiracetam (1), greater than or equal to 30% and less than or equal to 60%.

ⁿ / ^N U / ^N \ I /=° \ I /=° \______

O(1) O(2)

Another object of the present invention is a pharmaceutical composition containing a composition of the present invention, such as a non-racemic mixture of the present invention, and a pharmaceutically acceptable carrier.

Another object of the present invention is a set of components, including (R)-dimiracetam (1) and (S)-dimiracetam (2), and instructions for combining (R)-dimiracetam (1) and (S)-dimiracetam (2) with obtaining an enantiomeric excess (EI) of the specified (R)-dimiracetam (1), greater than or equal to 30% and less than or equal to 60%. In this aspect, the same preferred ranges for the enantiomeric excess (EI) of said (R)-dimiracetam (1) and the ratios of the enantiomers of (R)-dimiracetam (1) and (S)-dimiracetam (2) apply as specified in the present invention in regarding composition.

Another object of the present invention is a composition of the present invention, or a pharmaceutical composition of the present invention, or a kit of the present invention for use as a medicine.

Another object of the present invention is 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 a disease or disorder, where the disease or disorder is usually and preferably selected from number of the following: peripheral sensory neuropathy, preferably peripheral neuropathic pain and other symptoms of peripheral sensory neuropathy; and neuropsychiatric pathological conditions such as seizure; depression or cognitive impairment; and motor neuron diseases such as amyotrophic lateral sclerosis.

Another object of the present invention is a method of treating and/or preventing a disease or disorder in an animal, preferably a human, where the disease or disorder

- 6 041317 usually and preferably selected from among the following: peripheral sensory neuropathy, preferably peripheral neuropathic pain and other symptoms of peripheral sensory neuropathy; and neuropsychiatric pathological conditions such as seizure; depression or cognitive impairment; and motor neuronal diseases such as amyotrophic lateral sclerosis, wherein said method comprises administering to an animal, preferably a human, a composition of the present invention or a pharmaceutical composition of the present invention or a kit of the present invention.

Another object of the present invention is the use of a composition of the present invention, or a pharmaceutical composition of the present invention, or a kit of the present invention, for the preparation of a medicament for the treatment and/or prevention of a disease or disorder, where the disease or the disorder is usually and preferably selected from the following: peripheral sensory neuropathy, preferably peripheral neuropathic pain and other symptoms of peripheral sensory neuropathy; and neuropsychiatric pathological conditions such as seizure; depression or cognitive impairment; and motor neuron diseases such as amyotrophic lateral sclerosis.

Another object of the present invention is a finished product comprising a composition of the present invention, or a pharmaceutical composition of the present invention, a container or packaging and a written description and instructions for administration, such as a leaflet.

It should be understood that the composition of the present invention contains a non-racemic mixture of the present invention, thus any reference to a composition of the present invention should also be understood as a reference to a non-racemic mixture of the present invention.

Other objects and embodiments of the present invention will become clear from the following present description.

Description of figures

Fig. 1A: Effect of increasing the molar concentration of the composition of the present invention, having an enantiomeric excess of (R)-dimiracetam, equal to 33.3% (corresponding to the ratio of enantiomers (R):(S), equal to 2:1), caused by NMDA ( 10 μM) and glycine (1 μM) release of preloaded [ ³ H]-D-Asp from spinal cord synaptosomes.

Fig. 1B: Effect of increasing the molar concentration of the composition of the present invention, having an enantiomeric excess of (R)-dimiracetam equal to 50% (corresponding to the ratio of enantiomers (R):(S), equal to 3:1), caused by NMDA (10 μm ) and glycine (1 μM) release of preloaded [ ³ H]-D-Asp from spinal cord synaptosomes.

Fig. 1B: Effect of increasing the molar concentration of dimiracetam racemate on NMDA (10 μM) and glycine (1 μM) induced release of preloaded [ ³ H]-D-Asp from spinal cord synaptosomes.

Fig. 1D: Effect of increasing molar concentration of (R)-dimiracetam on NMDA (10 μM) and glycine (1 μM) induced release of preloaded [ ³ H]-D-Asp from spinal cord synaptosomes.

Fig. 1E: Effect of increasing molar concentration of (S)-dimiracetam on NMDA (10 μM) and glycine (1 μM) induced release of preloaded [ ³ H]-D-Asp from spinal cord synaptosomes.

In FIG. 1A-E, the results are presented as a % increase in release over baseline release, and the results are the averages obtained from 3 times 6 experiments±SPS (standard error of the mean).

Fig. 2: Comparison of the antihyperalgesic effect of a single dose of the composition of the present invention having an enantiomeric excess of (R)-dimiracetam equal to 50% (corresponding to an enantiomeric ratio of (R):(S) equal to 3:1) and the effect of the dimiracetam racemate and the composition having an excess of the (S)-enantiomer of dimiracetam at a (R):(S) ratio of 1:3 in a rat model of MIA-induced osteoarthritis. The pain threshold was determined using the Randal and Selito algesimeter. The results are expressed in grams and each value is the mean value ± ATP for 20 rats. **P<0.01 compared to solvent-MIA mixture.

Fig. 3: Effect of repeated oral administration of a composition of the present invention having an enantiomeric excess of (R)-dimiracetam of 50% (corresponding to an enantiomeric ratio of (R):(S) of 3:1) and dimiracetam racemate on oxaliplatin-induced mechanical hyperalgesia. Pain threshold was determined with a Randal and Selito algesimeter prior to morning administration, and each value is the mean ± SPS for 6 rats. *P<0.05 and **P<0.01 compared to animals treated with oxaliplatin + vehicle; °P<0.05 and °°P<0.01 compared with a mixture of oxaliplatin + 15 mg/kg dimiracetam; #P<0.05 and ^## P<0.01 compared to a mixture of oxaliplatin + 50 mg/kg dimiracetam.

Fig. 4A: Comparison of (R)-enantiomer plasma concentration versus time after oral administration of (R)-dimiracetam (75 mg/kg) and after oral administration of racemic dimiracetam (150 mg/kg).

Fig. 4B: Comparison of (S)-enantiomer plasma concentration versus time after oral administration of (S)-dimiracetam (2) (75 mg/kg) and after oral administration of racemic dimiracetam (150 mg/kg).

In FIG. 4A and 4B show that the in vivo pharmacological superiority of the compositions of the present invention is not due to pharmacokinetic differences.

Fig. 5: Inhibition of NMDA and glycine induced release of [ ³ H]-D-aspartate (square) by racemic dimiracetam (circle) and five different enantiomeric mixtures (circles at an R:S ratio of 2:1 to 4:1). These results are obtained in example 5.

Fig. 6: Passive avoidance test. Dimiracetam enantiomeric mixtures having three different R:S ratios (1:1, 2:1, and 3:1) were administered orally at a dose of 3, 10, or 30 mg/kg 30 min prior to reflex training on day 1 Immediately after the shock on day 1, scopolamine (1.5 mg/kg, ip) was administered by injection. The value of the latent period, determined during the development of the reflex, was comparable for all groups (approximately 15 s). On day 2, memory testing was performed, and latency values are given as columns.

The results are given as the average of the values obtained for 12 mice studied in two different groups, ± ATP. **P<0.01 compared to a mixture of solvent + solvent (solvent); *P<0.05 and **P<0.01 compared to scopolamine + diluent (scopolamine).

Fig. 7: Forced dive test. Dimiracetam enantiomeric mixtures having three different R:S ratios (1:1, 2:1 and 3:1) were administered orally at a dose of 10, 30 or 100 mg/kg 25 minutes prior to the test. Mice were placed in water-containing glass cylinders for 6 minutes, during the last 4 minutes the duration of movement was determined. The results are given as the average of the values obtained for 12 mice studied in two different groups, ± ATP. *P<0.05 and **P<0.01 compared to vehicle+vehicle (indicates those animals treated with vehicle in place of scopolamine and then re-injected with vehicle in place of test compound).

Detailed description of the invention

Unless other definitions are given, all technical and scientific terms used in the present invention have the same meanings as known to a person with a general background in the technical field to which the present invention pertains.

The term approximately when used to characterize the enantiomeric excess means ±4% of the given numerical value, unless otherwise indicated. In each of the embodiments of the present invention, the word may approximately be deleted.

The term is preferably used to describe features or embodiments that are not necessary in the present invention but may provide improved technical effects and thus are desirable rather than mandatory.

With regard to the numerical values given in the present invention, unless expressly indicated otherwise, it is preferable if the last decimal place of the numerical value characterizes the degree of its accuracy. Thus, unless other tolerances are specified, it is preferable if the maximum error value is set by using the rounding rule to the last decimal place. Thus, it is preferable if a value of 2.5 has a margin of error between 2.45 and 2.54.

The present invention relates to compositions containing (R)-3,6,7,7a-tetrahydro-1Hnirrolo[1,5-a]umidazole-2,5-dione ((R)-dimiracetam (1)) and (S) -3,6,7,7a-tetrahydro-1H-pyrrolo[1,5a]imidazole-2,5-dione ((S)-dimiracetam (2)) in a certain ratio. It should be understood that the term composition does not mean the requirement that (R)-dimiracetam (1) and (S)-dimiracetam (2) must be mixed. They can be prepared together or separately and administered simultaneously or sequentially, provided that the ratio of (R)-dimiracetam (1) and (S)-dimiracetam (2) required in the present invention is provided to the subject being treated. Preferably, if the composition of the present invention is a mixture of (R)-dimiracetam (1) and (S)-dimiracetam (2), however, the composition of the present invention may also include a combination of one or more products containing (R)-dimiracetam (1) and one or more products containing (S)-dimiracetam (2), or a combination of one or more products containing (R)-dimiracetam (1) and one or more products containing racemate dimiracetam.

In addition, the dimiracetam contained in the composition of the present invention should be contained in the overall range of ratios of (R)-dimiracetam (1) and (S)-dimiracetam (2), alternatively expressed as an enantiomeric excess of (R)-dimiracetam (1 ) required in the present invention. In other words, the theoretical division of a composition containing equal amounts of (R)-dimiracetam (1) and (8)-dimiracetam (2) into a component containing an excess of (R)-dimiracetam (1) and another component containing an excess of (8 )-dimiracetam (2), contrary to the essence of the present invention. Thus, whatever the physical form of the composition proposed in the present invention, the composition as a whole must satisfy the requirements described in the present invention for the range of ratios of (K)-dimiracetam (1) and (8)-dimiracetam (2), alternatively expressed as an enantiomeric excess of (R)-dimiracetam (1). It should be understood that the ratios of (R)-dimiracetam (1) and (8)-dimiracetam (2), alternatively expressed as an enantiomeric excess of (R)-dimiracetam (1), are based on a statistically significant number of dimiracetam molecules, which usually exceeds 1000 molecules dimiracetam. In the present invention, the relative amounts of (R)-dimiracetam (1) and (8)-dimiracetam (2) are expressed either as the ratio of (R)-dimiracetam (1) and (8)-dimiracetam (2), or as an enantiomeric excess (R)-dimiracetam (1).

