EA040556B1 - PHARMACEUTICAL COMBINATION CONTAINING T-TYPE CALCIUM CHANNEL BLOCKER - Google Patents

Abstract

The invention relates to a pharmaceutical combination containing a first active substance, which is N-[1-(5-cyano-pyridin-2-ylmethyl)-1H-pyrazol-3-yl]-2[4-(1-trifluoromethyl-cyclopropyl)phenyl]acetamide or a pharmaceutically acceptable salt thereof, and a second active substance having an antiepileptic effect, or a pharmaceutically acceptable salt thereof.

Description

The present invention relates to a pharmaceutical combination containing a first active substance which is N[1-(5-cyano-pyridin-2-ylmethyl)-1H-pyrazol-3-yl]-2-[4-(1trifluoromethyl-cyclopropyl) phenyl]acetamide or a pharmaceutically acceptable salt thereof, and a second antiepileptic active or a pharmaceutically acceptable salt thereof.

Epilepsy is a brain disease characterized by a persistent predisposition to seizures and the neurobiological, cognitive, psychological, and social consequences of this condition (Berg A.T. et al. (2011) New concepts in classification of the epilepsies: entering the 21st century (2010) Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology. concepts for classifying seizures and types of epilepsy: Report of the Commission on Classification and Terminology], 2005-2009 Epilepsia 51:676-685). Patients with epilepsy experience intermittent spontaneous seizures, which can represent a variety of phenotypes ranging from mild short-term disturbances in attention or muscle twitching to severe and prolonged seizures. Seizures are short-term events due to abnormal, excessive, or synchronous activity of neurons in the brain. They are classified as focal seizures when they remain confined to networks in one hemisphere, or as generalized (absence, myoclonic, tonic-clonic, tonic, and atonic) seizures when they rapidly involve bilaterally distributed networks.

Antiepileptic drugs (AEDs) aim to reduce seizure activity. Currently approved AEDs mainly act on multiple ion channels (Ca ²⁺ , Na ⁺ , K ⁺ or Cl ^- ), synaptic systems and amino acid receptors, neurons and glial cells. Currently, AEDs are prescribed primarily based on the individual's seizure type(s), comorbidities, and concomitant medications (Perucca E. et al. (2011) The pharmacological treatment of epilepsy in adults. Lancet Neurol 10 :446-456; Franco V. et al. (2016) Challenges in the clinical development of new antiepileptic drugs [Problems in the clinical development of new antiepileptic drugs]. Pharmacol Res 103:95104), and also take into account age, gender, childbearing potential. Even today, there are no reliable tools for predicting clinical responses in an individual patient.

Newly diagnosed patients are treated with first-line drugs (such as carbamazepine, ethosuximide, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, topiramate, valproic acid, or their salts), which are chosen based on the individual patient. As a rule, treatment is started with a low dose, which is increased over a period that varies for each drug separately. The maintenance dose is usually tailored to each patient and should be the lowest dose to ensure no seizures. This initial selected maintenance dose may be increased for recurrent seizures (Perucca E. et al. (2011) The pharmacological treatment of epilepsy in adults. Lancet Neurol 10:446-456). Approximately 50% of adult patients with epilepsy will remain on monotherapy with their initial AED prescribed, meaning that they do not have seizures without intolerable side effects. For the remaining 50%, treatment requires adaptation, and a combination of AEDs is a common option. Drug-resistant forms of epilepsy account for about 30% of the epilepsy population and have been defined by the World League Against Epilepticus (ILAE) as the inability to achieve seizure freedom despite sufficient testing of at least two well-chosen and tolerable AED regimens, alone or in combination (Kwan P. et al. (2010) Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies Epilepsia 51 :1069-1077). Most patients with refractory epilepsy take 2, 3, or 4 different AEDs. With over 25 AEDs currently available on the market, there are theoretically a huge number of possible combinations. This explains the recommendations for rational polytherapy, i.e. combinations of AEDs with different pharmacological properties (Brodie M.J. et al. (2011) Antiepileptic drug therapy: does mechanism of action matter? Epilepsy Behav 21:331-341; Brodie M.J. et al (2011) Combining antiepileptic drugs - rational polytherapy? Seizure 20:369-375; Brodie M. J. (2016) Pharmacological Treatment of Drug-Resistant Epilepsy in Adults: a Practical Guide in adults: a practical guide], Curr. Neurol. Neurosci. Rep. 16:82). In fact, the most successful combination therapy is observed with drugs that have different mechanisms of action (Stephen L.J. et al. (2012) Antiepileptic drug combinations - have newer agents altered clinical outcomes? Brodie M.J. (2016) Pharmacological Treatment of Drug-Resistant Epilepsy Res 98:194-198

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Epilepsy in Adults: a Practical Guide. Curr. Neurol. neurosci. Rep. 16:82). However, a retrospective analysis of a large database of AED therapy in patients with refractory disease has shown that a combination of more than 2 drugs in most cases does not provide significant benefits to patients (Poolos N.P. et al. (2012) Comparative efficacy of combination drug therapy in refractory epilepsy [Comparative efficacy of combination drug therapy in refractory epilepsy], Neurology 78:62-68).

Calcium (Ca ²⁺ ) is an important element of signaling in neurons and its entry into the cell is tightly regulated by two main classes of voltage-gated calcium channels: high voltage activated (HVA; L-, N-, P/Q- and R-types) and activated low voltage (LVA; T-type) calcium channels (Catterall WA et al. (2005) International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels [International Union of Pharmacology. XLVIII. Nomenclature and structural- functional linkages of voltage-gated calcium channels] Pharmacol Rev. 57:411-425).

Three subtypes of T-type calcium channels with different electrophysiological properties have been described: Ca _v 3.1, Ca _v 3.2, and Ca _v 3.3 (Lee JH et al. (1999) Cloning and expression of a novel member of the low voltage-activated T-type calcium channel family [Molecular physiology of low-voltage-activated t-type calcium channels] J. Neurosci 19:1912-1921; Perez-Reyes E. (2003) low-voltage-activated T-type calcium channels, Physiol Rev. 83:117-161). T-type calcium channels are widely expressed in the brain (Talley EM et al. (1999) Differential distribution of three members of a gene family encoding low voltage-activated (T-type) calcium channels. low-voltage calcium channels (T-type)]. J. Neurosci 19:1895-1911), where they play an important role in the control of rhythmic neuronal burst and emerging thalamocortical oscillations (Cheong E. et al. (2014) T-type Ca( 2+) channels in absence epilepsy Pflugers Arch 466:719-734; Lambert RC et al. (2014) The many faces of T-type calcium channels. Ttype channels] Pflugers Arch 466:415-423).

During attacks of idiopathic generalized epilepsy (IGE), in particular absence seizures, both in humans and animals, abnormal fluctuations mediated by T-type calcium channels can be observed (Khosravani H. et al. (2006) Voltage-gated calcium channels and idiopathic generalized epilepsies Pflugers Arch 460:395-403 Cheong E et al (2014) T-type Ca(2+) channels in the absence of epilepsy Pflugers Arch 466:719-734.

In accordance with these observations, mutations were identified in the gene expressing the Ca _v 3.2 subtype in patients with childhood absence epilepsy and other forms of IGE (Khosravani H. et al. (2006) Voltage-gated calcium channels and idiopathic generalized epilepsies. Physiol Rev 86: 941-966 Heron SE et al (2007) Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants Ann Neurol 62:560-568 Zamponi GW et al (2010) Role of voltage-gated calcium channels in epilepsy Pflugers Arch 460:395-403;Eckle VS et al (2014) Mechanisms by which a CACNA1H mutation in epilepsy patients increases seizure susceptibility [Mechanisms by which CACNA1H mutation in patients with epilepsy increases susceptibility to seizures] J Physiol 592:795-809). Some of these mutations increase the intrinsic activity of the channels, while others increase the intracellular migration of the channels to the plasma membrane; most mutations increase calcium fluxes. A direct consequence of this is increased excitability in neurons, which exhibit increased bursting activity, thereby contributing to the generation of epileptiform discharges. Several rodent models support the importance of the Ca _v 3.2 channel subtype. In rat genetic models of spontaneous absence-like epilepsy (GAERS, Genetic Absence Epilepsy in Rats from Strasbourg; WAG/Rij), an acquisition-of-function mutation in the Ca _v 3.2 gene has been reported (Powell KL et al. (2009) ). A T-type Ca _v 3.2 calcium channel point mutation has a splice-variant-specific effect on function and separates with seizure expression in a polygenic rat model of absence epilepsy. J. Neurosci. 29:371-380), as well as increased Ca _v 3.2 mRNA levels, and increased T-type calcium fluxes (Tsakiridou E. et al. (1995) Selective increase in T-type calcium conductance of reticular thalamic neurons in a rat model of absence epilepsy Talley EM et al (2000) Low-voltage-activated calcium channel subunit expression in a genetic model of absence epilepsy in the rat Brain Res. Mol. Brain Res. 75:159-165; Broicher T. et al. (2008) Correlation of T-channel coding gene expression, IT, and the low threshold Ca2+ spike in the thalamus of a rat model of absence epilepsy

- 2 040556 gene for the T-channel, IT and low-threshold Ca2+ peak in the thalamus of the rat model of absence epilepsy]. Mol. cell. Neurosci 39:384-399; Powell KL et al. (2009) Ttype calcium channel point mutation Ca _v 3.2 has a splice variant-specific effect on function and detaches with seizure expression in a polygenic rat model of absence epilepsy. J. Neurosci 29:371-380). An acquired channelopathy involving thalamic T-type Ca2 ₊ channels after status epilepticus has also been described in a mouse model of temporal lobe epilepsy (Graef JD et al. (2009)). type after status epilepticus] J. Neurosci 29:4430-4441).

Several lines of evidence have linked mutations in the Ca _v 3.1 subtype to epilepsy in humans and rodent animal models. Genetic variants have been found in patients with juvenile myoclonic epilepsy, another form of IGE (Lory P. et al. (2010) Calcium channelopathies in inherited neurological disorders: Relevance to drug screening for aquired channel disorders. [Calcium channelopathies in inherited neurological disorders: Relevance for drug screening in acquired channel disorders] IDrugs 13:467-471). Overexpression of Ca _v 3.1 channels in mice leads to frequent bilateral cortical seizures (Ernst WL et al. (2009) Genetic enhancement of thalamocortical network activity by increased α-1g-mediated low-voltage-activated calcium flux causes pure absence epilepsy. J. Neurosci 29: 1615-1625) and Ca _v 3.1 knockout mice are protected from absence seizures (Kim D. et al. (2001). No burst of thalamocortical interneuron activity and resistance to absence seizures in mice lacking Ca(2+) a(1G) channels) Neuron 31:35-45 Song I et al (2004) Role of the alG T-type calcium channel in spontaneous absence seizures in mutant mice -mutants] J. Neurosci 24:5249-5257).

Surprisingly, N-[1-(5-cyano-pyridin-2-ylmethyl)-1H-pyrazol-3yl]-2-[4-(1-trifluoromethyl-cyclopropyl)phenyl]acetamide was found to have a synergistic effect on mouse models of generalized tonic-clonic seizures when administered together with existing AEDs.

Description of the invention

1) In the first embodiment, the present invention relates to a pharmaceutical combination containing the first active substance, which is N-[1-(5-cyano-pyridin-2ylmethyl)-1H-pyrazol-3-yl]-2-[4- (1-trifluoromethyl-cyclopropyl)phenyl]acetamide (hereinafter also referred to as Compound 1) or a pharmaceutically acceptable salt thereof, and a second antiepileptic active or a pharmaceutically acceptable salt thereof.

Compound 1 is a selective and orally available triple T-type calcium channel blocker, ie. Compound 1 blocks three subtypes of Ca _v 3.1, Ca _v 3.2, and Ca _v 3.3 T-type calcium channels. Compound 1 has been described as being useful in the prevention/prevention and/or treatment of diseases or disorders in which calcium T channels are involved and especially in the treatment of epilepsy (WO 2015/186056). Compound 1 can be obtained in accordance with the methodology disclosed in WO 2015/186056.

It is to be understood that the present invention encompasses Compound 1 in any form, including amorphous as well as crystalline forms of Compound 1. It is further understood that crystalline forms of Compound 1 encompass all types of crystalline forms of Compound 1, including single molecule polymorphs, solvates and hydrates, molecular salts and co-crystals (where the same molecule can be co-crystallized with different co-crystal forming agents), provided they are suitable for pharmaceutical administration.

2) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is selected from the group consisting of 5H-dibenzo[b,f]azepine-5-carboxamide (carbamazepine), (RS)-3 -ethyl-3-methyl-pyrrolidine2,5-dione (ethosuximide), 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine (lamotrigine), (S)-2-( 2oxopyrrolidin-1-yl)butanamide (levetiracetam), 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5carboxamide (oxcarbazepine), 2-propylpentanoic acid (valproic acid), N-(5- sulfamoyl1,3,4-thiadiazol-2-yl)acetamide (acetazolamide), (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide (brivaracetam), 7-chloro-1 -methyl-5-phenyl-1,5-benzodiazepin-2,4-dione (clobazam), 5-(2-chlorophenyl)-7nitro-1,3-dihydro-1,4-benzodiazepin-2-one (clonazepam) , (S)-10-acetoxy-10,11-dihydro-5Hdibenz[b,f]azepine-5-carboxamide (eslicarbazepine acetate), (3-carbamoyloxy-2-phenylpropyl) carbamate (felbamate), 1-(aminomethyl) cyclohexaneacetic acid (gabapentin ), (R)-2-acetamido-N-benzyl-3methoxypropanamide (lacosamide), 5'-(2-cyanophenyl)-1'-phenyl-2,3'-bipyridinyl-6'(1'H)-one ( perampanel), 5-ethyl-5-phenyl-1,3-diazinan-2,4,6-trione (phenobarbital), 5,5-diphenylimidazolidine-2,4-dione (phenytoin), 2-(2-oxopyrrolidine- 1-yl)acetamide (piracetam), (3S)-3-(aminomethyl)-5-methylhexanoic acid (pregabalin), 5-ethyl-5-phenyl-1,3-diazinan-4,6-dione (primidone), ethyl (2-amino-4-((4fluorobenzyl)amino)phenyl)carbamate (retigabine), 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide (rufinamide), (RS )-(E)-4,4-dimethyl-1-[3,4(methylenedioxy)-phenyl]-1-penten-3-ol (styripentol), (3R)-1[4,4-bis(3- methyl-2-thienyl)-3-buten-1-yl]-3-piperidinecarboxylic acid (tiagabine), 2,3:4,5-bis-O-(1-

- 3 040556 methylethylidene)-β-D-fructopyranose sulfamate (topiramate), (RS)-4-α-minohex-5-enoic acid (vigabatrin) and benzo[d]isoxazol-3-ylmethanesulfonamide (zonisamide) or a pharmaceutically acceptable salt of any of above.

Carbamazepine (5H-dibenzo[b,f]azepine-5-carboxamide) has been described as effective in the treatment of focal seizures and tonic-clonic seizures. Pharmaceutical compositions containing carbamazepine are available in various dosage forms such as tablets, chewable tablets, suspensions and suppositories; tablets are also available in extended release form. The average total dose administered per day for adults ranges from 600 to 2000 mg and is usually administered in 2-4 divided doses. Carbamazepine can be prepared according to methods known in the art, for example as described in US 2948718.

(RS)-3-Ethyl-3-methyl-pyrrolidine-2,5-dione (Ethosuximide) has been described as effective for the treatment of absence seizures. Pharmaceutical compositions containing Ethosuximide are available in various dosage forms such as capsules or syrups. The average total dose administered per day for adults ranges from 750 to 1500 mg and is usually administered in 2 or 3 divided doses. Ethosuximide can be prepared according to methods known in the art, for example, as described in Sircar SSG (1927), J. Chem. soc. 1252-1256.

6-(2,3-Dichlorophenyl)-1,2,4-triazine-3,5-diamine (Lamotrigine) has been described as effective in the treatment of focal seizures and tonic-clonic seizures. Pharmaceutical compositions containing Lamotrigine are available in various dosage forms such as tablets and dispersible tablets. The average total dose administered per day for adults ranges from 100 to 400 mg and is usually administered in 1 or 2 divided doses. Lamotrigine can be prepared according to methods known in the art, for example as described in EP 0021121.

(S)-2-(2-Oxopyrrolidin-1-yl)butanamide (Levetiracetam) has been described as effective in the treatment of focal, tonic-clonic and myoclonic seizures. Pharmaceutical compositions containing Levetiracetam are available in various dosage forms such as tablets and oral solutions. The average total dose administered per day for adults ranges from 1000 to 3000 mg and is usually administered in 2 divided doses. Levetiracetam can be obtained in accordance with methods known in the art, for example, as described in US 4943639.

,11-Dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide (Oxcarbazepine) has been described as effective in the treatment of focal seizures and secondary generalized seizures. Pharmaceutical compositions containing oxcarbazepine are available in various dosage forms such as tablets and oral suspensions. The average total dose administered per day for adults ranges from 1200 to 2400 mg and is usually administered in 2 or 3 divided doses. Oxcarbazepine can be prepared according to methods known in the art, for example as described in US 3,642,775.

2-Propylpentanoic acid (Valproic acid) has been described as effective in the treatment of focal seizures, tonic-clonic seizures, and absence seizures. Of course, sodium valproate is the preferred pharmaceutically acceptable salt of valproic acid. In addition, it is understood that any reference to valproic acid or a pharmaceutically acceptable salt thereof refers to valproic acid, to a pharmaceutically acceptable salt of valproic acid (especially sodium valproate) and to a mixture of valproic acid and a pharmaceutically acceptable salt of valproic acid, such as in particular a mixture valproic acid and sodium valproate (namely, a mixture in a 1:1 molar ratio: sodium divalproex, half sodium valproate). Pharmaceutical compositions containing valproic acid and/or sodium valproate are available in various dosage forms such as tablets, crushable tablets, liquids and syrups; tablets and granules are also available in extended release form. The average total dose administered per day for adults ranges from 400 to 2000 mg and is usually administered in 1 or 2 divided doses. Valproic acid and sodium valproate can be prepared according to methods known in the art, for example as described in EP 0835859.

