Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2, and their use

The present invention is a positive allosteric modulator ("PAM") of the metabotropic glutamate receptor subtype 2 ("mGluR2") or a pharmaceutically acceptable salt or solvate thereof, or a metabotropic glutamate agonist. It relates to a combination comprising an orthosteric agonist compound of receptor subtype 2 or a pharmaceutically acceptable salt or solvate thereof and a synaptic vesicle protein 2A ("SV2A") ligand.

Epilepsy represents a condition with recurrent seizures resulting from a chronic underlying disorder. Due to the many forms and causes of epilepsy, epilepsy refers to a clinical phenomenon rather than a single disease entity. Using the definition of epilepsy as two or more non-induced seizures, the incidence of epilepsy is estimated to be about 0.3-0.5% in various populations worldwide, and the prevalence of epilepsy is 5-10 per 1000. It is estimated to be.

An essential step in assessing and managing patients with seizures is determining the type of seizure that has occurred. The main feature that distinguishes between different types of seizures is whether the seizure activity is focal epilepsy (synonymous with focal epilepsy) or generalized seizures.

Focal epilepsy is one in which seizure activity is limited to scattered areas of the cerebral cortex. If full consciousness is maintained during the seizure, the clinical symptoms are considered to be relatively simple, and the seizure is referred to as a simple focal epilepsy. If there is impaired consciousness, the seizure is called a complex partial epilepsy. Other important subgroups include those that begin as focal epilepsy and then spread diffusely throughout the cortex, known as focal epilepsy with secondary generalization.

Generalized seizures are bilaterally symmetrical with diffuse lesions of the brain. Absence seizures or minor seizures are characterized by a sudden loss of consciousness for a short period of time without loss of postural control. Atypical absence seizures typically include relatively long loss of consciousness, less abrupt onset and termination, and relatively obvious motor signs that may include localized or lateralized features. The predominant type of generalized seizures, generalized tonic-clonic seizures or major seizures, are characterized by a sudden onset without warning. In the early stages of a seizure, there is usually a marked increase in sympathetic tone that leads to tonic muscle contractions, respiratory distress, heart rate, blood pressure and increased pupil size. After 10-20 seconds, the tonic phase of the seizure typically shifts to the clonic phase caused by the overlap of muscle relaxation time with tonic muscle contraction. Relaxation time gradually increases until the end of the seizure phase, the duration of which is usually less than 1 minute. The postictal phase is characterized by refractory, muscle relaxant, and excessive salivation, thereby stridorous. Breathing) and partial airway obstruction can occur. Atonic seizures are characterized by a sudden loss of postural muscle tone that lasts 1-2 seconds. Disturbance of consciousness occurs for a short time, but there is usually no post-seizure confusion. Myoclonic attacks are characterized by sudden, short-term muscle contractions that can involve part or whole body.

Synaptic vesicle protein 2A ("SV2A") has been identified as a target for a wide range of anticonvulsants in models of partial epilepsy and generalized epilepsy. Studies conducted in animal models and human tissues suggest that altered expression of SV2A is involved in epilepsy (for an overview, eg: (a) Mendoza-Torreblanca et al. "Synaptic vesicle protein 2A" : basic facts and role in synaptic function "European Journal of Neuroscience 2013, pp.1-11; (b) Kaminski RM, et al." Targeting SV2A for Discovery of Antiepileptic Drugs ", Noebels JL, Avoli M, Rogawski MA, et al., editors. Jasper's Basic Mechanisms of the Epilepsies [Internet] .4th edition.Bethesda (MD): National Center for Biotechnology Information (US); 2012 (available at http://www.ncbi.nlm.nih.gov/books/NBK98183/).

The exact role of SV2A remains unclear, but studies suggest that altered SV2A expression affects synaptic function (Nowack et al. "Levetiracetam reverses synaptic deficits produced by overexpression of SV2A" PLoS One 2011. , Volume 6 (12), e29560). It has also been suggested that SV2A plays an important role in exocytosis and is involved in neurotransmission (Crowder et al. "Abnormal neurotransmission in mice lacking synaptic vesicle protein 2A (SV2A)" Proc Nat Acad Sci USA 1999. , 96, pp.15268-15273), studies in knockout mice suggest that the lack of SV2A results in an imbalance between glutamatergic neurotransmission and GABAergic neurotransmission (Venkatesan et al. " Altered balance between excitatory and inhibitory inputs onto CA pyramidal neurons from SV2A-deficient but not SV2B-deficient mice "J Neurosci Res 2012,90, pp.2317-2327). Decreased SV2A expression may be the result of seizure activity. , Van Vliet et al. "Decreased expression of synaptic vesicle protein 2A, the binding site for levetiracetam, during epileptogenesis and chronic epilepsy" Epilepsy 2009, 50, pp.422-433; Feng et al. of synaptic vesicle protein 2A in the anterior temporal neocortex of patients with intractable epilepsy "J Mol Neurosci 2009,39, pp.354-359; Toering et al." Expression patterns of synaptic vesicle protein 2A in focal cortical dysplasia and TSC-cortical tubers "Epilepsia 2009,50, pp. 1409-1418), and epilepsy-associated brain tumors and in the peritumoral cortex, de Groot et al. "Expression of synaptic vesicle protein 2A in epilepsy-associated brain tumors and in the peritumoral cortex" Neuro-Oncology 2010,12, pp.265-273) May be involved in.