It should be understood that the ratio of (R)-dimiracetam (1) and (8)-dimiracetam (2) when used in the present invention means the weight ratio of (R)-dimiracetam (1) and (8)-dimiracetam (2), unless explicitly not otherwise specified. If solvates of (R)-dimiracetam (1) and/or (8)-dimiracetam (2) are used, then the solvent should be excluded from this calculation. In other words, the ratio of (R)-dimiracetam (1) and (8)-dimiracetam (2) is calculated as follows:

The ratio of (K)-dimiracetam mass amount of (R)-dimiracetam (1) (1) and (3)-dimiracetam (2) mass amount of (3)-dimiracetam (2)

As will be known to those skilled in the art, the ratio of compounds differing only in chirality, as in the case of (K)-dimiracetam (1) and (8)-dimiracetam (2), can be determined using a number of techniques known in the art, including , but not limited to, chromatography using a chiral support, polarimetric examination of the rotation of the plane of polarized light, nuclear magnetic resonance spectroscopy using chemical shifts of chiral reagents, or derivatization of a compound using a chiral compound such as Mosher's acid, followed by chromatography or spectroscopy nuclear magnetic resonance. Enantiomers can also be isolated from mixtures by techniques known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and direct fractional crystallization of the racemate, i.e. dimiracetam, according to the methods of co-crystallization of chiral compounds, which use the occurrence of hydrogen-bonding interactions in co-crystals (see Springuel G.R., et al., 2012; and US patent No. 6570036). Suitable components for co-crystallization include the enantiomers of mandelic acid, malic acid, tartaric acid and its derivatives, or the enantiomers can be obtained by asymmetric synthesis. See, for example, Eliel and Wilen, 1994.

The ratio of (B)-dimiracetam (1) and (8)-dimiracetam (2) (which may also be referred to as chiral purity) contained in a composition of the present invention, such as a non-racemic mixture, may be expressed as an enantiomeric excess (EI) , usually and preferably determined by chiral HPLC (detailed in the examples) and calculated from the equation:

EI = (A _r - A _s )/(A _r + A _s )xl00%, in which A _r denotes the peak area of (B)-3,6,7,7a-tetrahydro-1H-pyrrolo[1,5-a ]imidazole-2,5dione, i.e. (B)-enantiomer of (1) dimiracetam, in the HPLC chromatogram obtained from a sample solution; And

A _s denotes the peak area of (8)-3,6,7,7a-tetrahydro-1H-pyrrolo[1,5-a]imidazole-2,5-dione, i.e. (8)-enantiomer of (2) dimiracetam, in the HPLC chromatogram obtained from a sample solution.

In this regard, it should be noted that although chiral purity has been described above, it is not the essence of the present invention to provide high chiral purity of (B)-dimiracetam (1) or (8)-dimiracetam (2). Instead, the essence of the present invention is that a certain range of ratios of (B)-dimiracetam (1) and (8)-dimiracetam (2) provides a particularly significant synergistic effect. In contrast to cases in which only the purity of the compound needs to be improved, i.e. in which the goal is known, namely the preparation of one particular compound, ideally having a purity of 100%, the present invention is based on a previously unknown ratio of two compounds, namely ^)-dimiracetam (1) and (8)-dimiracetam (2) .

The term "pharmaceutically acceptable" means that the compound or composition, usually and preferably solvates, co-crystals or carriers, must be chemically or toxicologically compatible with the other ingredient(s), usually and preferably with the composition according to the present invention, if they are usually and preferably used. together with it in a preparation, or if they are usually and preferably used together with it in the treatment of an animal,

-9041317 preferably human. Preferably, if the term pharmaceutically acceptable means that the compound or composition, usually and preferably solvates, co-crystals or carriers, must be chemically or toxicologically compatible with other ingredient (s), usually and preferably with the composition proposed in the present invention, if they are usually and preferably used together with it in the preparation or if they are usually and preferably used together with it for the treatment of an animal, preferably a human. It should be noted that the pharmaceutical compositions can be formulated according to methods known to those skilled in the art, such as those described in Remington: The Science and Practice of Pharmacy, Pharmaceutical Press, 22 edition.

The term solvate means an associate or complex formed by one or more solvent molecules and the (R)-enantiomer (1) of dimiracetam or the (S)-enantiomer (2) of dimiracetam. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, and ethanolamine.

The term hydrate means a complex in which the solvent molecule is a water molecule.

The term co-crystal means a crystalline structure that contains at least two different compounds that are solid in their pure form under ambient conditions. At least two different compounds may include (R)-dimiracetam (1), and/or (S)-dimiracetam (2), and/or any other components contained in the composition, or excipients contained in the pharmaceutical composition. Co-crystals are obtained from neutral molecules of substances, and all substances remain neutral after crystallization; in addition, usually and preferably, if they are materials having a homogeneous crystalline phase, in which two or more compounds forming the structure are contained in a certain stoichiometric ratio. See Wang Y. and Chen A., 2013; and Springuel G.R., et al., 2012; and US Pat. No. 6,570,036. It should be understood that (R)-dimiracetam (1) and/or (S)dimiracetam (2) may be in any polymorphic form. A range of co-crystals and co-crystal techniques are described in the 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 chapters 15 and 16 Preferred examples of co-crystal-forming compounds are shown in this publication in Table. 16.1. Even more preferred co-crystals include co-crystals formed by α-hydroxy acids, α-keto acids and/or α-ketoamides with dimiracetam enantiomers in the (R):(S) ratios disclosed in the present invention. Examples of α-hydroxy acids include atrolactic acid, benzyl 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-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, sugar 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 (methylbenzoylformate), ethyl 2-phenyl-2-ketoethanoate (ethylbenzoylformate), 3-phenyl-2 -ketopropanoic acid (phenylpyruvic acid), methyl 3-phenyl-2-ketopropanoate (methylphenylpyruvate), ethyl 3-phenyl2-ketopropanoate (ethylphenylpyruvate), 2-ketobutanoic acid, 2-ketopentanoic acid, 2-ketohexanoic acid, 2-ketoheptanoic acid acid, 2-ketooctanoic acid, 2-ketododecanoic acid and methyl 2-ketooctanoate. Examples of α-ketoamides include any compounds obtained by reacting any of the above exemplified α-keto acids with primary or secondary amines.

The first object of the present invention is a composition containing (E)-3,6,7,7atetrahydro-1H-pyrrolo[1,5-a]imidazole-2,5-dione ((R)-dimiracetam (1)) and (S )-3,6,7,7a-tetrahydro-1Нpyrrolo[1,5-a]imidazole-2,5-dione ((S)-dimiracetam (2)):

- 10 041317

S/ ^H o o (1) (2) and/or pharmaceutically acceptable solvates or co-crystals thereof, wherein the enantiomeric excess (EI) of said (R)-dimiracetam (1) is greater than or equal to 30% and less than or equal to 60%.

This composition, as well as any other compositions and pharmaceutical compositions of the present invention, preferably inhibit NMDA and glycine induced release of [ ³ H]-D-aspartic acid from rat spinal cord synaptosomes by at least about 36%, preferably at least than about 40%, more preferably not less than about 45%, even more preferably about 50%, at a concentration of about 10 nM. A study designed to determine this parameter is shown in example 5.

One example of such a composition is a non-racemic mixture of 3,6,7,7a-tetrahydro-1Hpyrrolo[1,5-a]imidazole-2,5-dione and pharmaceutically acceptable solvates or co-crystals thereof, wherein said non-racemic mixture contains (R)- 3,6,7,7a-tetrahydro-1H-pyrrolo[1,5a]imidazole-2,5-dione ((H)-dimiracetam (1)) and (S)-3,6,7,7a-tetrahydro- 1H-pyrrolo[1,5-a]imidazole-2,5dione ((S)-dimiracetam (2)) with an enantiomeric excess (EI) of (R)-dimiracetam (1) greater than or equal to 30% and less than or equal to 60 %.

In general, non-solvated and co-crystallized compositions are preferred. More preferred are unsolvated and co-crystallized compositions.

Thus, another object of the present invention is a composition containing 3,6,7,7a-tetrahydro-1H-pyrrolo[1,5-a]imidazole-2,5-dione, where the specified composition contains (R)-3,6 ,7,7a-tetrahydro-1H-pyrrolo[1,5-a]imidazole-2,5-dione ((R)-dimiracetam (1)) and (S)-3,6,7,7a-tetrahydro-1H-pyrrolo [1,5-a]imidazole-2,5-dione ((S)-dimiracetam (2)) with an enantiomeric excess (EI) of (R)-dimiracetam (1) greater than or equal to 30% and less than or equal to 60% .

More preferably, said enantiomeric excess (EI) of said (R)-dimiracetam (1) is greater than or equal to 30% and less than or equal to about 54%. Even more preferably, said enantiomeric excess (EI) of said (R)-dimiracetam (1) is greater than or equal to 30% and less than or equal to 54%.

More preferably, said enantiomeric excess (EI) of said (R)-dimiracetam (1) is greater than or equal to about 33% and less than or equal to about 54%. Even more preferably, said enantiomeric excess (EI) of said (H)-dimiracetam (1) is greater than or equal to 33% and less than or equal to 54%.

More preferably, said enantiomeric excess (EI) of said (R)-dimiracetam (1) is greater than or equal to 30% and less than or equal to about 53%. Even more preferably, said enantiomeric excess (EI) of said (R)-dimiracetam (1) is greater than or equal to 30% and less than or equal to 53%.

More preferably, said enantiomeric excess (EI) of said (R)-dimiracetam (1) is greater than or equal to about 33% and less than or equal to about 53%. Even more preferably, said enantiomeric excess (EI) of said (H)-dimiracetam (1) is greater than or equal to 33% and less than or equal to 53%.

Even more preferably, said enantiomeric excess (EI) of said (R)-dimiracetam (1) is greater than or equal to about 33% and less than or equal to about 50%. Even more preferably, said enantiomeric excess (EI) of said (R)-dimiracetam (1) is greater than or equal to 33% and less than or equal to 50%.

More preferably, said enantiomeric excess (EI) of said (R)-dimiracetam (1) is greater than or equal to about 30% and less than or equal to about 50%. Even more preferably, said enantiomeric excess (EI) of said (R)-dimiracetam (1) is greater than or equal to 30% and less than or equal to 50%.

More preferably, said enantiomeric excess (EI) of said (R)-dimiracetam (1) is greater than or equal to about 35% and less than or equal to about 54%, and preferably less than or equal to about 53%. Even more preferably, said enantiomeric excess (EI) of said (R)-dimiracetam (1) is greater than or equal to 35% and less than or equal to 54%, preferably less than or equal to 53%.

More preferably, if the specified enantiomeric excess (EI) of the specified

- 11 041317 (R)-dimiracetam (1) is greater than or equal to about 40% and less than or equal to about 54%, preferably less than or equal to about 53%. Even more preferably, said enantiomeric excess (EI) of said (R)-dimiracetam (1) is greater than or equal to 40% and less than or equal to 54%, preferably less than or equal to 53%.

More preferably, said enantiomeric excess (EI) of said (R)-dimiracetam (1) is greater than or equal to about 45% and less than or equal to about 54%, preferably less than or equal to about 53%. Even more preferably, said enantiomeric excess (EI) of said (R)-dimiracetam (1) is greater than or equal to 45% and less than or equal to 54%, preferably less than or equal to 53%.

Even more preferably, said enantiomeric excess (EI) of said (R)-dimiracetam (1) is selected from the following: about 33%, about 35%, about 37%, about 39%, about 41%, about 43%, about 45%, about 47%, about 50% and about 53%. Even more preferably, said enantiomeric excess (EI) of said (R)-dimiracetam (1) is selected from the following: 33%, 35%, 37%, 39%, 41%, 43%, 45%, 47%, 50% and 53%.

Even more preferably, said enantiomeric excess (EI) of said (R)-dimiracetam (1) is about 50%.

Even more preferably, said enantiomeric excess (EI) of said (R)-dimiracetam (1) is 50%.