K-(5-Sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide (Acetazolamide) has been described as effective in the treatment of focal seizures, tonic-clonic seizures, and absence seizures. Pharmaceutical compositions containing acetazolamide are available in various dosage forms such as tablets and powders; the capsules are available in extended release form. The average total dose administered per day for adults ranges from 250 to 1000 mg and is usually administered in 2 or 3 divided doses. Acetazolamide can be prepared according to methods known in the art, for example as described in US 2554816.

(2S)-2-[(4R)-2-Oxo-4-propylpyrrolidin-1-yl]butanamide (Brivaracetam) has been described as effective for the treatment of focal seizures. Pharmaceutical compositions containing Brivaracetam are available in various dosage forms such as tablets and solutions. The average total dose administered per day for adults ranges from 50 to 200 mg and is usually administered in 2 divided doses. Brivaracetam can be prepared according to methods known in the art, for example, as described in Kenda B.M. et al. (2004), J. Med. Chem., 47, 530-549.

7-Chloro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4-dione (Clobazam) has been described as effective in the treatment of focal seizures and tonic-clonic seizures. Pharmaceutical compositions containing Clobazam are available in various dosage forms such as tablets and suspensions. The average total dose administered per day for adults ranges from 20 to 60 mg and is usually administered in 1 or 2 divided doses. Clobazam can be prepared according to methods known in the art, for example as described in US 3,984,398.

5-(2-Chlorophenyl)-7-nitro-1,3-dihydro-1,4-benzodiazepin-2-one (Clonazepam) has been described as effective in the treatment of focal seizures, tonic-clonic seizures, myoclonic seizures, and absence seizures. Pharmaceutical compositions containing Clonazepam are available in various dosage forms such as tablets and solutions. The average total dose administered per day for adults is 1 to 4 mg and is usually administered in 2 divided doses. Clonazepam can be prepared according to methods known in the art, for example as described in US 3,121,076.

(S)-10-Acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (Eslicarbazepine acetate) has been described as effective in the treatment of focal seizures. Pharmaceutical compositions containing eslicarbazepine acetate are available as tablets. The average total dose administered per day for adults ranges from 800 to 1200 mg and is usually administered as a single dose. Eslicarbazepine acetate can be prepared according to methods known in the art, for example as described in WO 2007/012793.

(3-Carbamoyloxy-2-phenylpropyl)carbamate (Felbamate) has been described as effective in the treatment of focal seizures and tonic-clonic seizures. Pharmaceutical compositions containing Felbamate are available in various dosage forms such as tablets and suspensions. The average total dose administered per day for adults ranges from 1200 to 3600 mg and is usually administered in 3 or 4 divided doses. Felbamate can be prepared according to methods known in the art, for example as described in US 2,884,444.

1-(Aminomethyl)cyclohexaneacetic acid (Gabapentin) has been described as effective for the treatment of focal seizures. Pharmaceutical compositions containing Gabapentin are available in various dosage forms such as tablets, capsules and solutions. The average total dose administered per day for adults ranges from 1800 to 3600 mg and is usually administered in 3 divided doses. Gabapentin can be prepared according to methods known in the art, for example as described in US 4,024,175.

(R)-2-Acetamido-N-benzyl-3-methoxypropanamide (Lacosamide) has been described as effective in the treatment of focal seizures. Pharmaceutical compositions containing Lacosamide are available in various dosage forms such as tablets, solutions and syrups. The average total dose administered per day for adults ranges from 200 to 400 mg and is usually administered in 2 divided doses. Lacosamide can be obtained in accordance with methods known in the art, for example, as described in Choi D. et al. (1996), J. Med. Chem., 39, 1907-1916.

5'-(2-Cyanophenyl)-1'-phenyl-2,3'-bipyridinyl-6'(1H)-one (Perampanel) has been described as effective in the treatment of focal seizures and tonic-clonic seizures. Pharmaceutical compositions containing Perampanel are available as tablets. The average total dose administered per day for adults is 4 to 12 mg and is usually given as a single dose. Perampanel can be obtained in accordance with methods known in the art, for example, as described in Hibi S. et al. (2012), J. Med. Chem., 55(23), 10584-10600.

5-Ethyl-5-phenyl-1,3-diazinan-2,4,6-trione (Phenobarbital) has been described as effective in the treatment of focal seizures and tonic-clonic seizures. Pharmaceutical compositions containing Phenobarbital are available in various dosage forms such as tablets and solutions. The average total dose administered per day for adults ranges from 30 to 180 mg and is usually administered in 2 divided doses. Phenobarbital can be prepared according to methods known in the art, for example as described in US 1,025,872.

5,5-Diphenylimidazolidine-2,4-dione (Phenytoin) has been described as effective in the treatment of focal seizures and tonic-clonic seizures. It is understood that sodium phenytoin is the preferred pharmaceutically acceptable salt of phenytoin. In addition, it is understood that any reference to Phenytoin or a pharmaceutically acceptable salt thereof refers to Phenytoin and a pharmaceutically acceptable salt of Phenytoin (especially Phenytoin sodium). Pharmaceutical compositions containing phenytoin or sodium phenytoin are available in various dosage forms such as tablets, chewable tablets, capsules, solutions and suspensions. The average total dose administered per day for adults ranges from 150 to 500 mg and is usually administered in 1 or 2 divided doses. Phenytoin can be prepared according to methods known in the art, for example as described in US 2409754.

2-(2-Oxopyrrolidin-1-yl)acetamide (Piracetam) has been described as effective for the treatment of myoclonic seizures. Pharmaceutical compositions containing Piracetam are available in various dosage forms such as tablets and solutions. The average total dose administered per day for adults ranges from 7.2 to 24 mg and is usually administered in 2 or 3 divided doses. Piracetam can be obtained in accordance with methods known in the art, for example, as described in US 3459738.

(3S)-3-(Aminomethyl)-5-methylhexanoic acid (Pregabalin) has been described as effective in the treatment of focal seizures. Pharmaceutical compositions containing Pregabalin are available in various dosage forms such as capsules and solutions. The average total dose administered per day for adults ranges from 300 to 600 mg and is usually administered in 2 divided doses. Pregabalin can be obtained in accordance with methods known in the art, for example, as described in Hoekstra et al., Org. Process Res. dev. 1997, 1, 26-38.

5-Ethyl-5-phenyl-1,3-diazinan-4,6-dione (Primidon) has been described as effective in the treatment of focal seizures and tonic-clonic seizures. Pharmaceutical compositions containing Primidone are available in tablet form. The average total dose administered per day for adults ranges from 500 to 1500 mg and is usually administered in 2-4 divided doses. Primidone can be prepared according to methods known in the art, for example as described in GB 1597796.

Ethyl-(2-amino-4-((4-fluorobenzyl)amino)phenyl)carbamate (Retigabine) has been described as effective for the treatment of focal seizures. Pharmaceutical compositions containing Retigabine are available in tablet form. The average total dose administered per day for adults ranges from 900 to 1200 mg and is usually administered in 3 divided doses. Retigabine can be prepared according to methods known in the art, for example as described in US 5384330 or WO 2012/098075.

1-(2,6-Difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide (Rufinamide) has been described as effective in the treatment of seizures associated with Lennox-Gastaut syndrome. Pharmaceutical compositions containing Rufinamide are available in various dosage forms such as tablets and suspensions. The average total dose administered per day for adults ranges from 200 to 3600 mg and is usually administered in 2 divided doses. Rufinamide can be prepared according to methods known in the art, for example as described in US 4,789,680.

(RS)-(-E)-4,4-dimethyl-1-[3,4(methylenedioxy)phenyl]-1-penten-3-ol (Stiripentol) has been described as effective for the treatment of tonic-clonic seizures in severe myoclonic epilepsy in infants (SMEI or Dravet syndrome). Pharmaceutical compositions containing Styripentol are available in various dosage forms such as capsules and powders. The average total dose administered per day for adults is up to 50 mg/kg and is usually given in 2 or 3 divided doses. Stiripentol can be obtained in accordance with methods known from the prior art, for example, as described in DE 2308494.

(3R)-1-[4,4-bis(3-methyl-2-thienyl)-3-buten-1-yl]-3-piperidinecarboxylic acid (Tiagabine) has been described as effective in the treatment of focal seizures. It is understood that (3R)-1-[4,4-6uc(3methyl-2-thienyl)-3-buten-1-yl]-3-piperidinecarboxylic acid hydrochloride is the preferred pharmaceutically acceptable salt of Tiagabine. In addition, it is understood that any reference to (3R)-1-[4,4-6uc(3methyl-2-thienyl)-3-buten-1-yl]-3-piperidinecarboxylic acid or a pharmaceutically acceptable salt thereof refers to ( 3R)-1-[4,4-bis(3-methyl-2-thienyl)-3-buten-1-yl]-3-piperidinecarboxylic acid and the pharmaceutically acceptable salt of (3R)-1-[4,4- bis(3-methyl-2-thienyl)-3-buten-1-yl]-3-piperidinecarboxylic acid (especially (3R)-1-[4,4-bis(3-methyl-2-thienyl)-)- 3-buten-1-yl]-3piperidinecarboxylic acid).

Pharmaceutical compositions containing (3R)-1-[4,4-bis(3-methyl-2-thienyl)-3-buten-1-yl]-3-piperidinecarboxylic acid and/or (3R)-1-[4, 4-bis(3-methyl-2-thienyl)-3-buten-1-yl]-3-piperidinecarboxylic acid is available in tablet form. The average total dose administered per day for adults ranges from 30 to 45 mg and is usually administered in 1-3 doses. (3R)-1-[4,4-bis(3-methyl-2thienyl)-3-buten-1-yl]-3-piperidinecarboxylic acid and (3R)-1-[4,4-bis(3- methyl-2thienyl)-3-buten-1-yl]-3-piperidinecarboxylic acid can be prepared according to methods known in the art, for example, as described in Andersen et al., J. Med. Chem. 1993, 36(12), 1716.

2, 3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate (Topiramate) has been described as effective in the treatment of focal seizures and tonic-clonic seizures. Pharmaceutical compositions containing Topiramate are available in various dosage forms such as tablets and capsules. The average total dose administered per day for adults ranges from 200 to 400 mg and is usually administered in 2 divided doses. Topiramate can be prepared according to methods known in the art, for example, as described in Maryanoff et al., J. Med. Chem. 1987, 30(5), 880.

(RS)-4-Aminohex-5-enoic acid (Vigabatrin) has been described as effective for the treatment of focal seizures. Pharmaceutical compositions containing Vigabatrin are available in various dosage forms such as tablets and granules. The average total dose administered per day for adults ranges from 1000 to 4000 mg and is usually administered in 1 or 2 divided doses. Vigabatrin can be prepared according to methods known in the art, for example as described in EP 0427197.

Benzo[d]isoxazol-3-ylmethanesulfonamide (Zonisamide) has been described as effective for the treatment of focal seizures. Pharmaceutical compositions containing Zonisamide are available in capsule form. The average total dose administered per day for adults is 300 to 500 mg and is usually administered in 1 or 2 divided doses. Zonisamide can be prepared according to methods known in the art, for example, as described in Uno et al., J. Med. Chem. 1979, 22(2), 180.

3) Another embodiment of the invention relates to a pharmaceutical combination in accordance with

- 6 040556 according to embodiment 1), wherein the second active substance is selected from the group consisting of 5H-dibenzo[b,f]azepine-5-carboxamide (Carbamazepine), (RS)-3-ethyl-3-methyl-pyrrolidine2 ,5-dione (Ethosuximide), 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine (Lamotrigine), (S)-2-(2oxopyrrolidin-1-yl)butanamide ( Levetiracetam) 2,3:4,5-bis-O-(1-methylethylidene)-v-O-fructopyranose sulfamate (Topiramate) or a pharmaceutically acceptable salt of any of the above.

4) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is selected from the group consisting of 5H-dibenzo[b,f]azepine-5-carboxamide (Carbamazepine), (RS)-3 -ethyl-3-methyl-pyrrolidine2,5-dione (Ethosuximide), 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine (Lamotrigine), (S)-2-( 2oxopyrrolidin-1-yl)butanamide (Levetiracetam), 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5carboxamide (Oxcarbazepine), and 2-propylpentanoic acid (Valproic acid) or a pharmaceutically acceptable salt of any of above.

5) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is selected from the group consisting of 5H-dibenzo[b,f]azepine-5-carboxamide (Carbamazepine), (RS)-3 -ethyl-3-methyl-pyrrolidine2,5-dione (Ethosuximide), 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine (Lamotrigine), 10,11-dihydro10-oxo -5H-dibenz[b,f]azepine-5-carboxamide (Oxcarbazepine), 2-propylpentanoic acid (Valproic acid), 7-chloro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4-dione (Clobazam), 5-(2-chlorophenyl)-7-nitro1,3-dihydro-1,4-benzodiazepin-2-one (Clonazepam), 5-ethyl-5-phenyl-1,3-diazinan-2,4 ,6-trione (Phenobarbital), 5,5-diphenylimidazolidine-2,4-dione (Phenytoin), 5-ethyl-5-phenyl-1,3-diazinan-4,6-dione (Primidone), 2.3: 4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate (Topiramate) and benzo[d]isoxazol3-ylmethanesulfonamide (Zonisamide) or a pharmaceutically acceptable salt of any of the above.

6) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is selected from the group consisting of (RS)-3-ethyl-3-methyl-pyrrolidine-2,5-dione (Ethosuximide) , 6-(2,3-dichlorophenyl)-1,2,4triazine-3,5-diamine (Lamotrigine), 2-propylpentanoic acid (Valproic acid) and 2,3:4,5-bisO-(1-methylethylidene) -v-O-fructopyranose sulfamate (Topiramate) or a pharmaceutically acceptable salt of any of the above.

7) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is selected from the group consisting of (RS)-3-ethyl-3-methyl-pyrrolidine-2,5-dione (Ethosuximide) , 6-(2,3-dichlorophenyl)-1,2,4triazine-3,5-diamine (Lamotrigine) and 2-propylpentanoic acid (Valproic acid) or a pharmaceutically acceptable salt of any of the above.

8) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is selected from the group consisting of 5H-dibenzo[b,f]azepine-5-carboxamide (Carbamazepine), 6-(2, 3-dichlorophenyl)-1,2,4-triazine3,5-diamine (Lamotrigine), 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide (Oxcarbazepine), 2-propylpentanoic acid (Valproic acid), 7-chloro-1-methyl-5-phenyl-1,5-benzodiazepine2,4-dione (Clobazam), 5-ethyl-5-phenyl-1,3-diazinan-2,4,6 -trione (Phenobarbital), 5,5-diphenylimidazolidine-2,4-dione (Phenytoin), 5-ethyl-5-phenyl-1,3-diazinan-4,6-dione (Primidon), 2.3:4, 5-bis-O-(1methylethylidene)-β-D-fructopyranose sulfamate (Topiramate) and benzo[d]isoxazol-3-ylmethanesulfonamide (Zonisamide) or a pharmaceutically acceptable salt of any of the above.

9) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is selected from the group consisting of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5- diamine (Lamotrigine), 2-propylpentanoic acid (Valproic acid) and 2,3:4,5-bis-O-(1-methylethylidene)-v-O-fructopyranose sulfamate (Topiramate) or a pharmaceutically acceptable salt of any of the above.

10) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is selected from the group consisting of (RS)-3-ethyl-3-methyl-pyrrolidine-2,5-dione (Ethosuximide) , 6-(2,3-dichlorophenyl)-1,2,4triazine-3,5-diamine (Lamotrigine), (S)-2-(2-oxopyrrolidin-1-yl)butanamide (Levetiracetam), 2-propylpentanoic acid (Valproic acid) and 5-(2-chlorophenyl)-7-nitro-1,3-dihydro-1,4benzodiazepin-2-one (Clonazepam) or a pharmaceutically acceptable salt of any of the above.

11) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is selected from the group consisting of (RS)-3-ethyl-3-methyl-pyrrolidine-2,5-dione (Ethosuximide) and 2-propylpentanoic acid (Valproic acid) or a pharmaceutically acceptable salt of any of the above.

- 7 040556

12) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is selected from the group consisting of 5H-dibenzo[b,f]azepine-5-carboxamide (Carbamazepine), (S)-2 -(2-oxopyrrolidin-1yl)butanamide (Levetiracetam), 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide (Oxcarbazepine), 2-propylpentanoic acid (Valproic acid), ( 2S)-2-[(4R)-2-oxo-4-propylpyrrolidin1-yl]butanamide (Brivaracetam), 7-chloro-1-methyl-5-phenyl-1,5-benzodiazepin-2,4-dione (Clobazam ), (S)-10acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (Eslicarbazepine acetate), 1-(aminomethyl)cyclohexaneacetic acid (Gabapentin), (R)-2-acetamido -N-benzyl-3-methoxypropanamide (Lacosamide), 5'-(2-cyanophenyl)-1'-phenyl-2,3'-bipyridinyl-6'(1'H)-one (Perampanel), 5-ethyl- 5-phenyl-1,3diazinan-2,4,6-trione (Phenobarbital), 5,5-diphenylimidazolidine-2,4-dione (Phenytoin), (3S)-3(aminomethyl)-5-methylhexanoic acid (Pregabalin) , 5-ethyl-5- phenyl-1,3-diazinan-4,6-dione (Primidon), ethyl (2-amino-4-((4-fluorobenzyl)amino)phenyl)carbamate (Retigabine), 1-(2,6-difluorobenzyl)- 1H1,2,3-triazol-4-carboxamide (Rufinamide), (3R)-1-[4,4-6uc(3-methyl-2-thienyl)-3-buten-1-yl]-3-piperidinecarboxylic acid (Tiagabine), 2,3:4,5-bis-O-(1-methylethylidene)-v-O-fructopyranose sulfamate (Topiramate), (RS)-4-aminohex-5-enoic acid (Vigabatrin) and benzo[ d]isoxazol-3ylmethanesulfonamide (Zonisamide) or a pharmaceutically acceptable salt of any of the above.

13) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is selected from the group consisting of 5H-dibenzo[b,f]azepine-5-carboxamide (Carbamazepine), (S)-2 -(2-oxopyrrolidin-1yl)butanamide (Levetiracetam), 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide (Oxcarbazepine), 2-propylpentanoic acid (Valproic acid), ( S)-10-acetoxy-10,11-dihydro-5Hdibenz[b,f]azepine-5-carboxamide (Eslicarbazepine acetate), 1-(aminomethyl)cyclohexaneacetic acid (Gabapentin), (R)-2-acetamido-N- benzyl-3-methoxypropanamide (Lacosamide), 5-ethyl-5-phenyl-1,3diazinan-2,4,6-trione (Phenobarbital), 5,5-diphenylimidazolidine-2,4-dione (Phenytoin), (3S) -3(aminomethyl)-5-methylhexanoic acid (Pregabalin), 5-ethyl-5-phenyl-1,3-diazinan-4,6-dione (Primidon), 1-(2,6-difluorobenzyl)- 1H-1 ,2,3-triazol-4-carboxamide (Rufinamide), (3R)- 1-[4,4-bis(3-methyl-2thienyl)-3-buten-1-yl]-3-piperidinecarboxylic acid (Tiagabine) , 2.3 :4,5-bis-O-(1-methylethylidene)-PD-fructopyranose sulfamate (Topiramate) and benzo[d]isoxazol-3-ylmethanesulfonamide (Zonisamide) or a pharmaceutically acceptable salt of any of the above.

14) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is selected from the group consisting of 5H-dibenzo[b,f]azepine-5-carboxamide (Carbamazepine), (S)-2 -(2-oxopyrrolidin-1yl)butanamide (Levetiracetam), 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide (Oxcarbazepine) and 2-propylpentanoic acid (Valproic acid) or pharmaceutically an acceptable salt of any of the above.

15) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is selected from the group consisting of 5H-dibenzo[b,f]azepine-5-carboxamide (Carbamazepine), 10,11-dihydro -10-oxo-5Hdibenz[b,f]azepine-5-carboxamide (Oxcarbazepine), 2-propylpentanoic acid (Valproic acid) and 5,5-diphenylimidazolidine-2,4-dione (Phenytoin), or a pharmaceutically acceptable salt of any of the following higher.

16) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is selected from the group consisting of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5- diamine (Lamotrigine), 2-propylpentanoic acid (Valproic acid), 5-(2-chlorophenyl)-7-nitro-1,3-dihydro-1,4-benzodiazepin-2-one (Clonazepam), 2-(2- oxopyrrolidin-1-yl)acetamide (Piracetam) and 2,3:4,5-bis-O-(1-methylethylidene)-b-Ofructopyranose sulfamate (Topiramate) or a pharmaceutically acceptable salt of any of the above.

17) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), in which the second active substance is selected from the group consisting of (S)-2-(2-oxopyrrolidin-1-yl)butanamide (Levetiracetam) and 2- propylpentanoic acid (Valproic acid) or a pharmaceutically acceptable salt of any of the above.

18) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is 5Hdibenzo[b,f]azepine-5-carboxamide (Carbamazepine) or a pharmaceutically acceptable salt thereof.

19) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is (RS)-3ethyl-3-methyl-pyrrolidine-2,5-dione (Ethosuximide) or a pharmaceutically acceptable salt thereof .

20) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), in which the second active substance is 6-(2,3-

- 8 040556 dichlorophenyl)-1,2,4-triazine-3,5-diamine (Lamotrigine) or a pharmaceutically acceptable salt thereof.

21) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), in which the second active substance is (S)-2(2-oxopyrrolidin-1-yl)butanamide (Levetiracetam) or a pharmaceutically acceptable salt thereof.

22) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is 10,11dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide (Oxcarbazepine) or its pharmaceutically acceptable salt.

23) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), in which the second active substance is 2-propylpentanoic acid (Valproic acid) or a pharmaceutically acceptable salt thereof.

24) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), in which the second active substance is N-(5sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide (Acetazolamide) or its pharmaceutically acceptable salt.

25) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), in which the second active substance is (2S)-2[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide (Brivaracetam ) or a pharmaceutically acceptable salt thereof.

26) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1) wherein the second active substance is 7-chloro1-methyl-5-phenyl-1,5-benzodiazepine-2,4-dione (Clobazam) or its pharmaceutically acceptable salt.

27) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), in which the second active substance is 5-(2chlorophenyl)-7-nitro-1,3-dihydro-1,4-benzodiazepin-2-one (Clonazepam) or a pharmaceutically acceptable salt thereof.

28) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), in which the second active substance is (S)-10acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (Eslicarbazepine acetate) or a pharmaceutically acceptable salt thereof.

29) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is (3-carbamoyloxy-2-phenylpropyl) carbamate (Felbamate) or a pharmaceutically acceptable salt thereof.

30) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is 1(aminomethyl)cyclohexaneacetic acid (Gabapentin) or a pharmaceutically acceptable salt thereof.

31) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is (R)-2acetamido-N-benzyl-3-methoxypropanamide (Lacosamide) or a pharmaceutically acceptable salt thereof.

32) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), in which the second active substance is 5'-(2cyanophenyl)-G-phenyl-2,3'-bipyridinyl-6'(1H)-one (Perampanel) or a pharmaceutically acceptable salt thereof.

33) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), in which the second active substance is 5-ethyl5-phenyl-1,3-diazinan-2,4,6-trione (Phenobarbital) or its pharmaceutical acceptable salt.

34) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is 5,5-diphenylimidazolidine-2,4-dione (Phenytoin) or a pharmaceutically acceptable salt thereof.

35) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is 2-(2oxopyrrolidin-1-yl)acetamide (Piracetam) or a pharmaceutically acceptable salt thereof.

36) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is (3S)-3(aminomethyl)-5-methylhexanoic acid (Pregabalin) or a pharmaceutically acceptable salt thereof.

37) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is 5-ethyl5-phenyl-1,3-diazinan-4,6-dione (Primidon) or a pharmaceutically acceptable salt thereof .

38) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is ethyl (2amino-4-((4-fluorobenzyl)amino)phenyl)carbamate (Retigabine) or a pharmaceutically acceptable salt thereof .

39) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), in which the second active substance is 1-(2,6-

- 9 040556 difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide (Rufinamide) or a pharmaceutically acceptable salt thereof.

40) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is (RS)(E)-4,4-dimethyl-1-[3,4-(methylenedioxy)phenyl] -1-penten-3-ol (Stiripentol) or a pharmaceutically acceptable salt thereof.

41) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), in which the second active substance is (3R)-1[4,4-bis(3-methyl-2-thienyl)-3-butene- 1-yl]-3-piperidinecarboxylic acid (Tiagabine) or a pharmaceutically acceptable salt thereof.

42) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1) wherein the second active substance is 2.3:4.5 bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate (Topiramate) or a pharmaceutically acceptable salt thereof.

43) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is (RS)-4-aminohex-5-enoic acid (Vigabatrin) or a pharmaceutically acceptable salt thereof.

44) Another embodiment of the invention relates to a pharmaceutical combination according to embodiment 1), wherein the second active substance is benzo[d]isoxazol-3-ylmethanesulfonamide (Zonisamide) or a pharmaceutically acceptable salt thereof.

45) Another embodiment of the invention relates to a pharmaceutical combination according to one of the embodiments 1) to 44), in which the first and second active substance are contained in one pharmaceutical composition.

In the specific case of embodiment 45) where one active is administered more frequently than the other active, only one or more (up to the number of administrations for the less frequently administered active) pharmaceutical compositions required per day will contain both the first and second actives. substances. For example, when one of the two active substances is administered once a day and the other active substance twice a day, then only one of the two pharmaceutical compositions required per day will contain both the first and the second active substance, while the other will contain only the active substance, which is administered twice a day.

Further, in the case of the pharmaceutical combination according to Embodiment 45) in which the first and/or second active agent is administered according to a dose escalation regimen, the pharmaceutical compositions required for the dose escalation will contain the amounts of active agent required for the various stages of the dose escalation regimen.

46) An additional embodiment of the invention relates to a pharmaceutical combination according to any one of embodiments 1) to 44), in which the first and second active substances are contained in separate pharmaceutical compositions.

In the case where the first and second active substances are contained in separate pharmaceutical compositions, it can be administered simultaneously, sequentially or separately; preferably, the individual pharmaceutical compositions are administered simultaneously or sequentially, in particular sequentially. In the case where the first active substance is administered, for example, once a day and the second active substance twice a day, the individual pharmaceutical compositions are preferably administered once a day simultaneously or sequentially, in particular sequentially. Whether administered sequentially or separately, the separated pharmaceutical compositions may be administered in either order. The number of administrations per day may be the same or different for individual pharmaceutical compositions. For example, one pharmaceutical composition may be administered twice daily and another pharmaceutical composition may be administered once or twice daily. Preferably, the pharmaceutical composition containing compound 1 is administered once a day, and the pharmaceutical composition containing the second active substance is administered once, twice or three times a day (most preferably once or twice a day). In addition, the individual pharmaceutical compositions may be administered by the same or different routes of administration, preferably by the same route of administration. Most preferably, the individual pharmaceutical compositions are administered orally. The first and/or second active agent may be administered independently of each other according to a dose escalation regimen to an appropriate maintenance dose; pharmaceutical compositions containing the first and/or second active agent required for dose escalation will contain the amounts of active agent required for the various stages of the dose escalation regimen.

47) Another embodiment of the invention relates to a pharmaceutical combination according to any one of embodiments 1) to 46) for use as a medicine.

48) Another embodiment of the invention relates to a pharmaceutical combination according to any of embodiments 1) to 46) for use in a preventive

- 10 040556 research / prevention and / or treatment of a disease or disorder associated with dysfunction of T-type calcium channels (namely, diseases or disorders in which blockade of T-type calcium channels of the subtypes Ca _v 3.1, Ca _v 3.2 and / or Ca _v 3.3).

49) Another embodiment of the invention relates to a pharmaceutical combination according to any one of embodiments 1) to 46) for use in the prevention/prevention and/or treatment of epilepsy (namely, idiopathic generalized epilepsy).

50) Another embodiment of the invention relates to a pharmaceutical combination according to any one of embodiments 1) to 46) for use in the prevention/prophylaxis and/or treatment of focal and/or generalized seizures.

51) Another embodiment of the invention relates to a pharmaceutical combination according to any one of embodiments 1) to 46) for use in the prevention/prophylaxis and/or treatment of focal, tonic, clonic, tonic-clonic, absences, myoclonic and/or atonic seizures.

52) Another embodiment of the invention relates to a pharmaceutical combination according to any one of embodiments 1) to 46) for use in the prevention/prophylaxis and/or treatment of tonic-clonic, absences, myoclonic and/or atonic seizures.

53) Another embodiment of the invention relates to a pharmaceutical combination according to any one of embodiments 1) to 46) for use in the prevention/prophylaxis and/or treatment of tonic-clonic and/or absence seizures.

54) Another embodiment of the invention relates to a pharmaceutical combination according to any one of embodiments 1) to 46) for use in the prevention/prophylaxis and/or treatment of tonic-clonic seizures.

55) Another embodiment of the invention relates to a pharmaceutical combination according to any one of embodiments 1) to 46) for use in the prevention/prevention and/or treatment of absence seizures.

The term epilepsy describes recurrent unprovoked seizures, and the term seizure refers to excessive and/or hypersynchronous electrical activity of neurons. Different types of seizures are described, for example, in Berg et al., Epilepsia. 2010; 51(4): 676-685, which is hereby incorporated herein by reference.

The present invention also relates to a method for preventing/preventing and/or treating a disease or disorder listed in any of embodiments 48) to 55), comprising administering to a subject in need (preferably a human subject), a pharmaceutically active amount of a pharmaceutical combination in according to any one of embodiments 1) to 46).

56) Another embodiment of the invention relates to a pharmaceutical composition containing N-[1-(5-cyano-pyridin-2-ylmethyl)-1H-pyrazol-3-yl]-2-[4-(1trifluoromethyl- cyclopropyl)phenyl]acetamide or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient, wherein the pharmaceutical composition is administered in combination with a second pharmaceutical composition containing 5Hdibenzo[b,f]azepine-5-carboxamide (Carbamazepine) as an active principle , (RS)-3-ethyl-3-methyl-pyrrolidine-2,5-dione (Ethosuximide), 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine (Lamotrigine) , (S)-2-(2-oxopyrrolidin-1yl)butanamide (Levetiracetam), 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide (Oxcarbazepine), 2-propylpentanoic acid (Valproic acid), N-(5-sulfαmoyl-1,3,4-tuαduαzol-2yl)acetamide (Acetazolamide), (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl] butanamide (Brivaracetam), 7-chloro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4-dione (Clobazam ), 5-(2-chlorophenyl)-7-nitro-1,3-dihydro1,4-benzodiazepin-2-one (Clonazepam), (S)-10-acetoxy-10,11-dihydro-5H-dibenz[b ,f]azepine-5carboxamide (Eslicarbazepine acetate), (3-carbamoyloxy-2-phenylpropyl) carbamate (Felbamate), 1(aminomethyl)cyclohexaneacetic acid (Gabapentin), (R)-2-acetamido-N-benzyl-3-methoxypropanamide (Lacosamide), 5'-(2-cyanophenyl)-1'-phenyl-2,3'-bipyridinyl-6'(1H)-one (Perampanel), 5-ethyl5-phenyl-1,3-diazinan-2, 4,6-trione (Phenobarbital), 5,5-diphenylimidazolidine-2,4-dione (Phenytoin), 2-(2oxopyrrolidin-1-yl)acetamide (Piracetam), (3S)-3-(aminomethyl)-5- methylhexanoic acid (Pregabalin), 5-ethyl-5-phenyl-1,3-diazinan-4,6-dione (Primidon), ethyl (2-amino-4-((4-fluorobenzyl)amino)phenyl)carbamate (Retigabine ), 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide (Rufinamide), (RS)-(E)4,4-dimethyl-1-[3,4(methylenedioxy )phenyl]-1-penten-3-ol (Stiripentol), (3R)-1-[4,4-bis(3-methyl-2thienyl)-3-buten-1-yl]-3-piperidinecarboxylic acid (Tiagabine ), 2,3:4,5-bis-O-(1-methylethylidene)-vD-fructopyr anoses sulfamate (Topiramate), (RS)-4-aminohex-5-enoic acid (Vigabatrin) or benzo[d]isoxazol-3-ylmethanesulfonamide (Zonisamide) or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.

57) Another embodiment of the invention relates to a pharmaceutical composition containing N-[1-(5-cyano-pyridin-2-ylmethyl)-1H-pyrazol-3-yl]-2-[4-(1trifluoromethyl- cyclopropyl)phenyl]acetamide or a pharmaceutically acceptable salt thereof, and at least

- 11 040556 at least one therapeutically inert excipient, wherein the pharmaceutical composition is administered in combination with a second pharmaceutical composition containing (RS) 3-ethyl-3-methyl-pyrrolidine-2,5-dione (Ethosuximide), 6-( 2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine (Lamotrigine), (S)-2-(2-oxopyrrolidin-1-yl)butanamide (Levetiracetam), 2-propylpentanoic acid (Valproic acid) or 5-(2-chlorophenyl)-7-nitro-1,3-dihydro-1,4-benzodiazepin-2-one (Clonazepam) or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.

58) Another embodiment of the invention relates to a pharmaceutical composition according to embodiment 56) or 57) for use as a medicine.

59) Another embodiment of the invention relates to a pharmaceutical composition according to embodiment 56) or 57) for use in the prevention/prevention and/or treatment of a disease or disorder listed in any of embodiments 48) to 55).