Levetiracetam (Lynch et al. "The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam" Proc.Natl.Acad.Sci.USA 2004, Vol.101, pp.9861-9866), Bribalacetam , And Levetiracetam (Kaminski RM, et al. "Targeting SV2A for Discovery of Antiepileptic Drugs", Noebels JL, Avoli M, Rogawski MA, et al., Editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition.Bethesda ( MD): National Center for Biotechnology Information (US); 2012 (available from http://www.ncbi.nlm.nih.gov/books/NBK98183/); Nowack et al. "Levetiracetam reverses synaptic deficits produced by overexpression of SV2A" PLoSone December 2011, Vol .6 (12), e29560).

Levetiracetam, ie (-)-(S) -α-ethyl-2-oxo-1-pyrrolidinacetamide or (S) -2- (2-oxopyrrolidine-1-yl) butaneamide<chemistry num="1"><img file="JP2019123723A_D0001.tif" /></chemistry>Is an antiepileptic drug. It showed no pharmacological activity in conventional acute models (maximum electric shock and pentylenetetrazol seizure test), but was found to be potent in chronic epilepsy models and genetic models of generalized epilepsy. It showed a high safety margin compared to other antiepileptic drugs (Klitgaard "Levetiracetam: the preclinical profile of a new class of antiepileptic drugs" Epilepsy 2001, 42 (Supplement). 4), pp.13-18). It is a trademark of Keppra® and is commercially available as tablets, as oral solutions, and as concentrates prepared as injectable solutions. Keppra® is the treatment of partial seizures (fits) with or without secondary generalization in Europe as monotherapy for patients aged 16 years and older who are newly diagnosed with seizure. Partial onset attacks with or without generalization in patients aged 1 month or older; myochrony attacks in patients aged 12 years or older with young myocrony epilepsy; and primary in patients aged 12 years or older with idiopathic generalized seizure Approved as an additional therapy used with other antiepileptic drugs to treat generalized levetiracetam (www.ema.europa.eu). Keppra® is also available in the United States for partial onset attacks in patients older than 1 month; myoclonic attacks in patients 12 years and older with juvenile myoclonic epilepsy; and in patients 6 years and older with idiopathic generalized epilepsy. It was also approved as an additional therapy to treat primary generalized tonic-clonic epilepsy. Keppra available as sustained release tablets XR® has been approved in the United States for the additional treatment of partial onset attacks in patients aged 16 years and older with epilepsy (http://www.accessdata.fda.gov/scripts/cder/drugsatfda). /index.cfm).

Bribalacetam, a 4-n-propyl analog of levetiracetam, ie (2S) -2-[(4R) -oxo-4-propylpyrrolidin-1-yl] butaneamide<chemistry num="2"><img file="JP2019123723A_D0002.tif" /></chemistry>Is in clinical trials and is used as monotherapy in partial onset and postherpetic neuralgia, as well as additional therapies for refractory partial onset, Unferricht-Lundborg's disease in adolescents and adults, and photosensitive epilepsy. Has been studied as (www.clinicaltrials.gov).

Celetracetam, ie (2S) -2-[(4S) -4- (2,2, -difluorovinyl) -2-oxopyrrolidine-1-yl] butaneamide<chemistry num="3"><img file="JP2019123723A_D0003.tif" /></chemistry>Was tested in clinical trials.

Methods for producing these three compounds are known in the literature. For example, a method for producing levetiracetam is disclosed, for example, in European Patent No. 0162036 and British Patent No. 2225322. The method for producing bribalacetam is disclosed, for example, in Pamphlet No. 01/62726 of International Publication No. 01/62726. A method for producing celetracetam is known, for example, from Pamphlet 2005/121082. Alternative production methods for these three compounds are disclosed in European Patent No. 1806339.

Antiepileptic drugs have been found to be useful for neurological and psychiatric disorders, including neuropathic pain, migraine, essential tremor, and for anxiety, schizophrenia, and bipolar disorder (Landmarck "Antiepileptic drugs"). in non-epilepsy disorders. Relations between mechanisms of action and clinical efficacy "CNS Drugs 2008, Vol.22 (1), pp.27-47; Calabresi et al." Antiepilepsy drugs in migraine: from clinical aspects to cellular mechanisms "Trends in Pharmacological Sciences 2007, Vol.28 (4), pp.188-195; Rogawski and Loescher "The neurobiology of antiepileptic drugs for the treatment" of nonepileptic conditions "Nat Med 2004, Vol.10, pp.685-692).