As is known to the person skilled in the art, instead of indicating an enantiomeric excess, an indication of the ratio of (R)-dimiracetam (1) and (S)-dimiracetam (2) can be given.

The preferred ranges for the ratios of (R)-dimiracetam (1) and (S)-dimiracetam (2) are from 2:1 to 3.5:1, preferably from 2:1 to 3.3:1, more preferably from 2, 0:1.0 to 3.3:1.0, even more preferably 2.00:1.00 to 3.30:1.00.

Other preferred ranges are 2.0:1.0 to 3.25:1.0, 2.00:1.00 to 3.25:1.00, 2:1 to 3:1, 2 0:1.0 to 3.0:1.0 and 2.00:1.00 to 3.00:1.00.

Other preferred ranges include 2.3:1 to 3.3:1, 2.6:1 to 3.3:1, 2.7:1 to 3.2:1, 2.8:1 up to 3.2:1, from 2.9:1 to 3.1:1, as well as 3:1 and 3.0:1.0.

Other preferred ranges include 2.1:1 to 2.9:1, 2.2:1 to 2.8:1, 2.3:1 to 2.7:1, 2.4:1 up to 2.6:1, as well as 2.5:1 and 2.5:1.0.

Another object of the present invention is a pharmaceutical composition containing the composition proposed in the present invention, and a pharmaceutically acceptable carrier.

Another object of the present invention is a set of components, including (R)-dimiracetam (1) and (S)-dimiracetam (2), and instructions for combining (R)-dimiracetam (1) and (S)-dimiracetam (2) to obtain enantiomeric excess (EI) of said (R)-dimiracetam (1) greater than or equal to 30% and less than or equal to 60%.

In the following description, it should be understood that when the use of the composition of the present invention is described, the kit of the present invention may alternatively be used. One of skill in the art will appreciate that the components of the kit may be combined prior to administration, and this is preferred, or the components of the kit may be administered separately. In the latter case, to ensure the results provided by the present invention, the components of the kit should usually be administered at intervals of no more than 30 minutes.

Another object of the present invention is a composition of the present invention, or a pharmaceutical composition of the present invention, or a kit of the present invention for use as a medicine.

Another object of the present invention is a composition according to the present invention, or a pharmaceutical composition according to the present invention, or a kit according to the present invention, intended for use in the treatment or prevention of a large number of diseases and disorders, such as the following:

a) to prevent or treat positive symptoms of peripheral neuropathy, including sensitivity to cold, tingling, burning or aching sensations such as those associated with chemotherapy, anticancer treatment, viral infection and treatment for viral infection, postherpetic neuralgia, osteonecrosis, trigeminal neuralgia, or diabetic peripheral neuropathy, including primary allodynia, secondary allodynia, or other types of pain or discomfort associated with sensitization of the spinal cord or higher brain structures or neural pathways;

b) for the prevention or treatment of pain, including bone and joint pain, osteonecrosis pain, repetitive pain on movement, toothache, dysmenorrhea pain, cancer pain, myofascial pain, operative pain, perioperative pain, and postoperative pain syndromes such as pain syndrome after mastectomy, pain syndrome after thoracotomy, or pain in the stump, as well as pain associated with angina pectoris, pain associated with neuroma, complex regional pain syndrome, chronic pelvic pain, chronic pain in the lower back;

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c) to prevent or treat inflammatory pain such as pain in osteoarthritis, rheumatoid arthritis, rheumatism, chronic arthritis and related neuralgias, tendosynovitis and gout;

d) for the prevention or treatment of neuropathic pain, such as pain caused by chemotherapy, pain after traumatic injury, pain after crush injury, pain in painful traumatic mononeuropathy, pain in painful polyneuropathy, pain due to spinal cord injury, lumbago, compression or pinching nerve pain, lumbosacral pain, pain of trigeminal neuralgia, migraine and migraine headache, pain of postherpetic neuralgia, phantom pain in amputees, postherpetic pain, pain of diabetic neuropathy, central pain syndrome caused by damage at any level of the peripheral nervous system ;

e) for the prevention or treatment of neuropsychiatric disorders. Examples of neuropsychiatric disorders include schizophrenia, psychosis including schizophrenia, schizophrenia-like disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, substance use disorder, paranoid schizophrenia, disorganized schizophrenia, catatonic schizophrenia or undifferentiated schizophrenia, substance-induced psychiatric disorder, substance abuse and addictive behavior;

f) epilepsy and other seizures, focal and generalized;

g) obesity or other eating disorders associated with excessive food intake, bulimia nervosa;

h) post-stroke cerebral insufficiency, cerebral edema, cerebral ischemia, cerebral hemorrhage, neurodegenerative diseases, bypass surgery and heart transplant, perinatal hypoxia, cardiac arrest and hypoglycemic brain damage;

i) sleep disorders such as insomnia, narcolepsy or restless leg syndrome;

j) anxiety disorders such as affective disorder, 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 ;

k) mood disorders such as depression, anhedonia, unipolar depression, bipolar disorder, psychotic depression;

l) addiction to substance use, drug or drug dependence, tolerance, dependence on or withdrawal from substances, including alcohol, amphetamines, marijuana, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, sleeping pills or tranquilizers;

m) cognitive impairment, such as age-related cognitive decline, or cognitive impairment, such as various types of dementia associated with Alzheimer's disease, ischemia, trauma, vascular problems or stroke, HIV disease (human immunodeficiency virus), Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, chemotherapy, perinatal hypoxia, other general pathological conditions or substance abuse;

n) Parkinson's disease, including drug-induced parkinsonism or post-encephalitic parkinsonism;

o) Attention deficit disorders such as attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder, phobia, post-traumatic stress disorder, autism and autism spectrum disorders, impulse control disorder;

p) tinnitus, presbycusis;

q) improvement of learning ability and memory;

r) for the prevention or treatment of hereditary or sporadic motor neuron diseases. Their examples include amyotrophic lateral sclerosis, primary lateral sclerosis, progressive muscle atrophy, progressive bulbar palsy, Friedreich's ataxia, fragile chromosome syndrome;

s) for the prevention or treatment of movement disorders. Examples thereof include dystonia, chorea, including Huntington's chorea, dystonia associated with Parkinson's disease, Creutzfeldt-Jakob disease, progressive supranuclear palsy, multisystem atrophy, corticobasal degeneration, calcification of the basal nuclei of the brain;

t) akinesias such as akinetic-rigid syndromes,

u) dyskinesias such as 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

- 13 041317 postural tremor, including resting tremor, postural tremor and intention tremor, chorea (such as Sydenham's chorea, Huntington's disease, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea and hemiballismus), generalized or focal myoclonus, tics (including simple tics, complex tics and symptomatic tics), and dystonia (including generalized dystonia such as idiopathic dystonia, drug-induced dystonia, symptomatic dystonia and paroxysmal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, spastic dysphonia, spastic torticollis, axial dystonia, dystonic graphospasm and hemiplegic dystonia), muscle spasms and disorders associated with muscle spasticity or weakness, including tremors;

v) Urinary incontinence, multiple system atrophy, tuberous sclerosis, olivo-pons-cerebellar atrophy, cerebral palsy, drug-induced optic neuritis, ischemic retinopathy, diabetic retinopathy, glaucoma, spasticity, myoclonus and dyskinesias associated with Tourette's syndrome.

It should be understood that the above list of diseases is provided only to provide specific examples and should not be understood as limiting the present invention. Of the diseases listed above, one or more of those listed in a), e), q), r) and s) are preferred.

The disease or disorder is usually and preferably selected from the following: peripheral sensory neuropathy, preferably peripheral neuropathic pain and other symptoms of peripheral sensory neuropathy; and neuropsychiatric pathological conditions such as seizure; depression or cognitive impairment; and motor neuron diseases such as amyotrophic lateral sclerosis.

In addition, the compositions of the present invention can also be used to improve learning and memory in healthy subjects, such as for non-therapeutic use.

Another object of the present invention is a method of treating and/or preventing a disease or disorder, where the disease or disorder is usually and preferably selected from the following: peripheral sensory neuropathy, preferably peripheral neuropathic pain and other symptoms of peripheral sensory neuropathy; and neuropsychiatric pathological conditions such as seizure; depression or cognitive impairment; and motor neuronal diseases such as amyotrophic lateral sclerosis, wherein said method comprises administering a composition of the present invention or a pharmaceutical composition of the present invention or a kit of the present invention.

It is also an object of the present invention to provide a method for treating a disease or disorder, wherein an animal, preferably a human, in need thereof is administered a composition of the present invention, or a pharmaceutical composition of the present invention, or a kit of the present invention, in a therapeutically effective form. quantity. In this case, the term "therapeutically effective amount" means an amount sufficient to modulate one or more of the symptoms of the condition or disease being treated, preferably from 10 to 3000 mg for each administration administered orally once a day or twice a day, or three times a day. Furthermore, it is also an object of the present invention to provide a method for preventing a disease or disorder, wherein an animal, preferably a human, that is reasonably believed to be in need, is administered a composition of the present invention or a pharmaceutical composition of the present invention, or a kit according to the invention in a therapeutically effective amount. In this case, the term therapeutically effective amount means an amount sufficient to modulate one or more of the expected symptoms of the pathological condition, preferably from 10 to 3000 mg for each administration administered orally once a day or twice a day, or three times a day. .

Another object of the present invention is the use of a composition of the present invention, or a pharmaceutical composition of the present invention, or a kit of the present invention, for the preparation of a medicinal product intended for use in the treatment and/or prevention of a disease or disorder, where the disease or disorder is usually and preferably selected from the following: peripheral sensory neuropathy, preferably peripheral neuropathic pain and other symptoms of peripheral sensory neuropathy; and neuropsychiatric pathological conditions such as seizure; depression or cognitive impairment; and motor neuron diseases such as amyotrophic lateral sclerosis.

It is also an object of the present invention to administer a composition of the present invention, or a pharmaceutical composition of the present invention, together

- 14 041317 but with active active substances or active agents, respectively, the action of which leads to side effects such as peripheral neuropathic pain and other symptoms of peripheral neuropathy, preferably together with antitumor and antiviral drugs. Preferably, the composition or pharmaceutical composition or kit is used alone or together with at least one antitumor drug or at least one antiviral drug. More preferably, the composition or pharmaceutical composition or kit is used separately. More preferably, the composition or pharmaceutical composition or kit is used together with at least one anticancer drug. Alternatively, it is preferred if the composition or pharmaceutical composition or kit is used with at least one antiviral drug.

It is further preferred if the composition or pharmaceutical composition or kit is co-administered with at least one anticancer drug or at least one antiviral drug, wherein said co-administration of said composition or said pharmaceutical composition with said at least one an antitumor drug or with said at least one antiviral drug is carried out together, simultaneously, sequentially or separately.

Non-limiting examples of such anticancer drugs are selected from the group consisting of the following: kinase inhibitor, proteasome inhibitor, taxane, vinca alkaloid, and platinum salt. Non-limiting examples of such antiviral drugs are selected from the following: nucleoside analog or nucleotide analog. Further preferably, said antitumor drug is selected from the group consisting of the following: a kinase inhibitor, a proteasome inhibitor, a taxane, a vinca alkaloid, and a platinum salt. Preferably, said anticancer drug is selected from among the following: sorafenib, sunitinib, afatinib, axitinib, vandetanib, vemurafenib, ixazomib, bortezomib, paclitaxel, docetaxel, cabazitaxel, vincristine, vinblastine, vindesin, vinorelbine, nedaplatin, lobaplatin, picoplatin, satraplatin, cisplatin, carboplatin and oxaliplatin. Preferably, said antiviral drug is selected from among the following: zalcitabine, didanosine, stavudine and zidovudine.