60) Another embodiment of the invention relates to a pharmaceutical composition containing 5H-dibenzo[b,f]azepine-5-carboxamide (Carbamazepine), (RS)3-ethyl-3-methyl-pyrrolidine-2,5- dione (Ethosuximide), 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine (Lamotrigine), (S)-2-(2-oxopyrrolidin-1-yl)butanamide (Levetiracetam ), 10,11-dihydro-10-oxo-5Hdibenz[b,f]azepine-5-carboxamide (Oxcarbazepine), 2-propylpentanoic acid (Valproic acid), N-(5-sulfamoyl-1,3,4-thiadiazole -2-yl)acetamide (Acetazolamide), (2S)-2-[(4R)-2-okco-4propylpyrrolidin-1 -yl]butanamide (Brivaracetam), 7-chloro-1-methyl-5-phenyl-1, 5-benzodiazepin-2,4-dione (Clobazam), 5-(2-chlorophenyl)-7-nitro-1,3-dihydro-1,4-benzodiazepin-2-one (Clonazepam), (S)-10- acetoxy10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (Eslicarbazepine acetate), (3-carbamoyloxy-2phenylpropyl) carbamate (Felbamate), 1-(aminomethyl)cyclohexaneacetic acid (Gabapentin), (R) -2acetamido-N-benzyl-3-methoxypropanamide (Lacosamide), 5' -(2-cyanophenyl)-1'-phenyl-2,3'-bipyridinyl6'(1H)-one (Perampanel), 5-ethyl-5-phenyl-1,3-diazinan-2,4,6-trione ( Phenobarbital), 5,5-diphenylimidazolidine-2,4-dione (Phenytoin), 2-(2-oxopyrrolidin-1-yl)acetamide (Piracetam), (3S)-3(aminomethyl)-5-methylhexanoic acid (Pregabalin) , 5-ethyl-5-phenyl-1,3-diazinan-4,6-dione (Primidon), ethyl (2-amino-4-((4-fluorobenzyl)amino)phenyl)carbamate (Retigabine), 1-( 2,6-difluorobenzyl)-1H1,2,3-triazole-4-carboxamide (Rufinamide), (RS)-(E)-4,4-dimethyl-1 -[3,4(methylenedioxy)-phenyl] -1 -penten3-ol (Stiripentol), (3R)-1-[4,4-bis(3-methyl-2-thienyl)-3-buten-1-yl]-3-piperidinecarboxylic acid (Tiagabine), 2.3 :4,5-bis-O-(1-methylethylidene)-b-O-fructopyranose sulfamate (Topiramate), (RS)-4-aminohex-5-enoic acid (Vigabatrin), or benzo[d]isoxazol-3-ylmethanesulfonamide ( Zonisamide) or a pharmaceutically acceptable salt thereof and at least one therapeutically inert excipient, wherein the pharmaceutical composition is administered in combination with a second pharmaceutical composition containing containing as active principle N-[1-(5-cyano-pyridin-2-ylmethyl)-1H-pyrazol-3yl]-2-[4-(1-trifluoromethyl-cyclopropyl)phenyl]acetamide or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.

61) Another embodiment of the invention relates to a pharmaceutical composition containing (RS)-3-ethyl-3-methyl-pyrrolidine-2,5-dione (Ethosuximide), 6(2,3-dichlorophenyl)-1, 2,4-triazine-3,5-diamine (Lamotrigine), (S)-2-(2-oxopyrrolidin-1-yl)butanamide (Levetiracetam), 2-propylpentanoic acid (Valproic acid), or 5-(2- chlorophenyl)-7-nitro-1,3dihydro-1,4-benzodiazepin-2-one (Clonazepam) or a pharmaceutically acceptable salt thereof and at least one therapeutically inert excipient, wherein the pharmaceutical composition is administered in combination with a second pharmaceutical composition containing N-[1(5-cyano-pyridin-2-ylmethyl)-1H-pyrazol-3-yl]-2-[4-(1-trifluoromethyl-cyclopropyl)phenyl]acetamide, or a pharmaceutically acceptable salt thereof, as the active principle, and at least one therapeutically inert excipient.

62) Another embodiment of the invention relates to a pharmaceutical composition according to embodiment 60) or 61) for use as a medicine.

63) Another embodiment of the invention relates to a pharmaceutical composition according to embodiment 60) or 61) for use in the prevention/prevention and/or treatment of a disease or disorder listed in any of embodiments 48) to 55).

64) Another embodiment of the invention relates to a kit of parts comprising a first pharmaceutical composition containing N-[1-(5-cyanopyridin-2-ylmethyl)-1H-pyrazol-3-yl]-2-[ 4-(1-trifluoromethyl-cyclopropyl)phenyl]acetamide or a pharmaceutically acceptable salt thereof and at least one therapeutically inert excipient; and a second pharmaceutical composition containing 5Hdibenzo[b,f]azepine-5-carboxamide (Carbamazepine), (RS)-3-ethyl-3-methyl-pyrrolidine-2,5-dione (Ethosuximide), 6- (2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine (Lamotrigine), (S)-2-(2-oxopyrrolidin-1yl)butanamide (Levetiracetam), 10,11-dihydro-10 -oxo-5H-dibenz[b,f]azepine-5-carboxamide (Oxcarbazepine), 2-propylpentanoic acid (Valproic acid), N-(5-sulfamoyl-1,3,4-thiadiazole-2-

- 12 040556 yl)acetamide (Acetazolamide), (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide (Brivaracetam),

7-chloro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4-dione (Clobazam), 5-(2-chlorophenyl)-7-nitro-1,3-dihydro1,4-benzodiazepine-2 -one (Clonazepam), (S)-10-acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (Eslicarbazepine acetate), (3-carbamoyloxy-2-phenylpropyl)carbamate (Felbamate ), 1(aminomethyl)cyclohexaneacetic (R)-2-acetamido-N-benzyl-3(Gabapentin), acid methoxypropanamide (Lacosamide), 5'-(2-cyanophenyl)-1'-phenyl-2,3'-bipyridinyl -6'( 1 H)-one (Perampanel), 5-ethyl-5-phenyl-1,3-diazinan-2,4,6-trione (Phenobarbital), 5,5-diphenylimidazolidine-2,4-dione ( Phenytoin), 2-(2-oxopyrrolidin-1-yl)acetamide (Piracetam), (3S)-3-(aminomethyl)-5-methylhexanoic acid (Pregabalin), 5-ethyl-5-phenyl-1,3-diazinan -4,6-dione (Primidone), ethyl (2-amino-4-((4-fluorobenzyl)amino)phenyl)carbamate (Retigabine), 1-(2,6-difluorobenzyl)-1H-1,2,3 -triazole-4-carboxamide (Rufinamide), (RS)-(E)-4,4-dimethyl-1-[3,4(methylenedioxy)-phenyl]-1-penten-3-ol (Stiripentol), (3R )-1-[4,4-6uc(3methyl-2-thienyl)-3-buten-1-yl]-3-piperidinecarboxylic acid (Tiagabine), 2,3:4,5-bis-O-(1methylethylidene)-β-D-fructopyranose sulfamate (Topiramate), (RS)-4-aminohex-5-enoic acid (Vigabatrin), or benzo[d ]isoxazol-3-ylmethanesulfonamide (Zonisamide) or a pharmaceutically acceptable salt thereof and at least one therapeutically inert excipient.

65) Another embodiment of the invention relates to a kit of parts comprising a first pharmaceutical composition containing, as an active principle, K-[1-(5-cyanopyridin-2-ylmethyl)-1H-pyrazol-3-yl]-2-[ 4-(1-trifluoromethyl-cyclopropyl)phenyl]acetamide or a pharmaceutically acceptable salt thereof and at least one therapeutically inert excipient; and a second pharmaceutical composition containing (RS)-3-ethyl-3methyl-pyrrolidine-2,5-dione (Ethosuximide), 6-(2,3-dichlorophenyl)-1,2,4-triazine-3 as an active principle ,5-diamine (Lamotrigine), (S)-2-(2-oxopyrrolidin-1-yl)butanamide (Levetiracetam), 2-propylpentanoic acid (Valproic acid), or 5-(2-chlorophenyl)-7-nitro-1 ,3-dihydro-1,4-benzodiazepin-2-one (Clonazepam) or a pharmaceutically acceptable salt thereof and at least one therapeutically inert excipient.

66) Another embodiment of the invention relates to a set of parts in accordance with embodiment 64) or 65), further including instructions for the simultaneous, sequential or separate administration of pharmaceutical compositions.

67) Another embodiment of the invention relates to a kit of parts according to any one of embodiments 64) to 66) for use as a medicine.

68) Another embodiment of the invention relates to a kit of parts according to any of embodiments 64) to 66) for use in the prevention/prevention and/or treatment of a disease or disorder listed in any of embodiments 48) to 55).

69) Another embodiment of the invention relates to the use of N-[1-(5-cyano-pyridin-2ylmethyl)-1 H-pyrazol-3 -yl]-2-[4-(1-trifluoromethyl-cyclopropyl)phenyl]acetamide or a pharmaceutically acceptable salt thereof and a second active substance selected from the group consisting of 5Hdibenzo[b,f]azepine-5-carboxamide (Carbamazepine), (RS)-3-ethyl-3-methyl-pyrrolidine-2,5-dione ( Ethosuximide), 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine (Lamotrigine), (S)-2-(2-oxopyrrolidin-1yl)butanamide (Levetiracetam), 10, 11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide (Oxcarbazepine), 2-propylpentanoic acid (Valproic acid), N-(5-sulfαmoyl-1,3,4-tuαduαzol-2yl )acetamide (Acetazolamide), (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide (Brivaracetam), 7-chloro-1-methyl-5-phenyl-1,5 -benzodiazepin-2,4-dione (Clobazam), 5-(2-chlorophenyl)-7-nitro-1,3-dihydro1,4-benzodiazepin-2-one (Clonazepam), (S)-10-acetoxy-10 ,11-dihydro-5H-dibenz[b,f]azepine-5carboxamide (Eslicarbazepine acetate), (3-carbamoyloxy- 2-phenylpropyl)carbamate (Felbamate), 1(aminomethyl)cyclohexaneacetic acid (Gabapentin), (R)-2-acetamido-N-benzyl-3methoxypropanamide (Lacosamide), 5'-(2-cyanophenyl)-1'-phenyl- 2,3'-bipyridinyl-6'( 1 H)-one (Perampanel), 5-ethyl-5-phenyl-1,3-diazinan-2,4,6-trione (Phenobarbital), 5,5-diphenylimidazolidine- 2,4-dione (Phenytoin), 2-(2-oxopyrrolidin-1-yl)acetamide (Piracetam), (3S)-3-(aminomethyl)-5-methylhexanoic acid (Pregabalin), 5-ethyl-5-phenyl -1,3-diazinan-4,6-dione (Primidon), ethyl (2-amino-4-((4fluorobenzyl)amino)phenyl)carbamate (Retigabine), 1-(2,6-difluorobenzyl)-1H-1 ,2,3-triazole-4-carboxamide (Rufinamide), (RS)-(E)-4,4-dimethyl-1-[3,4-(methylenedioxy)phenyl]-1-penten-3-ol (Stiripentol ), (3R)-1[4,4-bis(3-methyl-2-thienyl)-3-buten-1-yl]-3-piperidinecarboxylic acid (Tiagabin), 2,3:4,5-bis- O-(1methylethylidene)-β-D-fructopyranose sulfamate (Topiramate), (RS)-4-aminohex-5-enoic acid (Vigabatrin) or benzo[d]isoxazol-3-ylmethanesulfonamide (Zonisamide) or a pharmaceutically acceptable salt thereof for made a medicament for use in the prevention/prevention and/or treatment of a disease or disorder listed in any of embodiments 48) to 55).

70) Another embodiment of the invention relates to the use according to embodiment 69), wherein the second active substance is (RS)-3-ethyl-3-methylpyrrolidine-2,5-dione (Ethosuximide), 6-(2, 3-dichlorophenyl)-1,2,4-triazine-3,5-diamine (Lamotrigine), (S)2-(2-oxopyrrolidin-1-yl)butanamide (Levetiracetam), 2-propylpentanoic acid (Valproic acid), or 5-(2-chlorophenyl)-7-nitro-1,3-dihydro-1,4-benzodiazepin-2-one (Clonazepam) or its pharmaceutical

- 13 040556 a ceutically acceptable salt.

71) Another embodiment of the invention relates to the use of N-[1-(5-cyano-pyridin-2ylmethyl)-1 H-pyrazol-3 -yl]-2-[4-(1-trifluoromethyl-cyclopropyl)phenyl]acetamide) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in combination with a second drug such as 5H-dibenzo[b,f]azepine-5-carboxamide (Carbamazepine), (RS)-3-ethyl-3-methyl-pyrrolidine -2,5-dione (Ethosuximide), 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine (Lamotrigine), (S)-2-(2-oxopyrrolidine-1- yl)butanamide (Levetiracetam), 10,11-dihydro-10-oxo-5Hdibenz[b,f]azepine-5-carboxamide (Oxcarbazepine), 2-propylpentanoic acid (Valproic acid), K-(5-sulfamoyl-1, 3,4-thiadiazol-2-yl)acetamide (Acetazolamide), (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide (Brivaracetam), 7-chloro-1-methyl -5-phenyl-1,5-benzodiazepin-2,4-dione (Clobazam), 5-(2-chlorophenyl)-7-nitro-1,3-dihydro-1,4-benzodiazepin-2-one (Clonazepam) , (S)-10-acetoxy-10,11dihydro-5H-dibenz[b,f]azepine-5-carbock samid (Eslicarbazepine acetate), (3-carbamoyloxy-2phenylpropyl)carbamate (Felbamate), 1-(aminomethyl)cyclohexaneacetic acid (Gabapentin), (R)-2acetamido-N-benzyl-3-methoxypropanamide (Lacosamide), 5'-( 2-cyanophenyl)-1'-phenyl-2,3'-bipyridinyl6'(1H)-one (Perampanel), 5-ethyl-5-phenyl-1,3-diazinan-2,4,6-trione (Phenobarbital) , 5,5diphenylimidazolidine-2,4-dione (Phenytoin), 2-(2-oxopyrrolidin-1-yl)acetamide (Piracetam), (3S)-3(aminomethyl)-5-methylhexanoic acid (Pregabalin), 5-ethyl -5-phenyl-1,3-diazinan-4,6-dione (Primidon), ethyl (2-amino-4-((4-fluorobenzyl)amino)phenyl)carbamate (Retigabine), 1-(2,6- difluorobenzyl)-1H1,2,3-triazole-4-carboxamide (Rufinamide), (RS)-(E)-4,4-dimethyl-1-[3,4-(methylenedioxy)-phenyl]-1 pentene-3 -ol (Stiripentol), (3R)-1-[4,4-6uc(3-methyl-2-thienyl)-3-buten-1-yl]-3-piperidinecarboxylic acid (Tiagabine), 2.3:4 ,5-bis-O-(1-methylethylidene)-b-O-fructopyranose sulfamate (Topiramate), (RS)4-aminohex-5-enoic acid (Vigabatrin) or benzo[d]isoxazol-3-ylmethanesulfonamide (Zonisamide) silt and a pharmaceutically acceptable salt thereof in the prevention/prevention and/or treatment of a disease or disorder listed in any of embodiments 48) to 55).

72) Another embodiment of the invention relates to the use according to embodiment 71), where the second drug contains (RS)-3-ethyl-3-methyl-pyrrolidine 2,5-dione (Ethosuximide), 6-(2,3- dichlorophenyl)-1,2,4-triazine-3,5-diamine (Lamotrigine), (S)-2-(2oxopyrrolidin-1-yl)butanamide (Levetiracetam), 2-propylpentanoic acida (Valproic acid), or 5- (2-chlorophenyl)-7-nitro-1,3-dihydro-1,4-benzodiazepin-2-one (Clonazepam) or a pharmaceutically acceptable salt thereof.

73) Another embodiment of the invention relates to the use of 5H-dibenzo[b,f]azepine-5carboxamide (Carbamazepine), (RS)-3-ethyl-3-methyl-pyrrolidine-2,5-dione (Ethosuximide), 6-( 2,3dichlorophenyl)-1,2,4-triazine-3,5-diamine (Lamotrigine), (S)-2-(2-oxopyrrolidin-1-yl)butanamide (Levetiracetam), 10,11-dihydro-10- oxo-5H-dibenz[b,f]azepin-5-carboxamide (Oxcarbazepine), 2-propylpentanoic acid (Valproic acid), N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide (Acetazolamide), (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide (Brivaracetam), 7-chloro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4-dione (Clobazam), 5-(2-chlorophenyl)-7-nitro-1,3-dihydro-1,4benzodiazepin-2-one (Clonazepam), (S)-10-acetoxy-10,11-dihydro-5H-dibenz [b,f]azepine-5-carboxamide (Eslicarbazepine acetate), (3-carbamoyloxy-2-phenylpropyl)carbamate (Felbamate), 1-(aminomethyl) cyclohexaneacetic acid (Gabapentin), (R)-2-acetamido-N- benzyl-3-methoxypropanamide (Lacosamide), 5'-(2-cyanophenyl)-1'-phenyl-2,3'-bipyridinyl-6'(1'H) -one (Perampanel), 5-ethyl-5-phenyl-1,3diazinan-2,4,6-trione (Phenobarbital), 5,5-diphenylimidazolidine-2,4-dione (Phenytoin), 2-(2oxopyrrolidine-1 -yl)acetamide (Piracetam), (3S)-3-(aminomethyl)-5-methylhexanoic acid (Pregabalin), 5-ethyl-5-phenyl-1,3-diazinan-4,6-dione (Primidon), ethyl (2-Amino-4-((4-fluorobenzyl)amino)phenyl)carbamate (Retigabine), 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide (Rufinamide), ( RS)(S)-4,4-dimethyl-1-[3,4(methylenedioxy)phenyl]-1-penten-3-ol (Stiripentol), (3R)-1-[4,4-bis(3- methyl-2thienyl)-3-buten-1-yl]-3-piperidinecarboxylic acid (Tiagabine), 2,3:4,5-bis-O-(1-methylethylidene)-βD-fructopyranose sulfamate (Topiramate), (RS )-4-aminohex-5-enoic acid (Vigabatrin) or benzo[d]isoxazol-3-ylmethanesulfonamide (Zonisamide) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in combination with a second drug such as K-[ 1-(5-cyano-pyridin-2-ylmethyl)-1H-pyrazol-3-yl]-2-[4-(1-trifluoromethylcyclopropyl)phenyl] acetamide or a pharmaceutically acceptable salt thereof, in the prevention/prevention and/or treatment of a disease or disorder listed in any of embodiments 48) to 55).

74) Another embodiment of the invention relates to the use of (RS)-3-ethyl-3-methylpyrrolidine-2,5-dione (Ethosuximide), 6-(2,3-dichlorophenyl)-1,2,4-triazine-3, 5-diamine (Lamotrigine), 2-propylpentanoic acid (Valproic acid) or 5-(2-chlorophenyl)-7-nitro-1,3-dihydro-1,4benzodiazepin-2-one (Clonazepam) or a pharmaceutically acceptable salt thereof for manufacture of a medicinal product for use in combination with a second drug or a pharmaceutically acceptable salt thereof in the prevention/prevention and/or treatment of a disease, or

- 14 040556 disorder listed in any of the embodiments from 48) to 55).