Levetiracetam is a mood disorder (Muralidharan and Bhagwagar "Potential of levetiracetam in mood disorders: a preliminary review" CNS Drugs 2006, Vol.20, pp.969-979; Mula et al. critical review of the evidence "J Clin Pshycopharmacol 2007, Vol.27, pp.263-272), anxiety disorders (Kinrys et al." Levetiracetam as adjunctive therapy for refractory anxiety disorders "J Clin Psychiatry 2007, Vol.68, pp. 1010-1013; Zhang et al. "Levetiracetam in" social phobia: a placebo controlled pilot study "J Psychopharmacol 2005, Vol.19, pp.551-553; Kinrys et al." Levetiracetam for treatment-refractory posttraumatic stress disorder "J Clin Psychiatry 2006, Vol.67, pp.211- 214), Pain (Enggaard et al. "Specific effect of levetiracetam in experimental human pain models" Eur J Pain 2006, Vol.10, pp.193-198; Dunteman "Levetiracetam as an adjunctive analgesic in neoplastic plexopathies: case series and commentary "J Pain Palliative Care Pharmacother 2005, Vol.19, pp.35-43; Price "Levetiracetam in the treatment of neuropathic pain: three case studies" Clin J Pain 2004, Vol.20, pp.33-36), Movement Disorder (Bushara et al) "The effect of levetiracetam on essential tremor" Neurology 2005, Vol.64, pp.1078-1080; McGavin et al "Levetiracetam as a treatment for tardive dyskinesia: a case report" Neurology 2003, Vol.61, pp.419; Woods et al. "Effects of levetiracetam on tardive dyskinesia: a randomized, double-blind, placebo-controlled study "J Clin Psychiatry 2008, Vol.69, pp.546-554; Zivkovic et al." Treatment of tardive dyskinesia with levetiracetam in a transplant patient "Acta Neurol Scand 2008, Vol.117 , pp.351-353; Striano et al. "Dramatic response to levetiracetam in post-ischaemic Holmes'tremor" J Neurol Neurosurg Psychiatry 2007, Vol.78, pp.438-439) Or it turned out to be effective, but cognitive function (Piazzini et al. "Levetiracetam: An improvement of attention and of oral fluency in patients with partial epilepsy "Epilepsy Research 2006, Vol.68, pp.181-188; de Groot et al." Levetiracetam improves verbal memory in high-grade glioma patients "Neuro-oncology 2013, Vol.15 (2) ), Pp.216-223; Bakker et al. "Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment" Neuron 2012, Vol.74, pp.467-474 (for review): Eddy et al. "The cognitive impact" of antiepileptic drugs "Ther Adv Neurol Disord 2011, Vol.4 (6), pp.385-407 and references cited therein; Wheless "Levetiracetam in the treatment of childhood epilepsy" Neuropsychiatric Disease and Treatment 2007, Vol.3 (4), pp. 409-421), and Behavioral Symptoms in Dementia (Dolder and Nealy "The efficacy and safety of newer anticonvulsants in patients with dementia" Drugs Aging It has also been suggested that it may have beneficial effects on 2012, Vol.29 (8), pp.627-637). Animal data and some preliminary clinical trials suggest that levetiracetam may have the ability to control post-traumatic epilepsy, such as status epilepticus, traumatic brain injury and epilepsy caused by ischemic seizures. It seems to have a protective effect. Because levetiracetam has shown antiepileptic effects in mouse and rat kindling models, the ability of levetiracetam in alleviating epileptigenic or cognitive dysfunction must now be confirmed in final animal and clinical trials (overview). For: Loescher and Brandt "Prevention or modification of epileptogenesis after brain insults: experimental approaches and translational research" Pharmacol Rev 2010, Vol.62,668-700; Shetty "Prospects of levetiracetam as a neuroprotective drug against status epilepticus, traumatic brain injury and stroke "Front.Neur.2013,4: 172.Doi: 10.3389 / fneur.2013.00172). It was also suggested that levetiracetam suppresses the release of glutamate (). Lee et al. "Levetiracetam inhibits glutamate transmission through presynaptic P / Q-type calcium channels on the granule cells of the dentate gyrus" British Journal of Pharmacology 2009, Vol.158, pp.1753-1762).