Preferably, the composition or pharmaceutical composition or kit is used together with at least one antiviral drug, where preferably, if said antiviral drug is selected from the following: nucleoside or nucleotide, and where more preferably, if said antiviral drug is selected of the following: zalcitabine, didanosine, stavudine, or zidovudine.

Preferably, said disease or disorder is a seizure. Alternatively, preferably, if said disease or disorder is depression. More preferably, said disease or disorder is a cognitive impairment. Even more preferably, said disease or disorder is peripheral sensory neuropathy. Even more preferably, said disease or disorder is peripheral neuropathic pain.

More preferably, said disease or disorder is peripheral sensory neuropathy, wherein said peripheral sensory neuropathy is selected from the group consisting of the following:

(i) diabetic neuropathy, (ii) postherpetic neuropathy, (iii) lumbago, (iv) lumbosacral pain, (v) operative pain, (vi) crush injury, (vii) spinal cord injury, (viii) complex regional pain syndrome, (ix) amputee sensation, (x) peripheral sensory neuropathy associated with osteoarthritis, (xi) peripheral sensory neuropathy associated with rheumatoid arthritis, (xii) peripheral sensory neuropathy associated with autoimmune osteoarthritis, (xiii) severe headache, (xiv) fibromyalgia, (xv) peripheral sensory neuropathy due to anti-tumor agents, (xvi) peripheral sensory neuropathy due to a chemotherapeutic agent, (xvii) peripheral sensory neuropathy due to visceral injury, (xviii) peripheral sensory neuropathy associated with osteonecrosis, (xix) peripheral sensory neuropathy associated with infection with vi Rusom immunodeficiency

- 15 041317 that human, and (xx) peripheral sensory neuropathy caused by an antiviral agent.

Preferably, said disease or disorder is peripheral sensory neuropathy, wherein said peripheral sensory neuropathy is selected from the group consisting of the following:

(i) diabetic neuropathy, (ii) postherpetic neuropathy, (iii) lumbago, (iv) lumbosacral pain, (v) operative pain, (vi) crush injury, (vii) spinal cord injury, (viii) complex regional pain syndrome, (ix) amputee sensation, (x) peripheral sensory neuropathy associated with osteoarthritis, (xi) peripheral sensory neuropathy associated with rheumatoid arthritis, (xii) peripheral sensory neuropathy associated with autoimmune osteoarthritis, (xiii) severe headache (xiv) fibromyalgia, (xv) peripheral sensory neuropathy due to drugs that inhibit tumor growth, (xvi) peripheral sensory neuropathy due to a chemotherapeutic agent, (xvii) peripheral sensory neuropathy associated with internal organ injury, (xviii) peripheral sensory neuropathy associated with osteonecrosis, (xix) peripheral sensory neuropathy associated with viral infection human immunodeficiency, (xx) antiviral-induced peripheral sensory neuropathy, and (xxi) peripheral neuropathic pain.

More preferably, said disease or disorder is peripheral sensory neuropathy, wherein said peripheral sensory neuropathy is diabetic neuropathy. Even more preferably, said disease or disorder is peripheral sensory neuropathy, wherein said peripheral sensory neuropathy is postherpetic neuropathy. Preferably, said disease or disorder is peripheral sensory neuropathy, wherein said peripheral sensory neuropathy is lumbago. More preferably, said disease or disorder is peripheral sensory neuropathy, wherein said peripheral sensory neuropathy is lumbosacral pain. More preferably, said disease or disorder is peripheral sensory neuropathy, wherein said peripheral sensory neuropathy is operative pain. More preferably, said disease or disorder is peripheral sensory neuropathy, wherein said peripheral sensory neuropathy is tissue crush injury. More preferably, said disease or disorder is peripheral sensory neuropathy, wherein said peripheral sensory neuropathy is spinal cord injury. More preferably, said disease or disorder is peripheral sensory neuropathy, wherein said peripheral sensory neuropathy is complex regional pain syndrome. More preferably, said disease or disorder is peripheral sensory neuropathy, wherein said peripheral sensory neuropathy is the sensation of having an amputated limb. More preferably, said disease or disorder is peripheral sensory neuropathy, wherein said peripheral sensory neuropathy is peripheral sensory neuropathy associated with osteoarthritis. More preferably, said disease or disorder is peripheral sensory neuropathy, wherein said peripheral sensory neuropathy is peripheral sensory neuropathy associated with rheumatoid arthritis. More preferably, said disease or disorder is peripheral sensory neuropathy, wherein said peripheral sensory neuropathy is peripheral sensory neuropathy associated with autoimmune osteoarthritis. More preferably, said disease or disorder is peripheral sensory neuropathy, wherein said peripheral sensory neuropathy is severe headache. More preferably, said disease or disorder is peripheral sensory neuropathy, wherein said peripheral sensory neuropathy is fibromyalgia. Even more preferably, said disease or disorder is peripheral sensory neuropathy, wherein said peripheral sensory neuropathy is peripheral sensory neuropathy induced by anti-tumor agents. Even more preferably, said disease or disorder is peripheral sensory neuropathy, wherein said peripheral sensory neuropathy is chemotherapeutic agent-induced peripheral sensory neuropathy. Even more preferably, said disease or disorder is peripheral sensory neuropathy, wherein said peripheral sensory neuropathy is peripheral sensory neuropathy associated with damage to an internal organ. Even more preferably, said disease or disorder is peripheral sensory neuropathy, wherein said peripheral sensory neuropathy is peripheral sensory neuropathy associated with osteonecrosis. Even more preferably, said disease or disorder is peripheral sensory neuropathy, wherein said peripheral sensory neuropathy is peripheral sensory neuropathy associated with human immunodeficiency virus infection. Even more preferably, said disease or disorder is peripheral sensory neuropathy, wherein said peripheral sensory neuropathy is antiviral-induced peripheral sensory neuropathy. More preferably, said disease or disorder is peripheral sensory neuropathy, wherein said peripheral sensory neuropathy is peripheral neuropathic pain.

Preferably, said peripheral sensory neuropathy is selected from among the following: chemotherapeutic agent-induced peripheral sensory neuropathy or antiviral agent-induced peripheral sensory neuropathy.

Even more preferably, said disease or disorder is chemotherapeutic agent-induced peripheral sensory neuropathy, wherein said chemotherapeutic agent is usually and preferably selected from the group consisting of a kinase inhibitor, a proteasome inhibitor, a taxane, a vinca alkaloid, and a platinum salt. Even more preferably, said disease or disorder is chemotherapeutic agent-induced peripheral sensory neuropathy, wherein said chemotherapeutic agent is selected from the group consisting of a kinase inhibitor, a proteasome inhibitor, a taxane, a vinca alkaloid, and a platinum salt. Even more preferably, said disease or disorder is chemotherapeutic agent-induced peripheral sensory neuropathy, wherein said chemotherapeutic agent is selected from the group consisting of the following: sorafenib, sunitinib, afatinib, axitinib, vandetanib, vemurafenib, ixazomib, bortezomib, paclitaxel, docetaxel, cabazitaxel, vincristine, vinblastine, vindesine, vinorelbine, nedaplatin, lobaplatin, picoplatin, satraplatin, cisplatin, carboplatin or oxaliplatin. Even more preferably, said disease or disorder is chemotherapeutic agent-induced peripheral sensory neuropathy, wherein said chemotherapeutic agent is selected from the group consisting of the following: sorafenib, vincristine, paclitaxel, or oxaliplatin. It is particularly preferred if said peripheral sensory neuropathy is caused by a chemotherapeutic agent, wherein said chemotherapeutic agent is sorafenib, paclitaxel, vincristine, cisplatin, carboplatin or oxaliplatin.

It is also preferred if said disease or disorder is peripheral sensory neuropathy induced by an antiviral agent, where preferably said antiviral agent is a nucleoside reverse transcriptase inhibitor. Even more preferably, said disease or disorder is antiviral-induced peripheral sensory neuropathy, wherein said antiviral agent is selected from zalcitabine, didanosine, stavudine, or zidovudine. Even more preferably, said disease or disorder is zalcitabine-induced peripheral sensory neuropathy.

Preferably, said chemotherapy-induced peripheral sensory neuropathy causes symptoms of allodynia or dysesthesia, more preferably hand or foot allodynia or dysesthesia, and more preferably sorafenib, vincristine, paclitaxel or carboplatin, cisplatin or oxaliplatin induced allodynia or hand or foot dysesthesia.

Even more preferably, said peripheral sensory neuropathy is associated with pain, paresthesias, dysesthesias, or allodynia.

It is also preferred if the composition of the present invention or the pharmaceutical composition of the present invention can be administered prophylactically, starting before the antitumor chemotherapeutic active has caused the peripheral sensory neuropathy and associated symptoms.

It is also preferred if the composition of the present invention or the pharmaceutical composition of the present invention can be administered intermittently. Further, in the present invention, it is preferable if the composition of the present invention or the pharmaceutical composition of the present invention can be administered simultaneously with repeated administration cycles of the antitumor chemotherapeutic active.

- 17 041317

The dose will depend on the route of administration, the severity of the disease, the age and body weight of the patient or subject, and other factors generally taken into account by the attending physician in determining the individual regimen and dosage for a particular patient or subject.

The composition or pharmaceutical composition of the present invention may be administered by any route, including oral, intramuscular, subcutaneous, topical, transdermal, nasal, intravenous, sublingual or intrarectal administration. The pharmaceutical composition of the present invention is usually and preferably administered orally in a single dosage form 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.

The oral dose of the composition of the present invention or the pharmaceutical composition of the present invention is usually and preferably 10 to 3000 mg each administration, more preferably 20 to 2000 mg each administration, even more preferably 50 to 1000 mg with every introduction. Said composition or said pharmaceutical composition is usually and preferably administered orally twice a day at a dose of 10 to 3000 mg each administration, more preferably 20 to 2000 mg each administration, even more preferably 50 to 1000 mg each administration. .

The pharmaceutical composition of the present invention can be prepared by mixing suitably selected and pharmaceutically acceptable excipients, solvents, excipients, additives, surfactants, desiccants or diluents known to those skilled in the art and can suitably be prepared in a form suitable for oral, parenteral or topical administration. The pharmaceutical composition of the present invention is usually and preferably administered in the form of a tablet, capsule, sachet, powder, granule, pellet, oral or parenteral solution, suspension, suppository, ointment, cream, lotion, gel, paste and/or they may contain liposomes, micelles and/or microspheres.

The pharmaceutically acceptable carrier contained in the pharmaceutical composition of the present invention, without limitation, can be any pharmaceutically acceptable excipient, solvent, excipient, additive, surfactant, desiccant or diluent. Suitable pharmaceutically acceptable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, gum tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter. Pharmaceutically acceptable carriers of the present invention may be solid, semi-liquid or liquid.

Tablets, capsules or sachets intended for oral administration are usually supplied in dosage form and may contain the usual excipients such as binders, excipients, diluents, tabletting agents, lubricants, dispersants, disintegrants, coloring agents, flavoring agents and wetting agents. Tablets can be coated by methods well known in the art. Suitable fillers include or are preferably cellulose, mannitol, lactose and similar agents. Suitable disintegrators include or are preferably starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate. Suitable lubricants include or are preferably, for example, magnesium stearate. Suitable wetting agents include or are preferably sodium lauryl sulfate. These solid compositions intended for oral administration may be prepared by conventional mixing, filling or tableting techniques. The mixing procedures can be repeated to disperse the active agent in compositions containing large amounts of excipients. These procedures are common.