Based on the dependencies of the various embodiments 1) to 74) as described above, the following embodiments are thus possible and contemplated, and are specifically disclosed on a case-by-case basis:

1, 2+1, 3+1, 4+1, 5+1, 6+1, 7+1, 8+1, 9+1, 10+1, 11+1, 12+1, 13+1, 14+1,

15+1, 16+1, 17+1, 18+1, 19+1, 20+1, 21+1, 22+1, 23+1, 24+1, 25+1, 26+1, 27+ 1,

28+1, 29+1, 30+1, 31+1, 32+1, 33+1, 34+1, 35+1, 36+1, 37+1, 38+1, 39+1, 40+ 1, + 1, 42+1, 43 + 1, 44+1, 45+1, 45+2+1, 45+3+1, 45+4+1, 45+5+1, 45+6+1 , 45+7+1,

45+8+1, 45+9+1, 45+10+1, 45+11+1, 45+12+1, 45+13+1, 45+14+1, 45+15+1, 45+ 16+1, 45+17+1, 45+18+1, 45+19+1, 45+20+1, 45+21+1, 45+22+1, 45+23+1,

45+24+1, 45+25+1, 45+26+1, 45+27+1, 45+28+1, 45+29+1, 45+30+1, 45+31+1,

45+32+1, 45+33+1, 45+34+1, 45+35+1, 45+36+1, 45+37+1, 45+38+1, 45+39+1,

45+40+1, 45+41 + 1, 45+42+1, 45+43 + 1, 45+44+1, 46+1, 46+2+1, 46+3 + 1, 46+4+ 1,

46+5+1, 46+6+1, 46+7+1, 46+8+1, 46+9+1, 46+10+1, 46+11+1, 46+12+1, 46+ 13+1, 46+14+1, 46+15+1, 46+16+1, 46+17+1, 46+18+1, 46+19+1, 46+20+1, 46+21+ 1,

46+22+1, 46+23+1, 46+24+1, 46+25+1, 46+26+1, 46+27+1, 46+28+1, 46+29+1,

46+30+1, 46+31+1, 46+32+1, 46+33+1, 46+34+1, 46+35+1, 46+36+1, 46+37+1,

46+38+1, 46+39+1, 46+40+1, 46+41+1, 46+42+1, 46+43+1, 46+44+1, 47+1, 47+2+ 1, 47+3 + 1, 47+4+1, 47+5+1, 47+6+1, 47+7+1, 47+8+1, 47+9+1, 47+10+1, 47 + 11 + 1,

47+12+1, 47+13 + 1, 47+14+1, 47+15+1, 47+16+1, 47+17+1, 47+18+1, 47+19+1,

47+20+1, 47+21+1, 47+22+1, 47+23+1, 47+24+1, 47+25+1, 47+26+1, 47+27+1,

47+28+1, 47+29+1, 47+30+1, 47+31+1, 47+32+1, 47+33+1, 47+34+1, 47+35+1,

- 15 040556

47+36+1, 47+37+1, 47+38+1, 47+39+1, 47+40+1, 47+41+1, 47+42+1, 47+43+1, 47+ 44+1, 47+45+1, 47+45+2+1, 47+45+3 + 1, 47+45+4+1, 47+45+5+1, 47+45+6+1, 47+45+7+1, 47+45+8+1, 47+45+9+1, 47+45+10+1, 47+45+11+1, 47+45+12+1, 47+ 45+13 + 1, 47+45+14+1, 47+45+15+1, 47+45+16+1, 47+45+17+1, 47+45+18+1, 47+45+ 19+1, 47+45+20+1, 47+45+21+1, 47+45+22+1, 47+45+23+1, 47+45+24+1, 47+45+25+ 1, 47+45+26+1, 47+45+27+1, 47+45+28+1, 47+45+29+1, 47+45+30+1, 47+45+31+1, 47+45+32+1, 47+45+33+1, 47+45+34+1, 47+45+35+1, 47+45+36+1, 47+45+37+1, 47+ 45+38+1, 47+45+39+1, 47+45+40+1, 47+45+41+1, 47+45+42+1, 47+45+43+1, 47+45+ 44+1, 47+46+1, 47+46+2+1, 47+46+3 + 1, 47+46+4+1, 47+46+5+1, 47+46+6+1, 47+46+7+1, 47+46+8+1, 47+46+9+1, 47+46+10+1, 47+46+11+1, 47+46+12+1, 47+ 46+13+1, 47+46+14+1, 47+46+15+1, 47+46+16+1, 47+46+17+1, 47+46+18+1, 47+46+ 19+1, 47+46+20+1, 47+46+21+1, 47+46+22+1, 47+46+23+1, 47+46+24+1, 47+46+25+ 1, 47+46+26+1, 47+46+27+1, 47+46+28+1, 47+46+29+1, 47+46+30+1, 47+46+31+1, 47+46+32+1, 47+ 46+33 + 1, 47+46+34+1, 47+46+35+1, 47+46+36+1, 47+46+37+1, 47+46+38+1, 47+46+ 39+1, 47+46+40+1, 47+46+41+1, 47+46+42+1, 47+46+43+1, 47+46+44+1, 48+1, 48+ 2+1, 48+3 + 1, 48+4+1, 48+5+1, 48+6+1, 48+7+1, 48+8+1, 48+9+1, 48+10+ 1, 48+11 + 1, 48+12+1, 48+13 + 1, 48+14+1, 48+15+1, 48+16+1, 48+17+1, 48+18+1, 48+19+1, 48+20+1,

48+21 + 1, 48+22+1, 48+23 + 1, 48+24+1, 48+25+1, 48+26+1, 48+27+1, 48+28+1,

48+29+1, 48+30+1, 48+31+1, 48+32+1, 48+33+1, 48+34+1, 48+35+1, 48+36+1,

48+37+1, 48+38+1, 48+39+1, 48+40+1, 48+41+1, 48+42+1, 48+43+1, 48+44+1,

48+45+1, 48+45+2+1, 48+45+3 + 1, 48+45+4+1, 48+45+5+1, 48+45+6+1, 48+45+ 7+1, 48+45+8+1, 48+45+9+1, 48+45+10+1, 48+45+11+1, 48+45+12+1, 48+45+13+ 1, 48+45+14+1, 48+45+15+1, 48+45+16+1, 48+45+17+1, 48+45+18+1, 48+45+19+1, 48+45+20+1, 48+45+21+1, 48+45+22+1, 48+45+23+1, 48+45+24+1, 48+45+25+1, 48+ 45+26+1, 48+45+27+1, 48+45+28+1, 48+45+29+1, 48+45+30+1, 48+45+31+1, 48+45+ 32+1, 48+45+33+1, 48+45+34+1, 48+45+35+1, 48+45+36+1, 48+45+37+1, 48+45+38+ 1, 48+45+39+1, 48+45+40+1, 48+45+41 + 1, 48+45+42+1, 48+45+43 + 1, 48+45+44+1, 48+46+1, 48+46+2+1, 48+46+3 + 1, 48+46+4+1, 48+46+5+1, 48+46+6+1, 48+46+ 7+1, 48+46+8+1, 48+46+9+1, 48+46+10+1, 48+46+11+1, 48+46+12+1, 48+46+13+ 1, 48+46+14+1, 48+46+15+1, 48+46+16+1, 48+46+17+1, 48+46+18+1, 48+46+19+1, 48+46+20+1, 48+46+21+1, 48+46+22+1, 48+46+23+1, 48+46+24+1, 48+46+25+1, 48+ 46+26+1, 48+46+27+1, 48+46+28+1, 48+46+29+1, 48+46+30+1, 48+46+31+1, 48+46+ 32+1, 48+46+33+1, 48+46+34+1,

- 16 040556

48+46+35+1, 48+46+36+1, 48+46+37+1, 48+46+38+1, 48+46+39+1, 48+46+40+1,

48+46+41 + 1, 48+46+42+1, 48+46+43 + 1, 48+46+44+1, 49+1, 49+2+1, 49+3 + 1,

49+4+1, 49+5+1, 49+6+1, 49+7+1, 49+8+1, 49+9+1, 49+10+1, 49+11 + 1, 49+ 12+1,

49+13 + 1, 49+14+1, 49+15+1, 49+16+1, 49+17+1, 49+18+1, 49+19+1, 49+20+1,

49+21+1, 49+22+1, 49+23+1, 49+24+1, 49+25+1, 49+26+1, 49+27+1, 49+28+1,

49+29+1, 49+30+1, 49+31+1, 49+32+1, 49+33+1, 49+34+1, 49+35+1, 49+36+1,

49+37+1, 49+38+1, 49+39+1, 49+40+1, 49+41+1, 49+42+1, 49+43+1, 49+44+1,

49+45+1, 49+45+2+1, 49+45+3 + 1, 49+45+4+1, 49+45+5+1, 49+45+6+1, 49+45+ 7+1, 49+45+8+1, 49+45+9+1, 49+45+10+1, 49+45+11+1, 49+45+12+1, 49+45+13+ 1, 49+45+14+1, 49+45+15+1, 49+45+16+1, 49+45+17+1, 49+45+18+1, 49+45+19+1, 49+45+20+1, 49+45+21+1, 49+45+22+1, 49+45+23+1, 49+45+24+1, 49+45+25+1, 49+ 45+26+1, 49+45+27+1, 49+45+28+1, 49+45+29+1, 49+45+30+1, 49+45+31+1, 49+45+ 32+1, 49+45+33+1, 49+45+34+1, 49+45+35+1, 49+45+36+1, 49+45+37+1, 49+45+38+ 1, 49+45+39+1, 49+45+40+1, 49+45+41 + 1, 49+45+42+1, 49+45+43 + 1, 49+45+44+1, 49+46+1, 49+46+2+1, 49+46+3 + 1, 49+46+4+1, 49+46+5+1, 49+46+6+1, 49+46+ 7+1, 49+46+8+1, 49+46+9+1, 49+46+10+1, 49+46+11+1, 49+46+12+1, 49+46+13+ 1, 49+46+14+1, 49+46+15+1, 49+46+16+1, 49+46+17+1, 49+46+18+1, 49+46+19+1, 49+46+20+1, 49+46+21+1, 49+46+22+1, 49+46+23+1, 49+46+24+1, 49+46+25+1, 49+ 46+26+1, 49+46+27+1, 49+46+28+1, 49+46+29+1, 49+46+30+1, 49+46+31+1, 49+46+ 32+1, 49+46+33 + 1, 49+46+34+1, 49+46+35+1, 49+46+36+1, 49+46+37+1, 49+46+38+ 1, 49+46+39+1, 49+46+40+1, 49+46+41 + 1, 49+46+42+1, 49+46+43 + 1, 49+46+44+1, 50+1, 50+2+1, 50+3 + 1, 50+4+1, 50+5+1, 50+6+1, 50+7+1, 50+8 + 1, 50+9+1, 50+10+1, 50+ 11+1, 50+12+1, 50+13+1, 50+14+1, 50+15+1, 50+16+1, 50+17+1, 50+18+1, 50+19+ 1, 50+20+1,

50+21+1, 50+22+1, 50+23+1, 50+24+1, 50+25+1, 50+26+1, 50+27+1, 50+28+1,

50+29+1, 50+30+1, 50+31+1, 50+32+1, 50+33+1, 50+34+1, 50+35+1, 50+36+1,

50+37+1, 50+38+1, 50+39+1, 50+40+1, 50+41+1, 50+42+1, 50+43+1, 50+44+1,

50+45+1, 50+45+2+1, 50+45+3 + 1, 50+45+4+1, 50+45+5+1, 50+45+6+1, 50+45+ 7+1, 50+45+8+1, 50+45+9+1, 50+45+10+1, 50+45+11+1, 50+45+12+1, 50+45+13+ 1, 50+45+14+1, 50+45+15+1, 50+45+16+1, 50+45+17+1, 50+45+18+1, 50+45+19+1, 50+45+20+1, 50+45+21+1, 50+45+22+1, 50+45+23+1, 50+45+24+1, 50+45+25+1, 50+ 45+26+1, 50+45+27+1, 50+45+28+1, 50+45+29+1, 50+45+30+1, 50+45+31+1, 50+45+ 32+1, 50+45+33+1, 50+45+34+1, 50+45+35+1, 50+45+36+1, 50+45+37+1, 50+45+38+ 1, 50+45+39+1, 50+45+40+1, 50+45+41 + 1, 50+45+42+1,

-17040556

50+45+43 + 1, 50+46+5+1, 50+46+11+1, 50+46+17+1, 50+46+23 + 1, 50+46+29+1, 50+ 46+35+1,

50+45+44+1 50+46+6+1, 50+46+12+1, 50+46+18+1, 50+46+24+1, 50+46+30+1, 50+46 +36+1, , 50+46+1, 50+46+7+1, 50+46+13+1, 50+46+19+1, 50+46+25+1, 50+46+31+ 1, 50+46+37+1,

50+46+2+1, 50+46+8+1, 50+46+14+1, 50+46+20+1, 50+46+26+1, 50+46+32+1, 50+ 46+38+1,

50+46+3 + 1, 50+46+9+1, 50+46+15+1, 50+46+21+1, 50+46+27+1, 50+46+33 + 1, 50+ 46+39+1,

50+46+4+1, 50+46+10+1, 50+46+16+1, 50+46+22+1, 50+46+28+1, 50+46+34+1, 50+ 46+40+1,

50+46+41+1,

50+46+42+1,

50+46+43 + 1, 50+46+44+1, 51 + 1, 51+2+1, 51+3 + 1,

51+4+1, 51+5+1, 51+6+1, 51+7+1, 51+8+1, 51+9+1, 51+10+1, + 11+1, 51+12 +1, + 13 + 1, 51 + 14+1, 51 + 15+1, 51 + 16+1, 51+21 + 1, 51+22+1, 51+23 + 1, 51+24+1, 51+29+1, 51+30+1, 51+31 + 1, 51+32+1, 51+37+1, 51+38+1, 51+39+1, 51+40+1, + 17 +1, 51 + 18+1, 51 + 19+1, 51+20+1, 51+25+1, 51+26+1, 51+27+1, 51+28+1, 51+33+1 , 51+34+1, 51+35+1, 51+36+1, 51+41 + 1, 51+42+1, 51+43 + 1, 51+44+1,

51+45+1, 51+45+2+1, 51+45+3 + 1, 51+45+4+1,

51+45+5+1, 51+45+6+1,

51+45+7+1, 51+45+8+1,

51+45+9+1, 51+45+10+1,

51+45+11+1, 51+45+12+1,

51+45+13 + 1, 51+45+19+1, 51+45+25+1, 51+45+31+1, 51+45+37+1, 51+45+43 + 1, 51+ 46+5+1, 51+46+11+1, 51+46+17+1, 51+46+23+1, 51+46+29+1, 51+46+35+1,

51+45+14+1, 51+45+20+1, 51+45+26+1, 51+45+32+1, 51+45+38+1,

51+45+44+1 51+46+6+1, 51+46+12+1, 51+46+18+1, 51+46+24+1, 51+46+30+1, 51+46 +36+1,

51+45+15+1, 51+45+21+1, 51+45+27+1, 51+45+33+1, 51+45+39+1, , 51+46+1, 51+46 +7+1, 51+46+13+1, 51+46+19+1, 51+46+25+1, 51+46+31+1, 51+46+37+1,

51+45+16+1, 51+45+22+1, 51+45+28+1, 51+45+34+1, 51+45+40+1, 51+46+2+1,

51+46+8+1, 51+46+14+1, 51+46+20+1, 51+46+26+1, 51+46+32+1, 51+46+38+1,

51+45 + 17+1, 51+45+23 + 1, 51+45+29+1, 51+45+35+1, 51+45+41 + 1,

51+46+3 + 1, 51+46+9+1, 51+46+15+1, 51+46+21+1, 51+46+27+1, 51+46+33 + 1, 51+ 46+39+1,

51+45+18+1, 51+45+24+1, 51+45+30+1, 51+45+36+1, 51+45+42+1, 51+46+4+1,

51+46+10+1, 51+46+16+1, 51+46+22+1, 51+46+28+1, 51+46+34+1, 51+46+40+1,

51+46+41+1,

51+46+42+1,

51+46+43 + 1, 51+46+44+1, 52+1, 52+2+1, 52+3 + 1,

52+4+1, 52+5+1, 52+6+1, 52+7+1, 52+8+1, 52+9+1, 52+10+1, 52+11 + 1, 52+ 12+1, 52+13 + 1, 52+14+1, 52+15+1, 52+16+1, 52+17+1, 52+18+1, 52+19+1, 52+20+ 1,