Liquid compositions intended for oral administration may be in the form of, for example, aqueous solutions, emulsions, syrups or elixirs, or as a dry product to be reconstituted with water or other suitable liquid carrier before use. Liquid compositions may 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 may include edible oils) such as almond oil, fractionated coconut oil, oily esters such as esters of glycerol, propylene glycol or ethyl alcohol; preservatives, for example methyl or propyl phydroxybenzoate or sorbic acid, and optionally customary flavorings or colorants. Formulations for oral administration may also include or may be formulated as conventional preparations such as tablets or granules. For parenteral administration, liquid dosage forms can be prepared containing the composition of the present invention and a sterile carrier.

- 18 041317

Formulations for oral administration may optionally additionally contain taste masking agents to optimize the taste perception of the oral preparation. Examples of such flavor-masking components are citrus, licorice, mint, grape, blackcurrant or eucalyptus flavors known to those skilled in the art.

Solutions for parenteral administration are usually prepared by dissolving the compound in a carrier and sterilizing by filtration, then they are placed in suitable vials or ampoules and sealed.

Adjuvants such as local anesthetics, preservatives, and buffering agents may be added to the pharmaceutical composition. To increase the stability of the composition, it can be frozen after filling the vial and the water removed in vacuo. To facilitate uniform distribution of the composition of the present invention, a surfactant or wetting agent may preferably be included in the pharmaceutical composition.

Formulations for topical administration include or are preferably ointments, creams, lotions, gels, chewing gums, solutions, pastes, or they may contain liposomes, micelles or microspheres.

The subjects to be treated with the composition or pharmaceutical composition of the present invention are humans and animals. Preferred animals are domestic and farm animals, including, but not limited to, guinea pig, rabbit, horse, donkey, camel, cow, sheep, goat, pig, cat, dog, and parrot. More preferred subjects are mammals, even more preferably humans.

Another object of the present invention is a finished product comprising a composition of the present invention, or a pharmaceutical composition of the present invention, or a kit of the present invention, a container or package, and a written description and instructions for administration, such as a leaflet. .

It is further contemplated that compositions containing (R)-dimiracetam or (S)-dimiracetam and other racemates such as aniracetam, brivaracetam, cebaracetam, coluracetam, doliracetam, dupracetam, etiracetam/levetiracetam, phasoracetam, imiracetam, methylphenylpiracetam, nebracetam, nefiracetam, omberacetam (noopept), oxiracetam, phenylpiracetam, phenylpiracetamhydrazide, piracetam, pramiracetam, rolipram, rolziracetam and/or seletracetam can also be used to produce synergistic mixtures or compositions, especially if the ratio of (R)-dimiracetam or (S)- dimiracetam and other racetam is in the range disclosed in the present invention for mixtures of (R)-dimiracetam and (S)-dimiracetam.

In addition, it is envisaged that compositions containing (R)-dimiracetam or (S)-dimiracetam and other dimiracetam derivatives, such as those disclosed in US 7544705 or US 8334286, can also be used to obtain synergistic mixtures or compositions, especially if the ratio of (R)-dimiracetam or (S)-dimiracetam and dimiracetam-like compound or enantiomer of dimiracetam-like compound is in the range disclosed in the present invention for mixtures of (R)-dimiracetam and (S)-dimiracetam.

The present invention also relates to a method of treating and/or preventing a disease, injury, or disorder, comprising administering to a subject a composition described in claim 1 of the claims, where the disease, injury, or disorder is peripheral sensory neuropathy, seizure, depression, or cognitive impairment. In this method, it is preferred if the disease, injury, or disorder is a peripheral sensory neuropathy, neuropsychiatric disorder, motor neuron disorder, or movement disorder. More preferably, the disease, injury, or disorder is peripheral sensory neuropathy. Preferably, the peripheral sensory neuropathy is peripheral neuropathic pain. Preferably, the peripheral sensory neuropathy is selected from among the following: diabetic neuropathy, postherpetic neuropathy, lumbago, sciatica pain, operative pain, crush injury, spinal cord injury, complex regional pain syndrome, amputee sensation, peripheral sensory neuropathy, associated with osteoarthritis, peripheral sensory neuropathy associated with rheumatoid arthritis, peripheral sensory neuropathy associated with autoimmune osteoarthritis, severe headache, fibromyalgia, peripheral sensory neuropathy due to drugs that inhibit tumor growth, peripheral sensory neuropathy due to a chemotherapeutic agent, peripheral sensory neuropathy associated with damage to the internal organ, peripheral sensory neuropathy associated with osteonecrosis, peripheral sensory neuropathy associated with infection with immunodeficiency virus human, peripheral neuropathic pain or antiviral-induced peripheral sensory neuropathy. In some cases, peripheral sensory neuropathy is chemotherapeutic agent-induced peripheral sensory neuropathy or antiviral agent-induced peripheral sensory neuropathy. In some cases, peripheral sensory neuropathy is a peripheral

- 19 041317 sensory neuropathy induced by a chemotherapeutic agent, where the chemotherapeutic agent is selected from the group consisting of the following: a kinase inhibitor, a proteasome inhibitor, a taxane, a vinca alkaloid and a platinum salt, and where it is preferred if the chemotherapeutic agent is selected from the following: sorafenib, sunitinib , afatinib, axitinib, vandetanib, vemurafenib, ixazomib, bortezomib, paclitaxel, docetaxel, cabazitaxel, vincristine, vinblastine, vindesine, vinorelbine, nedaplatin, lobaplatin, picoplatin, satraplatin, cisplatin, carboplatin, and oxaliplatin. In some cases, peripheral sensory neuropathy is antiviral-induced peripheral sensory neuropathy, where the antiviral agent is a nucleoside reverse transcriptase inhibitor. In some cases, the nucleoside reverse transcriptase inhibitor is zalcitabine, didanosine, stavudine, or zidovudine.

In some instances, the method further comprises administering an anticancer drug, wherein the anticancer drug is selected from the group consisting of the following: a kinase inhibitor, a proteasome inhibitor, a taxane, a vinca alkaloid, and a platinum salt. In some cases, the anticancer drug is selected from the group consisting of the following: sorafenib, sunitinib, afatinib, axitinib, vandetanib, vemurafenib, ixazomib, bortezomib, paclitaxel, docetaxel, cabazitaxel, vincristine, vinblastine, vindesin, vinorelbine, nedaplatin, lobaplatin, picoplatin, satraplatin, cisplatin, carboplatin and oxaliplatin. In some instances, the method further comprises administering an antiviral drug, wherein the antiviral drug is a nucleoside or nucleotide. In some cases, the antiviral drug is zalcitabine, didanosine, stavudine, or zidovudine. In some instances, the composition is administered twice daily at a dose of 10 to 3000 mg each administration, 20 to 2000 mg each administration, or 50 to 1000 mg each administration.

In addition, the present invention relates to a method for improving the ability to learn and memory, including the introduction to the subject of the composition proposed in the present invention and described in the present invention. In some embodiments of this method, the subject is a healthy subject.

Non-patent publications cited in the present invention are indicated by the name of the first author and the year of publication. The full list of publications is given below.

Attal N, Cruccu G, Baron R, Haanpaa M, Hansson P, Jensen TS, Nurmikko T;

European Federation of Neurological Societies. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol. 2010

Sep;17(9):1113-e88. PMID: 20402746

Bradford MM. A rapid and sensitive method for the microquantitation of proteins. Anal Biochem.

1976 May 7;72:248-54. PMID: 942051

Bril V, England J, Franklin GM, Backonja M, Cohen J, Del Toro D, Feldman E,

Iverson DJ, Perkins B, Russell JW, Zochodne D; American Academy of Neurology;

American Association of Neuromuscular and Electrodiagnostic Medicine; American

Academy of Physical Medicine and Rehabilitation. Evidence-based guideline:

Treatment of painful diabetic neuropathy: report of the American Academy of

- 20 041317

Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation.

Neurology. 2011 May 17;76(20): 1758-65. Erratum in: Neurology. 2011 Aug 9;77(6):603. PMID: 21482920

Camilleri P, Eggleston D, Farina C, Murphy JA, Pfeiffer U, Pinza M, Senior LA. Chiral high-performance liquid chromatography of some related bicyclic lactams. Journal of Chromatography A, 654 (1993) 207-213.

Cavaletti G, Tredici G, Petruccioli MG, Donde E, Tredici P, Marmiroli P, Minoia C, Ronchi A, Bayssas M, Etienne GG. Effects of different schedules of oxaliplatin treatment on the peripheral nervous system of the rat. Eur J Cancer. 2001 Dec;37(18):2457-63. PMID: 11720843

Christensen D, Idanpaan-Heikkila L, Guilbaud G, Kayser V. The antinociceptive effect of combined systemic administration of morphine and the glycine/NMDA receptor antagonist, (+)-HA966 in a rat model of peripheral neuropathy. Br J Pharmacol. 1998 Dec;125(8):1641-50. Erratum in: Br J Pharmacol 1999 Apr;126(8):1881. PMID: 9886755

Dubinsky RM, Kabbani H, El-Chami Z, Boutwell C, Ali H; Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: treatment of postherpetic neuralgia: an evidence-based report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2004 Sep 28;63(6):959-65. PMID: 15452284

Di Cesare Mannelli L, Maresca M, Farina C, Scherz MW, Ghelardini C. A model of neuropathic pain induced by sorafenib in the rat: Effect of dimiracetam.

neurotoxicology. 2015a Sep;50:101-7. PMID: 26254739

Di Cesare Mannelli L, Micheli L, Farina C, Scherz M, and Ghelardini C. Effects of dimiracetam on oxaliplatin-induced hyperalgesia and allodynia in the rat. Journal of Clinical Oncology 2015b 33:15_suppl, e20650-e20650.

Eliel EL, Wilen SH. Stereochemistry of Organic Compounds, Wiley-Interscience, New York (1994). ISBN: 978-0-471-01670-0

Fariello RG, Ghelardini C, Di Cesare Mannelli L, Bonanno G, Pittaluga A, Milanese M, Misiano P, Farina C. Broad spectrum and extend the efficacy of dimiracetam in models of neuropathic pain. neuropharmacology. Jun 2014;81:85-94. PMID: 24486381

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Fariello RG, Ghelardini C, Di Cesare Manneli L, Zanardelli M, Farina C. Antidepressant-like activity of dimiracetam (NT-11624) in the rat forced swimming test. Program no. 789.08/EE25. 2011 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience, 2011. Online.

Fernihough J, Gentry C, Malcangio M, Fox A, Radiske J, Pellas T, Kidd B, Bevan S, Winter J. Pain related behavior in two models of osteoarthritis in the rat knee. Pain. 2004; Nov;l 12(1-2):83-93. PMID: 15494188

Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, Gilron I, Haanpaa M, Hansson P, Jensen TS, Kamerman PR, Lund K, Moore A, Raja SN, Rice AS, Rowbotham M, Sena E , Siddall P, Smith BH, Wallace M. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015 Feb;14(2):162-73. PMID: 25575710

Gronseth G, Cruccu G, Alksne J, Argoff C, Brainin M, Burchiel K, Nurmikko T, Zakrzewska JM. Practice parameter: the diagnostic evaluation and treatment of trigeminal neuralgia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the European Federation of Neurological Societies. Neurology. 2008 Oct 7;71(15): 1183-90. PMID: 18716236 Guingamp C, Gegout-Pottie P, Philippe L, Terlain B, Netter P, Gillet P. Monoiodoacetate-induced experimental osteoarthritis: a dose-response study of loss of mobility, morphology, and biochemistry. Arthritis Rheum. 1997 Sep;40(9): 1670-9. PMID: 9324022

Guzman RE, Evans MG, Bove S, Morenko B, Kilgore K. Mono-iodoacetate-induced histologic changes in subchondral bone and articular cartilage of rat femorotibial joints: an animal model of osteoarthritis. Toxicol Pathol. 2003;31(6):619-24. PMID: 14585729

Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009 Sep; 10(9):895-926. PMID: 19712899.

Marieb EN, Wilhelm PB & Mallat JB, eds. Human Anatomy, ^8th edition. Pearson, London (2017).

Moulin D, Boulanger A, Clark AJ, Clarke H, Dao T, Finley GA, Furlan A, Gilron I, Gordon A, Morley-Forster PK, Sessle BJ, Squire P, Stinson J, Taenzer P, Velly A, Ware MA, Weinberg EL, Williamson OD; Canadian Pain Society. Pharmacological management of chronic neuropathic pain: revised consensus statement from the

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Canadian Pain Society. Pain Res Management. 2014 Nov-Dec; 19(6):328-35. PMID: 25479151

Nakamura Y, Iga K, Shibata T, Shudo M, Kataoka K. Glial plasmalemmal vesicles: a subcellular fraction from rat hippocampal homogenate distinct from synaptosomes. Glia. 1993 Sep;9(l):48-56. PMID: 7902337

Paluzzi S, Alloisio S, Zappettini S, Milanese M, Raiteri L, Nobile M, Bonanno G. Adult astroglia is competent for Na+/Ca2+ exchanger-operated exocytotic glutamate release triggered by mild depolarization. J Neurochem. Nov 2007; 103(3): 1196-207. PMID: 17935604

Pinza M, Farina C, Cerri A, Pfeiffer U, Riccaboni MT, Banfi S, Biagetti R, Pozzi O, Magnani M, Dorigotti L. Synthesis and pharmacological activity of a series of dihydro-lH-pyrrolo[l,2-a] imidazole-2,5(3H,6H)-diones, a novel class of potent cognition enhancers. J Med Chem. 1993 Dec 24;36(26):4214-20. PMID: 8277504 Randall LO, Selito L. A method for measurement of analgesic activity on inflamed tissue. Arch Int Pharmacodyn Ther. 1957 Sep 1; 111(4):409-19. PMID: 13471093 Smith BH, Torrance N, Bennett MI, Lee AJ. Health and quality of life associated with chronic pain of predominantly neuropathic origin in the community. Clin J Pain. 2007 Feb;23(2): 143-9. PMID: 17237663

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Torchio L, Lombardi F, Visconti M, Doyle E. Determination of the polar drug dimiracetam in human plasma and serum by column-switching high-performance liquid chromatography. J Chromatogr In Biomed Appl. 1995 Apr 7;666(1): 169-77. PMID: 7655615 van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N. Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain. 2014 Apr;155(4):654-62. Erratum in: Pain. 2014 Sep;155(9):1907. PMID: 24291734 Wang Y, Chen A. Crystallization-based separation of enantiomers, in Stereoselective Synthesis of Drugs and Natural Products, ^2nd volume; Andrushko V, Andrushko N, Eds. Wiley-Interscience, New York (2013). ISBN: 978-1-118-03217-6

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Examples

Proposed in the present invention, the examples are given only for the purpose of illustration and not limitation. Samples of racemic dimiracetam, (R)-dimiracetam and (S)-dimiracetam can be synthesized using commercially available starting materials, namely:

- 23 041317

Getting R, S-dimiracetam, described in US 5200406:

Provider Purity 2-Chloracetamide Sigma Aldrich 98% benzylamine Sigma Aldrich 99% Ethyl trans-4-oxo-2-butenoate Clariant 98.5% ethyl acetate Sigma Aldrich 99.8% Sodium hydroxide Sigma Aldrich 98% Toluene Sigma Aldrich 98% Palladium on charcoal Sigma Aldrich 5% methanol Sigma Aldrich 98% ammonium hydroxide Sigma Aldrich thirty% n-Butanol Sigma Aldrich 99%

Preparation of R,S-dimiracetam described in WO 2012/013640:

Glycinamide hydrochloride Sigma Aldrich 98% Ethyl trans-4-oxo-2-butenoate Clariant 98.5% Palladium on charcoal Sigma Aldrich 5% ethyl acetate Sigma Aldrich 99.8% Sodium carbonate Sigma Aldrich 99.5% Isopropanol Sigma Aldrich 99.7%

Preparation of R-dimiracetam described in WO 93/09120:

R-Pyroglutamic acid Sichuan Tongsheng Amino Acid Co. 98% methanol Sigma Aldrich 98% Methansulfonic acid Sigma Aldrich 99% Triethylamine Sigma Aldrich 99% ethyl acetate Sigma Aldrich 99.8% Toluene Sigma Aldrich 98% Sodium hydride in oil Sigma Aldrich 60% tert-Butyl bromoacetate Yancheng Longshen Chemical Co 98.5% Acetic acid Sigma Aldrich 99% ammonium hydroxide Sigma Aldrich thirty% Acetic anhydride Sigma Aldrich 98% sodium acetate Sigma Aldrich 99% dichloromethane Sigma Aldrich 98% sodium bicarbonate Sigma Aldrich 99% Isopropanol Sigma Aldrich 99% Hydrochloric acid Sigma Aldrich 32%

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Preparation of S-dimiracetam described in WO 93/09120:

S-Pyroglutamic acid Sigma Aldrich 98% methanol Sigma Aldrich 98% Methansulfonic acid Sigma Aldrich 99% Triethylamine Sigma Aldrich 99% ethyl acetate Sigma Aldrich 99.8% Toluene Sigma Aldrich 98% Sodium hydride in oil Sigma Aldrich 60% tert-Butyl bromoacetate Yancheng Longshen Chemical Co 98.5% Acetic acid Sigma Aldrich 99% ammonium hydroxide Sigma Aldrich thirty% Acetic anhydride Sigma Aldrich 98% sodium acetate Sigma Aldrich 99% dichloromethane Sigma Aldrich 98% sodium bicarbonate Sigma Aldrich 99.7% Isopropanol Sigma Aldrich 99.7% Hydrochloric acid Sigma Aldrich 32%

These commercially available materials can be used as received from the supplier, without further purification, using preparative synthesis techniques and methodologies well known to those skilled in the art.

Example 1. Synthesis of a composition containing dimiracetam.

(R)- and (S)-Dimiracetam, as well as the racemic mixture of dimiracetam was obtained according to the methods described in the following publications: WO 93/09120; Pinza et al., 1993; and WO 2012/013640 and Camilleri et al., 1993. The enantiomeric excess of synthesized (R)- and (S)-dimiracetam was determined as described in Camilleri et al., 1993. The enantiomeric excess of (R)- and ( S)-dimiracetam when used separately to obtain the composition proposed in the present invention, for each enantiomer was greater than or equal to 96%.

Several techniques can be used to provide the desired enantiomeric excess of greater than or equal to 30% EI (excess (R)) and less than or equal to 60% EI (excess (R)), as well as other specific desired compositions of the present invention. known to a person skilled in the art. Thus, for example, said compositions are prepared by mixing the individual enantiomers or by mixing dimiracetam racemate with appropriate amounts of (R)-dimiracetam. In addition, when racemic dimiracetam is used as the starting material, part of the (S)-enantiomer or all of the (S)-enantiomer can be removed by preparative chiral column chromatography.

Example 2 Inhibition of NMDA and Glycine-induced release of glutamate from rat spinal cord synaptosomes.

Neurotransmitter release experiments.

Rat spinal cord synaptosomes free of glial contaminants were prepared according to the method described in Paluzzi S. et al., 2007, modified from that described in Nakamura et al., 1993, as follows.

Sprague-Dawley rats aged 90 to 130 days were used. Animals were housed under conditions of constant temperature (22±1° C.) and relative humidity (50%) using a constant light-dark cycle (light from 7.00 am to 7.00 pm). They provided unlimited access to food and water.

Rats were sacrificed by decapitation and the entire spinal cord was quickly removed and kept at 4°C. The spinal cord of rats was homogenized (90 rpm; 24 up/down movements in 2 min) in 10 volumes (1 g of tissue in 10 ml) of ice-cold 0.32 M sucrose solution buffered to pH 7.4 using prepared from glass and Teflon tissue homogenizer (0.25 mm spacing). The homogenate was centrifuged (5 min, 1000xg, at 4°C) to remove nuclei and residues and the supernatant was carefully stratified at 0-4°C using Percoll® (Sigma Aldrich, St Louis, MO, USA) with a stepwise gradient (2, 6, 10 and 20 v/v% in Tris buffered (tris-(hydroxymethylaminomethane)) sucrose) and centrifuged at 33500xg for 5 min. Layers located between 10 and 20% Percoll (ie the synaptosome fraction) were collected and washed by centrifugation in physiological medium having the following composition (in mM): 140 NaCl; 3 KCl; 1.2 MgSO ₄ ; 1.2 NaH ₂ PO ₄ ; 5 NaHCO ₃ ; 1.2 CaCl ₂ ; 10 HEPES (N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid); 10 glucose; pH 7.4. Protein content was determined according to Bradford MM, 1976 using bovine

- 25 041317 serum albumin as standard.

Synaptosomes (approximately 70 μg of protein) were incubated at 37°C for 15 min in 2.5 ml of 0.05 μM solution of [ ³ H]-D-aspartate ([ ³ H]-D-Asp; Perkin Elmer Italia, Monza, Milano, Italy). Then the suspension was diluted to 122.5 ml with physiological medium, kept at 37°C, and aliquots of the synaptosome suspension with a volume of 5 ml were layered on microporous filters located at the bottom of a set of 24 parallel chambers for irrigation with a volume of 25 ml, maintained at 37°C ( Superfusion system, Ugo Basile, Comerio, Varese, Italy). Irrigation with physiological medium was then started at a rate of 0.5 ml/min and continued for 46 minutes. At t=37 min, nine samples of the filtrate were taken sequentially with an interval of 1 min.

At the time of completion of the selection of the first sample, NMDA (10 μM) and glycine (1 μM) were added and kept until the end of the experiment.

The radioactivity of each filtrate sample was determined by scintillographic techniques using Ultima Gold scintillation fluid (Perkin-Elmer Milan, Italy). The radioactivity of each 0.5 ml sample was determined by adding 3 ml of scintillation fluid.

The tritium content of each sample was expressed as a percentage (ie, the percentage content in each sample, based on the total [ ³ H] content at the start of the respective sampling time). Drug exposure was calculated as the ratio of the release value in the seventh selected fraction (which provided the maximum exposure to NMDA) to the value in the first fraction (initial release, before the addition of NMDA and glycine). This ratio of values was compared with the same ratio for the seventh and first fractions obtained under control conditions.

Effects on NMDA-induced glutamate release in the synaptosome fraction.

The possible effect of racemic and non-racemic mixtures of dimiracetam on NMDA- and glycine-induced neurotransmitter release from rat spinal cord synaptosomes was investigated.