52+21 + 1, 52+22+1, 52+23 + 1, 52+24+1, 52+25+1, 52+26+1, 52+27+1, 52+28+1,

52+29+1, 52+30+1, 52+31+1, 52+32+1, 52+33+1, 52+34+1, 52+35+1, 52+36+1,

52+37+1, 52+38+1, 52+39+1, 52+40+1, 52+41+1, 52+42+1, 52+43+1, 52+44+1,

52+45+1, 52+45+2+1, 52+45+3 + 1, 52+45+4+1, 52+45+5+1, 52+45+6+1,

- 18 040556

52+45+7+1, 52+45+8+1, 52+45+9+1, 52+45+10+1, 52+45+11+1, 52+45+12+1, 52+ 45+13 + 1, 52+45+14+1, 52+45+15+1, 52+45+16+1, 52+45+17+1, 52+45+18+1, 52+45+ 19+1, 52+45+20+1, 52+45+21+1, 52+45+22+1, 52+45+23+1, 52+45+24+1, 52+45+25+ 1, 52+45+26+1, 52+45+27+1, 52+45+28+1, 52+45+29+1, 52+45+30+1, 52+45+31+1, 52+45+32+1, 52+45+33+1, 52+45+34+1, 52+45+35+1, 52+45+36+1, 52+45+37+1, 52+ 45+38+1, 52+45+39+1, 52+45+40+1, 52+45+41+1, 52+45+42+1, 52+45+43+1, 52+45+ 44+1, 52+46+1, 52+46+2+1, 52+46+3 + 1, 52+46+4+1, 52+46+5+1, 52+46+6+1, 52+46+7+1, 52+46+8+1, 52+46+9+1, 52+46+10+1, 52+46+11+1, 52+46+12+1, 52+ 46+13+1, 52+46+14+1, 52+46+15+1, 52+46+16+1, 52+46+17+1, 52+46+18+1, 52+46+ 19+1, 52+46+20+1, 52+46+21+1, 52+46+22+1, 52+46+23+1, 52+46+24+1, 52+46+25+ 1, 52+46+26+1, 52+46+27+1, 52+46+28+1, 52+46+29+1, 52+46+30+1, 52+46+31+1, 52+46+32+1, 52+46+33+1, 52+46+34+1, 52+46+35+1, 52+46+36+1, 52+46+37+1, 52+ 46+38+1, 52+46+39+1, 52+46+40+1, 52+46+41 + 1, 52+46+42+1, 52+46+43 + 1, 52+46+ 44+1.53+1.53 +2+1, 53+3 + 1, 53+4+1, 53+5+1, 53+6+1, 53+7+1, 53+8+1, 53+9+1, 53 + 10 +1, 53 + 11 + 1, 53 + 12+1, 53 + 13 + 1, 53 + 14+1, 53 + 15+1, 53 + 16+1, 53 + 17+1, 53 + 18+1 , 53+19+1, 53+20+1,

53+21 + 1, 53+22+1, 53+23 + 1, 53+24+1, 53+25+1, 53+26+1, 53+27+1, 53+28+1,

53+29+1, 53+30+1, 53+31+1, 53+32+1, 53+33+1, 53+34+1, 53+35+1, 53+36+1,

53+37+1, 53+38+1, 53+39+1, 53+40+1, 53+41+1, 53+42+1, 53+43+1, 53+44+1,

53+45+1, 53+45+2+1, 53+45+3 + 1, 53+45+4+1, 53+45+5+1, 53+45+6+1, 53+45+ 7+1, 53+45+8+1, 53+45+9+1, 53+45+10+1, 53+45+11+1, 53+45+12+1, 53+45+13+ 1, 53+45+14+1, 53+45+15+1, 53+45+16+1, 53+45+17+1, 53+45+18+1, 53+45+19+1, 53+45+20+1, 53+45+21+1, 53+45+22+1, 53+45+23+1, 53+45+24+1, 53+45+25+1, 53+ 45+26+1, 53+45+27+1, 53+45+28+1, 53+45+29+1, 53+45+30+1, 53+45+31+1, 53+45+ 32+1, 53+45+33+1, 53+45+34+1, 53+45+35+1, 53+45+36+1, 53+45+37+1, 53+45+38+ 1, 53+45+39+1, 53+45+40+1, 53+45+41 + 1, 53+45+42+1, 53+45+43 + 1, 53+45+44+1, 53+46+1, 53+46+2+1, 53+46+3 + 1, 53+46+4+1,

53+46+5+1, 53+46+6+1, 53+46+7+1, 53+46+8+1, 53+46+9+1, 53+46+10+1, 53+ 46+11 + 1, 53+46+12+1, 53+46+13+1, 53+46+14+1, 53+46+15+1, 53+46+16+1, 53+46+ 17+1, 53+46+18+1, 53+46+19+1, 53+46+20+1, 53+46+21+1, 53+46+22+1, 53+46+23+ 1, 53+46+24+1, 53+46+25+1, 53+46+26+1, 53+46+27+1, 53+46+28+1, 53+46+29+1, 53+46+30+1, 53+46+31 + 1, 53+46+32+1, 53+46+33 + 1, 53+46+34+1, 53+46+35+1, 53+ 46+36+1, 53+46+37+1, 53+46+38+1, 53+46+39+1, 53+46+40+1, 53+46+41+1, 53+46+ 42+1, 53+46+43 + 1, 53+46+44+1, 54+1, 54+2+1, 54+3 + 1,

- 19 040556

54+4+1, 54+5+1, 54+6+1, 54+7+1, 54+8+1, 54+9+1, 54+10+1, 54+11 + 1, 54+ 12+1,

54+13 + 1, 54+14+1, 54+15+1, 54+16+1, 54+17+1, 54+18+1, 54+19+1, 54+20+1,

54+21+1, 54+22+1, 54+23+1, 54+24+1, 54+25+1, 54+26+1, 54+27+1, 54+28+1,

54+29+1, 54+30+1, 54+31+1, 54+32+1, 54+33+1, 54+34+1, 54+35+1, 54+36+1,

54+37+1, 54+38+1, 54+39+1, 54+40+1, 54+41+1, 54+42+1, 54+43+1, 54+44+1,

54+45+1, 54+45+2+1, 54+45+3 + 1, 54+45+4+1, 54+45+5+1, 54+45+6+1, 54+45+ 7+1, 54+45+8+1, 54+45+9+1, 54+45+10+1, 54+45+11+1, 54+45+12+1, 54+45+13+ 1, 54+45+14+1, 54+45+15+1, 54+45+16+1, 54+45+17+1, 54+45+18+1, 54+45+19+1, 54+45+20+1, 54+45+21+1, 54+45+22+1, 54+45+23+1, 54+45+24+1, 54+45+25+1, 54+ 45+26+1, 54+45+27+1, 54+45+28+1, 54+45+29+1, 54+45+30+1, 54+45+31+1, 54+45+ 32+1, 54+45+33+1, 54+45+34+1, 54+45+35+1, 54+45+36+1, 54+45+37+1, 54+45+38+ 1, 54+45+39+1, 54+45+40+1, 54+45+41 + 1, 54+45+42+1, 54+45+43 + 1, 54+45+44+1, 54+46+1, 54+46+2+1, 54+46+3 + 1, 54+46+4+1, 54+46+5+1, 54+46+6+1, 54+46+ 7+1, 54+46+8+1, 54+46+9+1, 54+46+10+1, 54+46+11+1, 54+46+12+1, 54+46+13+ 1, 54+46+14+1, 54+46+15+1, 54+46+16+1, 54+46+17+1, 54+46+18+1, 54+46+19+1, 54+46+20+1, 54+46+21+1, 54+46+22+1, 54+46+23+1, 54+46+24+1, 54+46+25+1, 54+ 46+26+1, 54+46+27+1, 54+46+28+1, 54+46+29+1, 54+46+30+1, 54+46+31+1, 54+46+ 32+1, 54+46+33 + 1, 54+46+34+1, 54+46+35+1, 54+46+36+1, 54+46+37+1, 54+46+38+ 1.54+46+39+1 , 54+46+40+1, 54+46+41 + 1, 54+46+42+1, 54+46+43 + 1, 54+46+44+1, 55+1, 55+2+1 , 55+3 + 1, 55+4+1, 55+5+1, 55+6+1, 55+7+1, 55+8+1, 55+9+1, 55+10+1, 55 +11 + 1, 55+12+1, 55+13 + 1, 55+14+1, 55+15+1, 55+16+1, 55+17+1, 55+18+1, 55+19 +1, 55+20+1,

55+21+1, 55+22+1, 55+23+1, 55+24+1, 55+25+1, 55+26+1, 55+27+1, 55+28+1,

55+29+1, 55+30+1, 55+31+1, 55+32+1, 55+33+1, 55+34+1, 55+35+1, 55+36+1,

55+37+1, 55+38+1, 55+39+1, 55+40+1, 55+41+1, 55+42+1, 55+43+1, 55+44+1,

55+45+1, 55+45+2+1, 55+45+3 + 1, 55+45+4+1, 55+45+5+1, 55+45+6+1, 55+45+ 7+1, 55+45+8+1, 55+45+9+1, 55+45+10+1, 55+45+11+1, 55+45+12+1, 55+45+13+ 1, 55+45+14+1, 55+45+15+1, 55+45+16+1, 55+45+17+1, 55+45+18+1, 55+45+19+1, 55+45+20+1, 55+45+21+1, 55+45+22+1, 55+45+23+1, 55+45+24+1, 55+45+25+1, 55+ 45+26+1, 55+45+27+1, 55+45+28+1, 55+45+29+1, 55+45+30+1, 55+45+31+1, 55+45+ 32+1, 55+45+33+1, 55+45+34+1, 55+45+35+1, 55+45+36+1, 55+45+37+1, 55+45+38+ 1, 55+45+39+1, 55+45+40+1, 55+45+41 + 1, 55+45+42+1, 55+45+43 + 1, 55+45+44+1, 55+46+1, 55+46+2+1, 55+46+3 + 1, 55+46+4+1, 55+46+5+1, 55+46+6+1, 55+46+ 7+1, 55+46+8+1, 55+46+9+1, 55+46+10+1,

- 20 040556

55+46+11+1, 55+46+17+1, 55+46+23+1, 55+46+29+1, 55+46+35+1,

55+46+12+1,

55+46+18+1,

55+46+24+1,

55+46+30+1,

55+46+36+1,

55+46+13+1,

55+46+19+1,

55+46+25+1,

55+46+31+1,

55+46+37+1,

55+46+14+1,

55+46+20+1,

55+46+26+1,

55+46+32+1,

55+46+38+1,

55+46+15+1, 55+46+21+1, 55+46+27+1, 55+46+33+1, 55+46+39+1,

55+46+16+1,

55+46+22+1,

55+46+28+1,

55+46+34+1,

55+46+40+1,

55+46+41 + 1, 55+46+42+1, 55+46+43 + 1, 55+46+44+1, 56, 57, 58, 59, 60, 61, 62, 63

64, 65, 66+64, 66+65, 67, 68, 69, 70+69, 71, 72+71, 73 and 74;

In the above list, the numbers refer to the embodiments according to their numbering set forth above, with + indicating a dependency on another embodiment. Various individual embodiments are separated by commas. In other words, 45+2+1, for example, refers to Embodiment 45) depending on Embodiment 2), depending on Embodiment 1), i.e. embodiment 45+2+1 corresponds to the pharmaceutical combination of embodiment 1) further limited by the features of embodiments 2) and 45).

The definitions provided in this application are intended to apply uniformly to the subject matter of the invention as defined in any of embodiments 1) to 74), and mutatis mutandis throughout the specification and claims, unless a different definition expressly stated provides a broader or more narrow definition. It is understood that the definition or preferred definition of a term or expression defines and may replace the corresponding term or expression independently of (and in conjunction with) any definition or preferred definition of any or all other terms or expressions defined in the present context.

Any reference to an active substance as defined in any of embodiments 1) to 74) should be understood to refer to pharmaceutically acceptable salts of such active substance as well, as appropriate and appropriate.

The term pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesirable toxicological effects. Such salts include inorganic or organic acid and/or base addition salts, depending on the presence of basic and/or acidic groups in the compound in question. For reference, see, for example, 'Handbook of Pharmaceutical Salts. Properties, Selection and Use.', P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008 and 'Pharmaceutical Salts and Cocrystals', Johan Wouters and Luc Quere (Eds.), RSC Publishing, 2012.

As used in this application, the term pharmaceutical combination refers to a combination of two or more, preferably two, active substances, in which the active substances are contained in one pharmaceutical composition or in separate pharmaceutical compositions.

Used in this application, the term active substance refers to the pharmaceutically active component of the pharmaceutical composition. Examples of active substances used in this application in the first group are K-[1-(5-cyano-pyridin-2-ylmethyl)-1H-pyrazol-3-yl]-2[4-(1-trifluoromethyl-cyclopropyl )phenyl]acetamide (compound 1), or a pharmaceutically acceptable salt thereof, and in the second group 5H-dibenzo[b,1]azepine-5-carboxamide (Carbamazepine), (RS)-3-ethyl-3methyl-pyrrolidine-2, 5-dione (Ethosuximide), 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine (Lamotrigine), (S)-2-(2-oxopyrrolidin-1-yl)butanamide (Levetiracetam), 10,11-dihydro-10-oxo-5Hdibenz[L,1]azepine-5-carboxamide (Oxcarbazepine), 2-propylpentanoic acid (Valproic acid), N-(5-sulfamoyl-1,3,4 -thiadiazol-2-yl)acetamide (Acetazolamide), (2S)-2-[(4R)-2-oxo-4propylpyrrolidin-1-yl]butanamide (Brivaracetam), 7-chloro-1-methyl-5-phenyl- 1,5-benzodiazepin-2,4-dione (Clobazam), 5-(2-chlorophenyl)-7-nitro-1,3-dihydro-1,4-benzodiazepin-2-one (Clonazepam), (S)- 10-acetoxy10,11-dihydro-5H-dibenz[b,1]azepine-5-carboxamide (Eslicarbazepine acetate), (3-carbamoyloxy-2-phenylpropyl) carbamate (Felbamate), 1-(aminomethyl)cyclohexaneacetic acid (Gabapentin), (R)-2acetamido-N-benzyl-3-methoxypropanamide (Lacosamide), 5'-(2-cyanophenyl)-1'-phenyl-2,3 '-bipyridinyl6'(1'H)-one (Perampanel), 5-ethyl-5-phenyl-1,3-diazinan-2,4,6-trione (Phenobarbital), 5,5-diphenylimidazolidine-2,4- dione (Phenytoin), 2-(2-oxopyrrolidin-1-yl)acetamide (Piracetam), (3S)-3(aminomethyl)-5-methylhexanoic acid (Pregabalin), 5-ethyl-5-phenyl-1,3- diazinan-4,6-dione (Primidon), ethyl (2-amino-4-((4-fluorobenzyl)amino)phenyl)carbamate (Retigabine), 1-(2,6-difluorobenzyl)-1H1,2,3- triazole-4-carboxamide (Rufinamide), (RS)-(E)-4,4-dimethyl-1-[3,4(methylenedioxy)-phenyl]-1-penten3-ol (Stiripentol), (3R)-1 -[4,4-bis(3-methyl-2-thienyl)-3-buten-1-yl]-3-piperidinecarboxylic acid (Tiagabin), 2.3:4,5-bis-O-(1-methylethylidene )-β-D-fructopyranose sulfamate (Topiramate), (RS)-4aminohex-5-enoic acid (Vigabatrin) or benzo[d]isoxazol-3-ylmethanesulfonamide (Zonisamide),

- 21 040556 or a pharmaceutically acceptable salt thereof. For the sake of clarity, an antiepileptic active is an active that can be used to prevent/prevent and/or treat epileptic seizures in a patient by partially or completely suppressing the clinical or electrographic signs of seizures.

The term "simultaneous" or "simultaneously", if used in relation to the administration of active substances or pharmaceutical compositions, means that the administration of the first active substance (or the first pharmaceutical composition, respectively) is still ongoing, the administration of the second active substance (or the second pharmaceutical composition, respectively) begins. In particular, the term simultaneous or simultaneously means that the two active substances (or two pharmaceutical compositions, respectively) are administered at the same time, i.e. with the same start and end time, as, for example, in the case of the introduction of two active substances included in one pharmaceutical composition.

The term sequentially or sequentially, when used in relation to the administration of active substances or pharmaceutical compositions, means that the administration of the second active substance (or the second pharmaceutical composition, respectively) begins less than one hour after the administration of the first active substance (or first pharmaceutical composition, respectively).

The term alone or alone, when used in relation to the administration of active substances or pharmaceutical compositions, means that the administration of the second active substance (or the second pharmaceutical composition, respectively) begins 1 hour or more (and up to about 12 hours or up to about 24 hours) after after how the last previous administration of the first active substance (or first pharmaceutical composition, respectively) was completed.

The expressions administered in combination or for use in combination mean the simultaneous, sequential or separate, preferably sequential, administration of active substances or pharmaceutical compositions.

As used herein, the term route of administration refers to the route by which an active substance (eg, in the form of a pharmaceutical composition in a specific dosage form) enters the body. The active substances may be administered by enteral (especially oral) or parenteral administration (including topical application or inhalation). Examples of dosage forms that can be used to administer active substances are tablets, capsules, pills, granules, powders, solutions, suspensions, emulsions, injectable aqueous or oily solutions or suspensions, suppositories, creams, gels, ear or eye drops, spray for the nose, skin patches or aerosols. Preference is given to dosage forms for oral administration, such as tablets, capsules, pills, solutions or suspensions. In the case where separate pharmaceutical compositions contain two active substances, then these separated pharmaceutical compositions can be administered by the same or different routes of administration using the same or different dosage forms.

The preparation of pharmaceutical compositions can be carried out in a manner that is well known to any person skilled in the art (see, for example, Remington, The Science and Practice of Pharmacy, 21st ed. (2005), Part 5, Pharmaceutical Manufacturing [published by Lippincott Williams & Wilkins]) by administering Compound 1 or a pharmaceutically acceptable salt thereof and/or a second active substance having an antiepileptic effect as defined in any of embodiments 1) to 44), or a pharmaceutically acceptable salt thereof, optionally in combination with other therapeutically valuable substances into a galenic dosage form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carriers and, if desired, conventional pharmaceutical auxiliaries.