The composition of the present invention, having an enantiomeric excess of (R)-dimiracetam equal to 33.3%, corresponding to the ratio of dimiracetam (R):(S) enantiomers equal to 2:1, inhibits the release of [ ³ H] induced by NMDA and glycine -D-aspartic acid from rat spinal cord synaptosomes with a calculated IC50 value of 10 nM (Fig. 1A), while the composition of the present invention having an enantiomeric excess of (R)-dimiracetam equal to 50%, corresponding to the ratio of enantiomers of dimiracetam (R):(S) of 3:1 inhibits NMDA and glycine-induced release of [ ³ H]-D-aspartic acid from rat spinal cord synaptosomes with a calculated IC50 of less than 1 nM (FIG. 1B). For comparison, it should be noted that racemic dimiracetam, i.e. (R):(S) ratio is 1:1, inhibits NMDA-glycine-induced release of [ ³ H]-D-aspartic acid from rat spinal cord synaptosomes with a calculated IC ₅₀ value of 14.6 nM (FIG. 1B; Table 1), while in the case of (R)-dimiracetam the calculated IC ₅₀ value is 123 nM (Fig. 1D) and in the case of (S)-dimiracetam the calculated IC ₅₀ value is 418 nM (Fig. 1E).

Additional confirmatory results are shown in table. 1.

Table 1: Inhibition by racemic dimiracetam and preferred non-racemic dimiracetam mixtures of the present invention induced by 10 μM NMDA and 1 μM glycine release of [ ³ H]-D-Asp from rat spinal cord-derived synaptosomes. The results are presented as % inhibition induced by NMDA and glycine release. The results are the average values obtained in conducted 3 times 3-6 experiments ± ATP.

Table 1

Enantiomeric mixtures of dimiracetam Percent inhibition of NMDA and glycine-induced release of glutamate from rat spinal cord synaptosomes Ratio (R):(S) Enantiomeric excess of (R)-dimiracetam 0.1 nM 1 nM 10 nM 1:1 0% 9±13% 29±3% 35±4% 2:1 33% 2±17% -3±11% 49±7% 3:1 50% 21±17% 49±10% 54±5%

Example 3 Rat Induced Peripheral Neuropathic Pain Model.

Assessment of pain responses.

The effects of a single dose of test compounds, solvents and comparative compounds were studied at maximum pain response according to the study design. The effect of repeated administration of racemic and non-racemic mixtures of dimiracetam was then examined to examine the possible development of tolerance. Investigated hyperalgesia and allodynia. All efficacy results were analyzed by a researcher not informed of the site of treatment in rats.

Paw pressure test (hyperalgesia).

The sensitivity of the paw to mechanical stress was determined using the Randal device and

- 26 041317

Selito (Randall and Selitto, 1957), which applied a force that increased at a constant rate (32 g/s). The magnitude of the paw withdrawal stimulus was determined before treatment and at various time intervals after treatment. The results are presented as the mean paw withdrawal mechanical threshold, expressed in grams. To avoid possible damage to the rat paw, the maximum applied force was set to 240 g. When using the single dose protocol, paw pressure tests were performed pre-treatment (pre-dose) and at regular intervals post-treatment.

Model of osteoarthritis of the knee.

A single injection of sodium monoiodoacetate (SIA) into the knee joints of rats was performed as described in Fernihough J. et al., 2004. Sodium monoiodoacetate (SIA) inhibits chondrocyte metabolism, resulting in cartilage destruction resulting in osteoarthritis-like focal lesions in cartilage associated with thickening of the subchondral bone 14 days after injection (Guingamp et al., 1997). Therefore, osteoarthritis-like lesions and functional impairments in rats similar to those observed in human disease can be easily and quickly reproduced with this model (Guzman et al., 2003). 7 after the injection, the inflammation subsides and the residual pain is considered to be neuropathic in nature. Briefly, the procedure was as follows: rats were subjected to deep anesthesia with diethyl ether. After the paw withdrawal reflex disappeared during pinching, a No. 27 needle was inserted into the joint cavity between the superior articular surface of the tibia and the femoral joint. was injected into one knee joint and the rats were allowed to recover for 14 days and then subjected to a pain study.

On day 16 after MIA injection, the animals received once racemic dimiracetam (150 and 300 mg/kg, po) or compositions of the (R)- and (S)-enantiomers of dimiracetam at a dose of 150 and 300 mg/kg and at a ratio of ( R):(S) equal to 3:1, and (R):(S) equal to 1:3. Control rats were treated with saline of the same volume.

Chemotherapy-induced peripheral sensory neuropathy - a model using oxaliplatin.

Peripheral sensory neuropathy was induced in adult rats by intraperitoneal administration of oxaliplatin (Tocris) at a dose of 2.4 mg/kg in saline once a day for 5 consecutive days every week for 3 weeks (total dose: 36 mg /kg) in accordance with the publication of Cavaletti et al., 2001. Starting from day 21 after the first administration of oxaliplatin, the effect of repeated administration of racemic dimiracetam or the preferred composition of the present invention, having an enantiomeric excess of (R)-dimiracetam, equal to 50%, was investigated, corresponding to the ratio of enantiomers (R):(S), equal to 3:1, caused by oxaliplatin mechanical hyperalgesia.

EXAMPLE 4 Results of Experiments Using Rat Models of Peripheral Neuropathic Pain.

1. Model of osteoarthritis of the knee joint.

The effect of racemic dimiracetam and different formulations containing non-racemic mixtures of dimiracetam enantiomers on peripheral neuropathic pain was studied by a paw pressure test after a single intra-articular injection of sodium monoiodoacetate (MIA) into the rat knee joint (model of knee osteoarthritis) as described above.

In FIG. 2 shows the results obtained in the paw pressure test after oral administration of a single dose of racemic dimiracetam and various non-racemic mixtures of (R)-dimiracetam and (S)-dimiracetam, namely the preferred composition of the present invention having an enantiomeric excess of (R)- dimiracetam, equal to 50%, corresponding to the ratio of enantiomers (R):(S) equal to 3:1, and the composition having the ratio (R):(S) equal to 1:3. According to the paw pressure test, the preferred composition of the present invention, having an enantiomeric excess of (R)-dimiracetam equal to 50%, is more effective in reducing peripheral neuropathic pain that occurs after the injection of sodium monoiodoacetate (MIA) than the racemic mixture of dimiracetam or a mixture having an excess of the (S)-enantiomer of dimiracetam [(R):(S)=1:3].

2. Model using oxaliplatin.

Oxaliplatin-induced mechanical hyperalgesia was studied following repeated oral administration of racemic dimiracetam or a preferred composition of the present invention having an enantiomeric excess of (R)-dimiracetam of 50%. The pain threshold was determined using the Randal and Selito algesimeter before morning administration. The preferred composition of the present invention, having an enantiomeric excess of (R)-dimiracetam of 50%, is more effective than racemic dimiracetam in reducing oxaliplatin-induced hyperalgesia (Fig. 3A), allodynia (Fig. 3B) and cold sensitivity ( Fig. 3B). Thus, in this model of chemotherapy-induced peripheral sensory neuropathy, the composition of the present invention having an excess of N-dimiracetam is also more effective in reducing peripheral neuropathic pain than the same amount of dimiracetam racemic mixture. The development of tolerance was not detected.

Example 5 In vitro inhibition of NMDA and glycine addition-induced release of preloaded [ ³ H]-D-aspartate from rat spinal cord synaptosomes.

To determine the range of ratios (R):(S) in enantiomeric mixtures of dimiracetam enantiomers with inhibitory ability that exceeds the inhibitory ability of racemic dimiracetam, a number of mixtures with a concentration of 10 nM and (R):(S) ratios equal to from 2:1 to 4:1. These experiments were performed using a previously published methodology (Fariello et al., Neuropharmacology. 2014, (81), 85-94) and the results are shown in FIG. 5.

In addition, the results can be summarized as shown in Table. 2.

table 2

Ratio R:S Inhibition,% (average value) Number of measurements SO joint venture 1:1 35.4 8 12.3 4.4 2:1 48.0 9 22.3 7.4 2.5:1 49.1 8 15.8 5.6 3:1 50.7 9 15.3 5.1 3.3:1 45.5 8 10.1 3.6 3.5:1 26.5 10 25.3 8.0 4:1 15.7 10 18.9 6.0

SD stands for standard deviation.

SP denotes the standard error of the mean.

As can be seen from these results, the compositions of the present invention, in particular those having a ratio of (R):(S) equal to from 2:1 to 3.3:1, or in between these values, have a significantly improved inhibitory an ability that clearly exceeds the inhibitory ability of racemic dimiracetam.

Example 6 In vivo antiamnesic activity in a passive avoidance mouse model.

Racemic dimiracetam and two different mixtures of its R- and S-enantiomers ((R):(S)=2:1 and (R):(S)=3:1, respectively) at doses of 3, 10 and 30 mg / kg, was examined using a passive avoidance test in mice 30 minutes after oral administration.

Methods.

The test was carried out according to the transition methodology described in Jarvik M.E. and Kopp R., Psychol. Rep., 21:221-224, 1967. The apparatus consisted of an acrylic polymer box containing two compartments, the illuminated compartment separated from the dark compartment by a lift door. As soon as the mice entered the darkened compartment, they were given electric shocks (0.3 mA, 1 s). Testing was carried out for two consecutive days. Mice were placed in the lighted compartment of a box containing two compartments: latency to the darkened compartment was determined on day 1 during reflex development and 24 hours later on day 2 during memory testing. Mice that were given electric shocks when they entered the darkened compartment during reflex development remembered it during testing the next day, unless their memory was impaired by an amnestic drug. During the development of the reflex, mice that did not enter the darkened compartment after a latency period of 60 s were not used in the further experiment; approximately 20-30% of mice were excluded from each group. All study drugs were administered orally 30 minutes prior to reflex development; to impair memory, the mice were injected with the amnestic drug scopolamine (1.5 mg/kg, ip) immediately after the reflex was complete.

Vehicle-treated mice were injected intraperitoneally with saline immediately after reflex elicitation, which was used as a control for scopolamine injections. The test was repeated 24 hours later (memory test); no drug was administered on day 2. The maximum transition latency allowed for memory testing was 180 s. The results are shown in FIG. 6.

Accordingly, it can be seen that the latencies obtained when using an R:S enantiomeric ratio of 3:1 or 2:1 are much longer than when dimiracetam racemate is used.

Example 7 Antidepressant activity in the forced immersion test (Porsolt) in mice.

Racemic dimiracetam and two mixtures of its R- and S-enantiomers (2:1 and 3:1, respectively) at doses of 10, 30 and 100 mg/kg were tested using a forced immersion test in mice 25 minutes after oral administration.

- 28 041317

Methods.

The forced immersion test used was the same as that described in Porsolt R.D., Bertin A., Jalfre M., Arch. Int Pharmacodyn. Ther. 1977, 229:327-336. Briefly, the procedure was as follows: mice were individually placed in glass cylinders (height: 25 cm, diameter: 10 cm) containing water to a height of 12 cm, the temperature of which was maintained at 22-23°C, and left in them for 6 min. A mouse was considered immobile if it swam in the water in a vertical position and moved only slightly to keep its head above the water. The duration of movement was determined during the last 4 minutes of the 6-minute test. An increase in the duration of movement was considered an indication of an antidepressant-like effect. The results are shown in FIG. 7.

Accordingly, it can be seen that the duration of mouse movement provided by the use of dimiracetam enantiomers at an R:S ratio of 3:1 or 2:1 is significantly greater than when dimiracetam racemate is used.

Taking into account the above results, it can be seen that the use of dimiracetam enantiomers at the stated R:S ratios leads to a decrease in the release of glutamate from the synaptosomes of the spinal cord of rats, a decrease in peripheral neuropathic pain, an antiamnesic effect and an antidepressant effect, which are more significant than in the case of using racemate dimiracetam.