The optimal dosing regimen (i.e. dose size and frequency of drug administration) for each of the two active substances of the pharmaceutical combination according to the present invention may vary depending on the route of administration, dosage form, type of epilepsy to be treated and the individual second active substance used. . In addition, the dose and/or frequency of taking the drug may differ at the initial stage and at the subsequent stage of treatment for the first and/or second active substance of the pharmaceutical combination. Usually, treatment is started at a low dose, increased over a period that varies with each antiepileptic drug, and continued with a maintenance dose that is usually adapted to each patient and should be the lowest seizure-free dose (Perucca E. et al. (2011) The pharmacological treatment of epilepsy in adults Lancet Neurol 10:446-456 Goldenberg M.M. (2010) Overview of Drugs Used For Epilepsy and Seizures Pharmacy and Therapeutics 35(7): 392-415). A preferred maintenance dose for Compound 1 is 5 to 600 mg orally once a day, especially 10 to 400 mg (preferably 20 to 400 mg) orally once a day, namely 10 to 200 mg (preferably 40 up to 200 mg) orally once a day.

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The present invention also covers isotopically labeled, especially ² H (deuterium) labeled active substances, the active substances being identical to the active substances as defined in any of the embodiments 1) to 44), except that one or each of the more of atoms has been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass normally found in nature. Isotopically labeled, in particular ² H (deuterium) labeled active substances and their pharmaceutically acceptable salts are included within the scope of the present invention. The replacement of hydrogen with the heavier isotope ² H (deuterium) may lead to greater metabolic stability, leading, for example, to an increased in vivo half-life or reduced doses required, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting in, for example, an improved profile security.

In one embodiment of the invention, only one of the two active substances of the pharmaceutical combination is isotopically labeled. In a preferred embodiment of the invention, the active substances are not isotopically labeled, or one active substance is not isotopically labeled and the other active substance is labeled with only one or more deuterium atoms, or both active substances are each labeled with only one or more deuterium atoms. In the most preferred embodiment, the active substances are not isotopically labeled at all. Isotopically labeled active substances can be obtained in analogy with the methods described for non-isotopically labeled active substances, but using a suitable isotopic variant of the acceptable reagents or starting materials.

The term approximately which precedes the numerical value X in this application refers to the range extending from X minus 10% of X to X plus 10% of X.

experimental part

Get connection 1.

Compound 1 can be prepared according to the procedure described in WO 2015/186056 or DOI: 10.1021/acs.jmedchem.7b01236. (Bezencon O. et al., J. Med. Chem. (2017)).

Audiogenic seizure-responsive juvenile DBA/2J mouse model with generalized tonic-clonic seizures.

An inbred strain of DBA/2J mice has an increased overall susceptibility to acute generalized seizures induced by both pharmacological, electrical, and juvenile, auditory stimuli. Between 17 and 28 days of age (juvenile) they exhibit tonic-clonic seizures when exposed to loud sound.

Male juvenile DBA/2J mice (aged 22-24 days, weighing 6.6 to 14.5 g) were used. Each mouse was placed individually in an exposure chamber, a hemispherical acrylic glass dome (50 cm diameter) inside a noise-absorbing box. After 60 s of habituation, an auditory stimulus of mixed frequency sound (15-20 kHz at 110 dB) was reproduced from a loudspeaker located in the upper central part of the dome. The stimulus was applied for a maximum of 60 s or until the mouse demonstrated tonic hindlimb extension.

The soundproof box was equipped with a light and a camera system to observe and record behavioral seizures classified as follows:

phase 0, no response, phase 1, uncontrolled seizures, phase 2, clonus, phase 3, tonic extension of the hind limbs.

At the end of the experiment, all mice were sacrificed by inhalation of CO2 to assess the concentration of drugs in plasma and in the brain, as well as the absence of pharmacokinetic interaction. Briefly, blood was taken from the tail vein using a syringe pre-filled with EDTA (ethylenediaminetetraacetic acid) as an anticoagulant and centrifuged to obtain plasma (for 10 min, at 4°C and 5000 rpm). Brain samples were taken and homogenized in one volume of cold phosphate buffer (pH 7.4). After extraction with methanol, plasma and brain concentrations of the compound were determined by liquid chromatography combined with mass spectrometry.

Conducted various experiments on the effectiveness of the combination. Three different first line antiepileptic drugs (i.e. valproic acid (VPA), levetiracetam (LEV) or lamotrigine (LTG)), referred to below as antiepileptic drugs (AEDs) below) were used in combination with K-[1-(5- cyano-pyridin-2-ylmethyl)-1H-pyrazol-3-yl]-2-[4-(1-trifluoromethylcyclopropyl)phenyl]acetamide (compound 1).

Each experiment consists of four treatment groups.

1. Drug base (10% polyethylene glycol 400 (PEG400)/90% methylcellulose (0.5% in water; MC0.5%)), 3 hours before auditory stimulus + drug base, 1 hour before auditory stimulus.

2. Compound 1 (in 10% PEG400/90% MC0.5%), 3 hours before auditory stimulus + drug base, 1 hour before auditory stimulus.

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3. Drug base, 3 hours before exposure to auditory stimulus + PEP (in 10% PEG400/90%

MS0.5%), 1 hour before exposure to auditory stimulus.

4. Compound 1 (in 10% PEG400/90% MC0.5%), 3 hours before exposure to auditory stimulus +

PEP (in 10% PEG400/90% MC0.5%), 1 hour before exposure to auditory stimulus.

The results of experiments on combined efficacy using compound 1 and valproic acid (VPA) are shown in table. 1.

Table 1

Efficacy of Compound 1, VPA, or its combination in audiogenic seizure-responsive juvenile DBA/2J mice, generalized seizure model (n=9-10/group) ___________ with appropriate brain and plasma concentrations __________

View Seizure-sensitive juvenile DBA/2J mice (n = 9-10) Introduction Gastric tube, 5 ml/kg in 10% PEG400 / 90% MC0.5% Evaluation The maximum phase of seizures observed when exposed to an auditory stimulus. Data shown as means ± Standard Error of the Mean (SEM) Statistical data Kruskal-Wallis test followed by Dunn's special analysis: * p < 0.05, ** p < 0.01, *** p < 0.001 vs. medicinal base; # p < 0.05, ## p < 0.01 , ### p < 0.01 vs. COMPOUND 1; + p < 0.05, ++ p < 0.01, +++ p < 0.001 vs. VPA Variable Treatment group drug base + drug base COMPOUND 1, 30 mg/kg ± drug base drug base ± VPA, 30 mg/kg COMPOUND 1, 30 mg/kg ± VPA, 30 mg/kg Seizure phase 3.0±0.0 1.8 ± 0.2 *** 2.9 ± 0.1 ## 2.0 ±0.3 * CONNECTION 1 Concentration in the brain - total (ng / g) Plasma concentration - total (ng/ml) 5228 ± 487 3087±297 5104 ± 375 3148±296 VPA Concentration in the brain - total (ng / g) Plasma concentration - total (ng/ml) 1264 ± 399 23027 ± 3609 1006 ± 117 19933 ± 1648

Variable Treatment group drug base ± drug base COMPOUND 1, 30 mg/kg ± drug base drug base ± VPA, 100 mg/kg COMPOUND 1, 30 mg/kg ± VPA, 100 mg/kg Seizure phase 2.9 ± 0.1 1.7 ± 0.3 2.7 ± 0.2 0.1 ± 0.1 ***; +++ CONNECTION 1 concentration in the brain - total (ng / g) Plasma concentration - total (ng/ml) 5233 ± 343 4621±556 5984 ± 336 2819 ± 256 VPA concentration in the brain - total (ng / g) Plasma concentration - total (ng/ml) 9278 ± 2535 68144 ± 6868 5948 ± 946 63400 ± 3213

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Treatment group

Variable drug base + drug base COMPOUND 1, 30 mg/kg + drug base drug base + VPA, 200 mg/kg COMPOUND 1, 30 mg/kg ± VPA, 200 mg/kg Seizure phase I Concentration in the brain I - total (ng / g) Concentration in and plasma O - total (ng/ml) Concentration in the brain < - total (ng / g) Plasma concentration - total (ng/ml) 3.0±0.0 1.2 ±0.2 ** 4387 ± 342 2832 ± 260 1.7 ± 0.4 24746 ± 3564 108600 ± 9893 0.0±0.0 *** · + 4994±245 2108 ± 118 27012 ± 6539 109520 ± 11385 Variable Treatment group drug base + drug base Compound 1, 10 mg/kg + drug base drug base + VPA, 100 mg/kg Compound 1, 10 mg/kg ± VPA, 100 mg/kg Seizure phase 3.0±0.0 3.0±0.0 2.8 ± 0.2 2.1 ± 0.2 ***; ### ; ±± K Concentration in u brain K - n - total (ng / g) I Plasma g concentration U - total (ng/ml) 1895±75 1128 ± 98 2043 ± 178 710±80 Concentration in the brain < - total (ng / g) > Plasma concentration - total (ng/ml) 10124 ± 2040 53690±4036 14628±2906 57270 ± 3762 Variable Seizure phase Treatment group drug base + drug base 2.9 ± 0.1 Compound 1, 10 mg/kg + drug base 2.7 ± 0.3 1452 ± 104 2116 ± 175 drug base + VPA, 200 mg/kg 1.3±0.3**; # Compound 1, 10 mg/kg ± VPA, 200 mg/kg 0.8 ± 0.3 *** ; ### 1638±52 1155±73 CONNECTION 1 Concentration in the brain - total (ng / g) Plasma concentration - total (ng/ml) VPA Concentration in the brain - total (ng / g) Plasma concentration - total (ng/ml) 44222 ± 4088 132578± 10721 34694 ± 4441 122640 ±11703

As can be seen from Table. 1, in juvenile DBA/2J mice, combinations of Compound 1 with valproic acid showed a synergistic antiepileptic effect on induced audiogenic seizure compared to effects seen when the drugs were administered alone. For example, the combination of a partially effective dose of compound 1 (30 mg/kg, seizure severity 2, corresponding to a clonic seizure) with an inactive dose of valproic acid (100 mg/kg, seizure severity 3, corresponding to hindlimb tonic extension) showed a synergistic antiepileptic effect and resulted in complete suppression of audiogenic-induced seizures. The synergistic effect is not the result of a pharmacokinetic interaction, since the plasma and brain concentrations of compound 1 and valproic acid were the same after administration of the compounds alone or in combination.

The results of experiments on combined efficacy using compound 1 and levetiracetam (LEV) are shown in table. 2.

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table 2

Efficacy of compound 1, LEV, or combination thereof in audiogenic seizure-responsive juvenile DBA/2J mice, a model of generalized seizures (n=9-10/group) _____________ with appropriate brain and plasma concentrations _____________

View Seizure-sensitive juvenile DBA/2J mice (n = 9-10) Introduction Gastric tube, 5 ml/kg in 10% PEG400 / 90% MC0.5% Evaluation The maximum phase of seizures observed when exposed to an auditory stimulus. Data shown as means ± S.E.M. Statistical data Kruskal-Wallis test followed by Dunn's special analysis: * p < 0.05, ** p < 0.01, *** p < 0.001 vs. medicinal base; # p < 0.05, ## p < 0.01 , ### p < 0.01 vs. COMPOUND 1; + p < 0.05, ++ p < 0.01, +++ p < 0.001 vs. LEV Variable Treatment group medicinal base + medicinal base Compound 1, 30 mg/kg + drug base drug base + LEV, 3 mg/kg Compound 1, 30 mg/kg + LEV, 3 mg/kg Seizure phase 3.0±0.0 1.9 ± 0.2 2.6 ± 0.3 0.6 ± 0.2 ***+++ CONNECTION 1 Concentration in the brain - total (ng / g) Plasma concentration - total (ng/ml) 5042±385 4453 ± 283 5956 ± 330 4534 ± 224 LEV Concentration in the brain - total (ng / g) Plasma concentration - total (ng/ml) 675 ± 82 1208 ± 76 714 ± 59 1230 ± 64

Variable Treatment group drug base + drug base Compound 1.30 mg/kg + drug base drug base + LEV, 10 mg/kg Compound 1, 30 mg/kg + LEV, 10 mg/kg Seizure phase 3.0±0.0 1.6±0.2* 1.4±0.3* 0.3 ± 0.2 ** * CONNECT E 1 Concentration in the brain - total (ng / g) Plasma concentration - total (ng/ml) 4370 ± 334 4460 ± 322 5466 ± 533 4123 ±315 LEV Concentration in the brain - total (ng / g) Plasma concentration - total (ng/ml) 2307 ± 207 4007 ± 199 2149 ± 142 3877 ± 226

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Variable Treatment group drug base + drug base Compound 1.30 mg/kg + drug base drug base + LEV, 50 mg/kg Compound 1, 30 mg/kg + LEV, 50 mg/kg Seizure phase 3.0±0.0 1.9 ± 0.3 0.5 ± 0.2 0.1 ± 0.1 *** # CONNECTION 1 Concentration in the brain - total (ng / g) Plasma concentration - total (ng/ml) 4662 ± 275 4142 ± 178 4690 ± 399 3715 ± 351 LEV Concentration in the brain - total (ng / g) Plasma concentration - total (ng/ml) 11318±1440 24156 ± 2669 13484 ± 1379 26208 ± 2403 Variable Treatment group drug base + drug base Compound 1, 10 mg/kg + drug base drug base + LEV, 1 mg/kg Compound 1, 10 mg/kg + LEV, 1 mg/kg Seizure phase 3.0±0.0 2.7 ± 0.2 3.0±0.0 1.6 ± 0.4 1 LEV CONNECTION Concentration in the brain - total (ng / g) Plasma concentration - total (ng/ml) Concentration in the brain - total (ng / g) Plasma concentration - total (ng/ml) 1435±55 1318 ± 77 224±20 541 ± 48 1934±100 1498 ± 112 310 ± 34 564 ± 42

Treatment group

Variable drug base + drug base COMPOUND 1, 10 mg/kg + drug base drug base + LEV, 3 mg/kg COMPOUND 1, 10 mg/kg + LEV, 3 mg/kg Seizure phase 2.8 ± 0.2 2.9 ± 0.1 2.1 ± 0.4 1.1 ± 0.2 **, ## CONNECTION 1 Concentration in the brain - total (ng / g) Plasma concentration - total (ng/ml) 2379 ± 164 1858±116 2517 ± 190 1598 ± 111 LEV Concentration in the brain - total (ng / g) Plasma concentration - total (ng/ml) 677 ± 70 1170±53 787 ± 39 1250±53

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Variable Treatment group drug base + drug base COMPOUND 1, 10 mg/kg + drug base drug base + LEV, 10 mg/kg COMPOUND 1, 10 mg/kg + LEV, 10 mg/kg Seizure phase 2.3 ± 0.4 2.7 ± 0.2 1.7 ± 0.4 0.6 ± 0.2 *, ## COMPOUND ττ,ν _{E t} Concentration in the brain - total (ng / g) Plasma concentration - total (ng/ml) Concentration in the brain - total (ng/g) Plasma concentration - total (ng/ml) 1965±138 1894±113 2131± 267 4527 ± 473 2026 ± 137 1586 ± 142 2593 ± 169 5779±232 Variable Treatment group drug base + drug base COMPOUND 1, 10 mg/kg + drug base drug base + LEV, 50 mg/kg COMPOUND 1, 10 mg/kg + LEV, 50 mg/kg Seizure phase 3.0±0.0 2.7 ± 0.2 1.1 ± 0.3 **# 0.5 ± 0.2 ***, ### CONNECTION 1 concentration in the brain - general (ng/g) Plasma concentration - total (ng/ml) 1743 ± 158 1785 ± 186 1811±93 1715±124 LEV concentration in the brain - general (ng/g) Plasma concentration - general (ng/ml) 11098±886 26502±2814 12622±549 27010 ± 1349

As can be seen from Table. 2, in juvenile DBA/2J mice, combinations of Compound 1 with levetiracetam showed a synergistic antiepileptic effect on induced audiogenic seizure compared to effects seen when the drugs were administered alone. For example, the combination of an inactive dose of compound 1 (10 mg/kg, seizure severity 3, corresponding to tonic hindlimb extension) and an inactive dose of levetiracetam (1 mg/kg, seizure severity 3, corresponding to tonic hindlimb extension) showed a synergistic antiepileptic effect and resulted in to audiogenically induced seizures of reduced severity (1.6). The synergistic effect is not the result of a pharmacokinetic interaction, since the plasma and brain concentrations of compound 1 and LEV were the same after administration of the compounds alone or in combination.

The results of experiments on combined efficacy using compound 1 and lamotrigine (LTG) are shown in table. 3.