Example 8 Paw Pressure Test, Von Frey Test and Cold Plate Test in the Oxaliplatin Rat Model.

Oxaliplatin-induced mechanical hyperalgesia was studied after repeated oral administration of racemic dimiracetam or the preferred composition of the present invention having an enantiomeric excess of (R)-dimiracetam of 50%. Pain threshold was determined using a Randal and Selito painmeter (Leighton et al., Br. J. Pharmacol. 93:553-560, 1988) prior to morning administration. On the morning of day 28, mechanical allodynia (Sakurai et al., Pain, 147:165-74, 2009) and cold sensitivity were also examined using von Frey and cold plate tests (Di Cesare Mannelli et al., Exp. Neurol. 261: 22-33, 2014) respectively. As shown in FIG. 3 and in table. 3, a preferred composition according to the present invention having an enantiomeric excess of (R)-dimiracetam equal to 50%. is more effective in reducing oxaliplatin-induced hyperalgesia, allodynia, and cold sensitivity. Thus, in this model of chemotherapy-induced peripheral sensory neuropathy, the composition of the present invention having an excess of (R)-dimiracetam is also more effective in reducing peripheral neuropathic pain than the dimiracetam racemic mixture. The development of tolerance was not detected.

Table 3

The impact of racemic dimiracetam and the mixture proposed in the present invention (R:S=3:1)

Dose in treatment, mg/kg, twice a day Paw pressure, Randal and Selito, g Paw withdrawal, von Frey, g Cold plate, lick latency, s Before research On day 28 Before research On day 28 Before research On day 28 Saline 65.8± 1.8 65.2±0.9 23.0±0.8 26.3±0.8 22.5±0.9 20.5±0.7 Oksaliplatin 68.5± 1.1 51.7± 1.9 ΛΛ 20.6±0.9 15.9 ± ^ΛΛ 1.0 23.5±0.6 14.2±0.6 ΛΛ R:S=1:1, 15 68.1 ± 1.2 48.7± 2.5 21.4 ± 1.0 16.0±1.5 1.5 ± 1.0 14.8± 1.5 R:S=3:1, 15 65.2 ± 1.7 62.5± 1.8 OO 25.1±0.5 24.7 ± ** 1.5 ^oo 20.8±1.3 18.7±0.7 OO R:S=1:1.50 67.1±0.8 55.2 ± 1.0 21.4± 0.5 18.5± 2.3 22.0±0.8 15.4± 1.0 R:S=3:1.50 65.4 ± 1.2 65.6 ± 1.2 21.2± 1.1 22.1±** 0.8° 21.9 ± 2.1 19.6±0.7

Oxaliplatin (2.4 mg/kg, ip) was administered once daily on weekdays from day 1 to day 15 (11 injections in total). Two mixtures of dimiracetam enantiomers (R:S=1:1 and R:S=3:1) were administered once a day from day 1 to day 27.

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Claims (18)

The behavioral study was performed on the morning of day 28 and the results are the mean values obtained from 6 rats ± SPS. ^LL P<0.01 compared with saline; **P<0.01 compared with °P<0.05 and °°P<0.01 compared with 15 mg/kg racemate; #P<0.05 and ##P<0.01 vs. 50 mg/kg racemate. The paw pressure test, the von Frey test, and the cold plate test were performed as follows. Paw pressure test. The sensitivity of the paw to mechanical impact was determined using the device Randall and Selitto (Randall and Selitto, 1957), which applied force, which increased at a constant rate (32 g/s). The magnitude of the paw withdrawal stimulus was determined before treatment and at various time intervals after treatment. The results are presented as the average mechanical impact threshold value expressed in grams. To avoid possible injury to the paw of the animal, the maximum applied force was set at 240 g (Leighton et al., Br. J. Pharmacol. 93:553-560, 1988). Von Frey test. Animals were placed in 20x20 cm boxes made of organic glass, equipped with a metal mesh floor located 20 cm above the bottom of the box. Before the start of the test, the animals were allowed to get used to their environment for 15 min. An electronic device with von Frey filaments (Ugo Basile, Varese, Italy) was used: the threshold value corresponding to withdrawal was determined by applying a force ranging from 0 to 50 g, with an accuracy of 0.2 g. parts of each forepaw from below through the mesh floor with a plastic tip, and the threshold value corresponding to withdrawal was automatically displayed on the screen. Paw threshold was defined as the minimum force required to provide a sustained and immediate paw withdrawal reflex. Voluntary movement associated with movement was not considered a withdrawal reflex. An impact was applied to each hind paw at intervals of 5 s. The experiments were repeated 5 times and the final value was obtained by averaging the values obtained in five experiments (Sakurai et al., Pain, 147:165-74, 2009). Cold plate test. Animals were placed in a stainless steel box (12x20x10 cm) with a cold plate on the floor. The temperature of the cold plate was maintained constant and equal to 4±1°C. Pain-related behaviors (ie, lifting and licking the hind paw) were observed and the time (s) of the first sign was recorded. The latency limit for raising or licking the paw was set at 60 s (Di Cesare Mannelli et al., Exp. Neurol. 261:22-33, 2014). All patents, publications and abstracts cited above are incorporated herein by reference in their entirety. Various embodiments of the present invention are described to implement different objectives of the present invention. It should be understood that these embodiments are only intended to illustrate the principles of the present invention. Those skilled in the art will readily recognize numerous modifications and changes that can be made without departing from the spirit and scope of the present invention as defined in the following claims. CLAIM 1. Pharmaceutical composition containing (R)-3,6,7,7a-tetrahydro-1H-pyrrolo[1,5-a]imidazole2,5-dione ((R)-dimiracetam (1)) and (S)- 3,6,7,7a-tetrahydro-1H-pyrrolo[1,5-a]imidazole-2,5-dione ((S)dimiracetam (2)): in which the enantiomeric excess (EI) of (R)-dimiracetam (1) is greater than or equal to 33% and less than or equal to 54%. 2. Composition according to claim 1, in which the ratio of the amount of (R)-dimiracetam (1) to the amount of (S)-dimiracetam (2) is from 2:1 to 3.3:1. 3. The composition according to claim 1, where the composition is a non-racemic mixture of 3,6,7,7a-tetrahydro-1H-pyrrolo[1,5-a]imidazole-2,5-dione (dimiracetam), where the non-racemic mixture contains ( R)-dimiracetam (1) to (S)-dimiracetam (2) in an enantiomeric excess (EI) of (R)-dimiracetam (1) greater than or equal to 33% and less than or equal to 54%. 4. A pharmaceutical composition comprising a composition according to any one of the preceding paragraphs and a pharmaceutically acceptable carrier. 5. Pharmaceutical set of components, including (R)-dimiracetam (1) and (S)-dimiracetam (2) - 30 041317 and instructions for combining (R)-dimiracetam (1) and (S)-dimiracetam (2) to obtain an enantiomeric excess (EI) of (R)-dimiracetam (1) greater than or equal to 33% and less than or equal to 54 %. 6. The kit according to claim 5, wherein (R)-dimiracetam (1) and (S)-dimiracetam (2) are packaged separately. 7. The use of a pharmaceutical composition according to any one of claims 1 to 3, or a pharmaceutical composition according to claim 4, or a set of components according to claim 5 as a drug that modulates the function of the NMDA receptor. 8. The use of a pharmaceutical composition according to any one of claims 1 to 4 or a kit according to claim 5 for the treatment and/or prevention of a disease, injury or disorder, where the disease, injury or disorder is selected from among the following: peripheral sensory neuropathy, seizure, depression or cognitive impairments. 9. The use of a pharmaceutical composition according to any one of claims 1 to 4 or a kit according to claim 5 for the treatment and/or prevention of a disease, injury or disorder, where the disease, injury or disorder is selected from among the following: peripheral sensory neuropathy, neuropsychiatric disorder, motor neuron disturbance or impairment of movement. 10. Use according to claim 8 or 9, wherein the disease, injury or disorder is peripheral sensory neuropathy, where it is preferred if the peripheral sensory neuropathy is peripheral neuropathic pain. 11. Use according to any one of claims 8 or 10, wherein the peripheral sensory neuropathy is diabetic neuropathy, postherpetic neuropathy, lumbago, sciatica pain, surgical pain, tissue crush injury, spinal cord injury, complex regional pain syndrome, amputee sensation. limbs, peripheral sensory neuropathy associated with osteoarthritis, peripheral sensory neuropathy associated with rheumatoid arthritis, peripheral sensory neuropathy associated with autoimmune osteoarthritis, severe headache, fibromyalgia, peripheral sensory neuropathy associated with agents that inhibit tumor growth, peripheral sensory neuropathy associated with chemotherapeutic agent, peripheral sensory neuropathy associated with damage to the internal organ, peripheral sensory neuropathy associated with osteonecrosis, peripheral sensory neuropathy associated with infection with immunodeficiency virus human cyte, peripheral neuropathic pain, or antiviral-induced peripheral sensory neuropathy. 12. Use according to any one of claims 8 to 11, wherein the peripheral sensory neuropathy is selected from the following: chemotherapeutic agent-induced peripheral sensory neuropathy or antiviral agent-induced peripheral sensory neuropathy. 13. Use according to any one of claims 8 to 12, wherein the peripheral sensory neuropathy is a peripheral sensory neuropathy induced by a chemotherapeutic agent, wherein the chemotherapeutic agent is selected from the group consisting of the following: a kinase inhibitor, a proteasome inhibitor, a taxane, a vinca alkaloid and a platinum salt, and where preferably the chemotherapeutic agent is selected from among the following: sorafenib, sunitinib, afatinib, axitinib, vandetanib, vemurafenib, ixazomib, bortezomib, paclitaxel, docetaxel, cabazitaxel, vincristine, vinblastine, vindesine, vinorelbine, nedaplatin, lobaplatin, picoplatin, satraplatin, cisplatin, carboplatin and oxaliplatin. 14. Use according to any one of claims 8 to 13, wherein the peripheral sensory neuropathy is peripheral sensory neuropathy induced by an antiviral agent, wherein the antiviral agent is a nucleoside reverse transcriptase inhibitor and where the antiviral agent is preferably selected from the following: zalcitabine, didanosine, stavudine and zidovudine. 15. The use according to any one of claims 8 to 14, wherein the pharmaceutical composition is used together with at least one anticancer drug, where preferably the anticancer drug is selected from the group consisting of the following: kinase inhibitor, proteasome inhibitor, taxane, alkaloid periwinkle and platinum salt; and where more preferably the anticancer drug is selected from the following: sorafenib, sunitinib, afatinib, axitinib, vandetanib, vemurafenib, ixazomib, bortezomib, paclitaxel, docetaxel, cabazitaxel, vincristine, vinblastine, vindesin, vinorelbine, nedaplatin, lobaplatin, picoplatin, satraplatin, cisplatin, carboplatin and oxaliplatin. 16. Use according to any one of claims 8 to 15, wherein the pharmaceutical composition is used together with at least one antiviral drug, where it is preferred if the antiviral drug is selected from the following: nucleoside or nucleotide, and where more preferably if the antiviral drug the agent is selected from among the following: zalcitabine, didanosine, stavudine and zidovudine. 17. Use according to any one of claims 8 to 16, wherein the pharmaceutical composition is to be administered orally twice a day at a dose of 10 to 3000 mg each administration, more preferably 20 to 2000 mg each administration, even more preferably from 50 to 1000 mg with each injection. 18. The use of a pharmaceutical composition according to any one of claims 1 to 3, or a pharmaceutical composition according to claim 4, or a set of components according to claim 5 in a method for improving learning and memory. -