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Table 3

Efficacy of compound 1, LTG, or combination thereof in audiogenic seizure-responsive DBA/2J juvenile mice, generalized seizure model (n=9-10/group) with appropriate brain and plasma concentrations

View Audiogenic Seizure Sensitive Juvenile Mice DBA/2J (U = 910) Introduction Gastric tube, 5 ml/kg in 10% PEG400 / 90% MC0.5% Evaluation The maximum phase of seizures observed when exposed to an auditory stimulus. Data shown as means ± S.E.M. Statistical data Kruskal-Wallis test followed by Dunn's special analysis: * p < 0.05, ** p < 0.01, *** p < 0.001 vs. medicinal base; # p < 0.05, ## p < 0.01 , ### p < 0.01 vs. COMPOUND 1; + p < 0.05, ++ p < 0.01, +++ p < 0.001 vs. LTG Variable Treatment group drug base + drug base Compound 1, 30 mg/kg + drug base drug base ± LTG, 3 mg/kg Compound 1.30 mg/kg ± LTG, 3 mg/kg Seizure phase 2.7 ± 0.2 2.0 ± 0.3 1.9 ± 0.2 0.9 ± 0.3 CONNECTION 1 concentration in the brain - general (ng/g) Plasma concentration - total (ng/ml) 4558±317 4652 ± 243 5032 ± 238 4550±293 LTG concentration in the brain - general (ng/g) Plasma concentration - total (ng/ml) 1491± 128 293 ± 27 1367±100 284 ± 18

Treatment group Variable Seizure phase drug base ± drug base 3.0±0.0 Compound 1, 30 mg/kg ± drug base 2.1 ± 0.2 drug base ± LTG, 10 mg/kg 1.4 ± 0.3 Compound 1, 30 mg/kg ± LTG, 10 mg/kg 0.2 ± 0.2 _{t tg} COMPOUND E 1 Concentration in the brain - total (ng / g) Plasma concentration - total (ng/ml) Concentration in the brain - total (ng / g) Plasma concentration - total (ng/ml) 4224 ± 261 4556±285 3262 ± 144 1203 ± 77 ***## 4260±350 3965 ± 372 3658 ± 310 1332 ± 102

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Variable Treatment group drug base + drug base COMPOUND 1, 30 mg/kg + drug base drug base + LTG, 30 mg/kg COMPOUND 1, 30 mg/kg + LTG, 30 mg/kg Seizure phase 3.0±0.0 1.9 ± 0.3 0.2 ± 0.2 *** # 0.0±0.0 ***## CONNECTION 1 Concentration in the brain - total (ng / g) Plasma concentration - total (ng/ml) 3618 ± 159 3968±258 3286±170 2915±150 1LTG Concentration in the brain - total (ng / g) Plasma concentration - total (ng/ml) 8888±248 3562±165 8562 ± 853 2797 ± 475

Treatment group

Variable drug base + drug base COMPOUND 1, 10 mg/kg + drug base drug base + LTG, 10 mg/kg COMPOUND 1, 10 mg/kg + LTG, 10 mg/kg Seizure phase 2.9 ± 0.1 2.8 ± 0.2 1.1 ± 0.3 ***, ### 1.4 ± 0.3 **, ## CONNECTION 1 Concentration in the brain - total (ng / g) Plasma concentration - total (ng/ml) 1197 ± 80 1522 ± 109 1420 ± 165 1286 ± 140 LTG Concentration in the brain - total (ng / g) Plasma concentration - total (ng/ml) 4054 ± 323 930 ± 77 3687 ± 393 859 ± 101

As can be seen from Table. 3, in juvenile DBA/2J mice, combinations of Compound 1 with lamotrigine showed a synergistic antiepileptic effect on induced audiogenic seizure compared to effects seen when the drugs were administered alone. For example, the combination of a partially effective dose of compound 1 (30 mg/kg, seizure severity 2, consistent with a clonic seizure) and a partially effective dose of lamotrigine (3 mg/kg, seizure severity 2, consistent with a clonic seizure) showed an increased antiepileptic effect and resulted in audiogenically induced seizures of reduced severity (1 corresponding to uncontrolled convulsions). The effect is not the result of a pharmacokinetic interaction, since the plasma and brain concentrations of compound 1 and lamotrigine were the same after administration of the compounds alone or in combination.

Pharmaceutical composition containing compound 1.

A pharmaceutical composition containing 10 mg of Compound 1 was prepared as hard gelatin capsules (350 mg) using the following ingredients:

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Ingredients Role mg/kps % CONNECTION 1 Active 10.00 2.86 substance MCC (Avicel РН101) Filler 1 207.38 59.25 Mannitol (Parteck M200) Filler 2 88.87 25.39 PVP (Povidone, Kollidon 30) Binder 17.50 5.00 substance cross-linked PVP (Crospovidone, Kollidon CL) Baking powder 17.50 5.00 Silica Anhydrous (Aerosil 200) Gliding agent 5.25 1.50 magnesium stearate Lubricating 3 so 1.00 (LUB Stab) substance General 350.00 100.00

Abbreviations: kps: capsule; MCC: microcrystalline cellulose;

PVP: polyvinylpyrrolidone.

Hard gelatin capsules can be prepared according to the following method:

Stage Operation 1 Screening of the internal phase (mixture of MCC, mannitol, povidone and crospovidone) with an 800 µm sieve 2 Mixing with Turbula® Shaker Mixer (10 min at 32 rpm: Mix A) 3 Combine COMPOUND 1 with mixture A (1:5 by weight) and mix with a Turbula® shaker mixer (15 min. at 32 rpm: Blend B) 4 Screening Mixture B with an 800 µm sieve 5 Agitation of Mixture B with Turbula® Shaker Mixer (15 min. at 32 rpm) 6 Transferring Mixture B to a container with the rest of Mixture A (Mixture C) 7 Stirring of Mixture C with a Turbula® Shaker Mixer (15 min. at 32 rpm) 8 Pressing and granulation on 800 µm sieve by roller press (Mini-Pactor) 9 Mixing with Turbula® Shaker Mixer (10 min at 32 rpm) 10 Screening anhydrous silica (glidant) with a 800 µm sieve and adding to Mix C eleven Mixing with a Turbula® Shaker Mixer (2 min at 32 rpm: Mix D) 12 Screening magnesium stearate (Lubricant) with a 800 µm sieve and adding to Mix D 13 Mixing with a Turbula® shaker mixer (10 min. at 32 rpm: Mixture A) Turbula® (2 min. at 32 rpm: Mixture E) 14 Encapsulation with size 0 hard gelatin capsules

rpm: number of revolutions per minute.

Claims (16)

CLAIM 1. Pharmaceutical combination containing the first active substance, which is N-[1-(5-cyano-pyridin-2-ylmethyl)-1H-pyrazol-3-yl]-2-[4-(1-trifluoromethyl-cyclopropyl ) phenyl]acetamide or a pharmaceutically acceptable salt thereof, and a second antiepileptic active or a pharmaceutically acceptable salt thereof. 2. Pharmaceutical combination according to claim 1, wherein the second active substance is selected from the group consisting of 5H-dibenzo[b,f]azepine-5-carboxamide, (RS)-3-ethyl-3-methyl-pyrrolidine-2,5 -dione, 6-(2,3dichlorophenyl)-1,2,4-triazine-3,5-diamine, (8)-2-(2-oxopyrrolidin-1-yl)butanamide, 10,11-dihydro-10oxo- 5H-dibenz[b,f]azepin-5-carboxamide, 2-propylpentanoic acid, N-(5-sulfamoyl-1,3,4thiadiazol-2-yl)acetamide, (2S)-2-[(4R)-2 -oxo-4-propylpyrrolidin-1-yl]butanαamide, 7-chloro-1-methyl-5phenyl-1,5-benzodiazepine-2,4-dione, 5-(2-chlorophenyl)-7-nitro-1,3 -dihydro-1,4-benzodiazepin-2-one, (S)-10acetoxy-10,11-dihydro-5H-dibenz[b,f]azenine-5-carboxamide, (3-carbamoyloxy-2-phenylpropyl)carbamate, 1-(aminomethyl)cyclohexaneacetic acid, (R)-2-acetamido-N-benzyl-3-methoxypropanamide, 5'(2-cyanophenyl)-1'-phenyl-2,3'-bipyridinyl-6'(1'H )-one, 5-ethyl-5-phenyl-1,3-diazinan-2,4,6-trione, 5,5diphenylimidazolidine-2,4-dione, 2-(2-oxopyrrolidin-1-yl)acetamide, ( 3S)-3-(α-mortar)-5-methyl- - 31 040556 hexanoic acid, 5-ethyl-5-phenyl-1,3-diazinan-4,6-dione, ethyl (2-amino-4-((4-fluorobenzyl)amino)phenyl)carbamate, 1 -(2 ,6-difluorobenzyl)- 1H-1,2,3-triazole-4-carboxamide, (RS)-(E)-4,4-dimethyl-1-[3,4(methylenedioxy)phenyl]-1-penten- 3-ol, (3R)-1-[4,4-bis(3-methyl-2-thienyl)-3-buten-1-yl]-3-piperidinecarboxylic acid, 2.3:4,5-bis- O-(1-methylethylidene)-β-D-fructopyranose sulfamate, (RS)-4aminohex-5-enoic acid, and benzo[d]isoxazol-3-ylmethanesulfonamide, or a pharmaceutically acceptable salt of any of the above. 3. Pharmaceutical combination according to claim 1, wherein the second active substance is selected from the group consisting of 5H-dibenzo[b,f]azepine-5-carboxamide, (RS)-3-ethyl-3-methyl-pyrrolidine-2,5 -dione, 6-(2,3dichlorophenyl)-1,2,4-triazine-3,5-diamine, (S)-2-(2-oxopyrrolidin-1-yl)butanamide, 10,11-dihydro-10oxo- 5H-dibenz[b,f]azepine-5-carboxamide; and 2-propylpentanoic acid or a pharmaceutically acceptable salt of any of the above. 4. Pharmaceutical combination according to claim 1, wherein the second active substance is selected from the group consisting of (RS)-3-ethyl-3-methyl-pyrrolidine-2,5-dione, 6-(2,3-dichlorophenyl)-1 ,2,4-triazine-3,5-diamine, (S)-2-(2-oxopyrrolidin-1-yl)butanamide, 2-propylpentanoic acid and 5-(2-chlorophenyl)-7-nitro-1,3dihydro -1,4-benzodiazepin-2-one or a pharmaceutically acceptable salt of any of the above. 5. Pharmaceutical combination according to claim 1, wherein the second active substance is selected from the group consisting of (S)-2-(2-oxopyrrolidin-1-yl)butanamide and 2-propylpentanoic acid or a pharmaceutically acceptable salt of any of the above. 6. The pharmaceutical combination according to claim 1, wherein the second active substance is (S)-2-(2-oxopyrrolidin-1-yl)butanamide or a pharmaceutically acceptable salt thereof. 7. Pharmaceutical combination according to claim 1, wherein the second active substance is 2-propylpentanoic acid or a pharmaceutically acceptable salt thereof. 8. The pharmaceutical combination according to claim 1, wherein the second active substance is (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide or a pharmaceutically acceptable salt thereof. 9. Pharmaceutical combination according to any one of claims 1 to 8, wherein the first and second active substances are contained in the same pharmaceutical composition. 10. Pharmaceutical combination according to any one of claims 1 to 8, in which the first and second active substances are contained in separate pharmaceutical compositions. 11. The use of a pharmaceutical combination according to any one of claims 1 to 10 as a medicine. 12. The use of a pharmaceutical combination according to any one of claims 1 to 10 for the prevention and/or treatment of epilepsy. 13. The use of a pharmaceutical combination according to any one of claims 1 to 10 for the prevention and/or treatment of tonic-clonic and/or absence seizures. 14. Pharmaceutical composition containing N-[1-(5-cyanopyridin-2-ylmethyl)-1H-pyrazol-3-yl]-2-[4-(1-trifluoromethyl-cyclopropyl)phenyl]acetamide or a pharmaceutically acceptable salt thereof and at least one therapeutically inert excipient, wherein the pharmaceutical composition is administered in combination with a second pharmaceutical composition containing 5H-dibenzo[b,f]azepine-5-carboxamide, (RS)-3-ethyl -3methyl-pyrrolidin-2,5-dione, 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, (S)-2-(2-oxopyrrolidin-1yl)butanamide, 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide, 2-propylpentanoic acid, N-(5-sulfamoyl-1,3,4-tiadiazol-2-yl)acetamide, (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1yl]butanamide, 7-chloro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4-dione, 5-( 2-chlorophenyl)-7-nitro-1,3dihydro-1,4-benzodiazepin-2-one, (S)-10-acetoxy-10,11-dihydro-5H-dibenz[b,f]azepin-5-carboxamide , (3-carbamoyloxy-2-phenylpropyl)carbamate, 1-(aminomethyl)cyclohe xanoacetic acid, (R)-2acetamido-N-benzyl-3-methoxypropanamide, 5'-(2-cyanophenyl)-1'-phenyl-2,3'-bipyridinyl-6'(1'H)-one, 5ethyl- 5-phenyl-1,3-diazinan-2,4,6-trione, 5,5-diphenylimidazolidine-2,4-dione, 2-(2-oxopyrrolidin-1yl)acetamide, (3S)-3-(aminomethyl) -5-methylhexanoic acid, 5-ethyl-5-phenyl-1,3-diazinan-4,6-dione, ethyl (2-amino-4-((4-fluorobenzyl)amino)phenyl)carbamate, 1-(2 ,6-difluorobenzyl)-1H-1,2,3-triazole-4carboxamide, (RS)-(S)-4,4-dimethyl-1-[3,4-(methylenedioxy)phenyl]-1-pentene-3 -ol, (3R)-1-[4,4-bis(3-methyl-2-thienyl)-3-buten-1-yl]-3-piperidinecarboxylic acid, 2.3:4,5-bis-O- (1-methylethylidene)-β-D-fructopyranose sulfamate, (RS)-4-aminohex-5-enoic acid or benzo[d]isoxazol-3ylmethanesulfonamide or a pharmaceutically acceptable salt, and at least one therapeutically inert excipient. 15. Pharmaceutical composition containing 5Hdibenzo[b,f]azepine-5-carboxamide, (RS)-3-ethyl-3-methyl-pyrrolidine-2,5-dione, 6-(2,3-dichlorophenyl) as an active principle )1,2,4-triazine-3,5-diamine, (S)-2-(2-oxopyrrolidin-1-yl)butanamide, 10,11-dihydro-10-oxo-5Hdibenz[b,f]azepin- 5-carboxamide, 2-propylpentanoic acid, N-(5-sulfamoyl-1,3,4-thiadiazol-2yl)acetamide, (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl ]butanamide, 7-chloro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4-dione, 5-(2-chlorophenyl)-7-nitro-1,3-dihydro-1,4-benzodiazepine-2 -one, (S)-10-acetoxy10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide, (3-carbamoyloxy-2-phenylpropyl)carbamate, 1- - 32 040556 (aminomethyl) cyclohexaneacetic acid, W)-2-acetamido-N-benzyl-3-methoxypropanamide, 5'-(2cyanophenyl)-G-phenyl-2,3'-bipyridinyl-6'(1'H)- he, 5-ethyl-5-phenyl-1,3-diazinan-2,4,6-trione, 5,5diphenylimidazolidine-2,4-dione, 2-(2-oxopyrrolidin-1-yl)acetamide, (3S )-3-(aminomethyl)-5-methylhexanoic acid, 5-ethyl-5-phenyl-1,3-diazinan-4,6-dione, ethyl (2-amino-4-((4-fluorobenzyl)amino)phenyl )carbamate, 1-(2,6-difluorobenzyl)-1 Η-1,2,3-triazole-4-carboxamide, (RS)-(E)-4,4-dimethyl-1-[3,4( methylenedioxy)phenyl]-1-penten-3-ol, (3 R)-1-[4,4-bis(3-methyl-2-thienyl)-3-buten-1-yl]-3-piperidinecarboxylic acid, 2,3:4,5-bis-O-(1-methylethylidene)-P-O-fructopyranose sulfamate, (RS)-4aminohex-5-enoic acid, or benzo[<1]isoxazol-3-ylmethanesulfonamide, or a pharmaceutically acceptable salt and at least one therapeutically inert excipient, wherein the pharmaceutical composition is administered in combination with a second pharmaceutical composition containing ]\1-[1-(5-cyano- pyridin-2-ylmethyl)-1H-pyrazol-3-yl]-2-[4-(1-trifluoromethylcyclopropyl)phenyl]acetamide or a pharmaceutically acceptable salt thereof; and at least one therapeutically inert excipient. 16. A set of parts, including the first pharmaceutical composition containing as an active principle M-[1-(5-cyano-pyridin-2-ylmethyl)-1H-pyrazol-3-yl]-2-[4-(1trifluoromethyl -cyclopropyl)phenyl]acetamide or a pharmaceutically acceptable salt thereof and at least one therapeutically inert excipient; and a second pharmaceutical composition containing as active principle 5H-dibenzo[b,1]azepine-5-carboxamide, (RS)-3-ethyl-3-methylpyrrolidine-2,5-dione, 6-(2,3-dichlorophenyl )-1,2,4-triazine-3,5-diamine, (S)-2-(2-oxopyrrolidin-1yl)butanamide, 10,11-dihydro-10-oxo-5H-dibenz[b,1]azepine -5-carboxamide, 2-propylpentanoic acid, M-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide, (28)-2-[(4E)-2-oxo-4-propylpyrrolidine- 1yl] butanamide, 7-chloro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4-dione, 5-(2-chlorophenyl)-7-nitro-1,3dihydro-1,4-benzodiazepine- 2-one, (S)-10-acetoxy-10,11-dihydro-5H-dibenz[b,1]azepin-5-carboxamide, (3-carbamoyloxy-2-phenylpropyl)carbamate, 1-(aminomethyl)cyclohexaneacetic acid, (R)-2acetamido-N-benzyl-3-methoxypropanamide, 5'-(2-cyanophenyl)-F-phenyl-2,3'-bipyridinyl-6'(GN)-one, 5ethyl-5-phenyl-1, 3-diazinan-2,4,6-trione, 5,5-diphenylimidazolidine-2,4-dione, 2-(2-oxopyrrolidin-1yl)acetamide, (38)-3-(aminomethyl)-5-methylhexanoic acid, 5-ethyl-5-phenyl-1,3-diazinan-4,6-dione, ethyl (2-amino-4 -((4-fluorobenzyl)amino)phenyl)carbamate, 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4carboxamide, (RS)-(E)-4,4-dimethyl- 1-[3,4-(methylenedioxy)phenyl]-1-penten-3-ol, (3R)-1-[4,4-bis(3-methyl-2-thienyl)-3-buten-1-yl] -3-piperidinecarboxylic acid, 2,3:4,5-bis-O-(1-methylethylidene)-P-Ofructopyranose sulfamate, N8)-4-aminohex-5-enoic acid, or benzo[<1]isoxazol-3ylmethanesulfonamide, or a pharmaceutically acceptable salt; and at least one therapeutically inert excipient.