Celetracetam and Bribalacetam are dt^szMutant hamster models have been shown to reduce the severity of dystonia and may be useful in some patients with dyskinesia and dystonia movement disorders (Hamann et al. "Brivaracetam and seletracetam, two) new SV2A ligands, improve paroxysmal dystonia in the dt^sz mutant hamster "European Journal of Pharmacology 2008, Vol.601, pp.99-102).

Positive allosteric modulators of mGluR2 have recently emerged as promising new therapies for the treatment of several CNS disorders, including epilepsy, and for some mGluR2 PAMs, schizophrenia and anxiety depression are currently emerging. (See JNJ-40411813 / ADX71149 by www.clinicaltrials.gov, eg: Addex Therapeutics and Janssen Pharmaceuticals, Inc.). Early recommendations that drugs that suppress glutamatergic transmission may be effective in the treatment of epilepsy were based on acute nonclinical studies with mixed mGlu2 / 3 receptor agonists (Moldrich et al. "Glutamate metabotropic receptors). as targets for drug therapy in epilepsy "Eur J Pharmacol.2003, Vol.476, pp.3-16). Two mGlu2 / 3 receptor agonists, such as LY379268 and LY389795, were found to be ineffective in suppressing MES attacks below doses that cause movement disorders, but were found to be dose-dependent in the 6 Hz model. (Barton et al. "Comparison of the effect of glutamate receptor modulators in the 6Hz and maximal electroshock seizure models" Epilepsy Research 2003, Vol.56, pp.17-26). In long-term toxicity studies, continuous administration of mGlu2 / 3 agonists induced seizure activity contrary to the original purpose (Dunayevich et al. "Efficacy and tolerability of an mGlu2 / 3 agonist in the treatment of generalized anxiety". disorder "Neuropsychopharmacology.2008, Vol.33 (7), pp.1603-10). This paradoxical reaction may be associated with agonist-induced changes in the sensitivity of the receptive system (tachyphylaxis). Not reported in preclinical epilepsy models. In contrast, positive allosteric regulators regulate but do not directly stimulate ongoing neurotransmission, thereby reducing the risk of tachyphylaxis.

An increase in extracellular glutamate was measured in the human hippocampus prior to seizure activity, and the increase persisted during epileptic activity (During and Spencer "Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain" Lancet 1993, Vol.341 (8861), pp.1607-10) supports the idea that lower glutamate levels may be beneficial in the treatment of epilepsy. In fact, during seizure activity, glutamate levels rise to potentially neurotoxic levels. Seizure activity results in progressive structural damage to the human brain, which induces further abnormalities in glutamate metabolism (Petroff et al. "Glutamate-glutamine cycling in the epileptic human hippocampus" Epilepsy 2002, Vol.43 (7), pp.703-10). Therefore, a positive allosteric modulator of mGluR2 or an orthosteric agonist of mGluR2 can be considered to prevent seizure-induced nerve damage.

WO 2009/033704 and WO 2010/130424 disclose the positive allosteric modulators of mGluR2, their use, and methods of synthesizing their compounds. The International Publication No. 1997/18199 and the International Publication No. 2003/104217 were later found to have mGlu2 / 3 orthosteric agonist activity (eg, Rorick-Kehn et al. (2007) The Journal of Pharmacology and Experimental therapeutics. (Refer to Vol.321, No.1, pp.308-317) Excitatory amino acid receptor regulator compounds are disclosed, and other scientific and patent documents have mGlu2 / 3 orthosteric agonist activity. Other examples of compounds are disclosed, and WO 2008/150233 discloses compounds with mGluR2 allosteric agonist activity.

Currently available antiepileptic drugs not only affect glutamatergic transmission. These mechanisms of action are generally thought to alter the balance between excitatory (glutamic acid-mediated) and inhibitory (GABA-mediated) transmissions (Johannessen Landmark "Antiepileptic drugs in non-epilepsy disorders: relaxations between mechanisms of mechanisms of). action and clinical efficacy "CNS Drugs 2008, Vol.22 (1), pp.27-47).

<p> A major limiting factor in the use of SV2A ligands is tolerability and side effect profiles. For example, the effective dose of levetiracetam for partial onset attacks is 1000 mg, 2000 mg, and 3000 mg given twice daily. Reported side effects of levetyracetam include aggressive or angry behavior, anxiety, personality changes, chills, coughing or hoarseness, crying, depersonalization, diarrhea, dry mouth, euphoria, fever, general discomfort or Illness, headache, hyperventilation, arrhythmia, irritability, joint pain, loss of appetite, lower back or flank pain, mental depression depression), myalgia and myalgia, nausea, dysuria or dysuria, paranoia, hasty emotional or overreaction, rapid mood changes, restlessness, tremors, chills, shortness of breath, drowsiness or abnormal drowsiness, sore throat , Nasal congestion or nasal discharge, sweating, sleep disorders, abnormal fatigue or weakness, and vomiting. Therefore, there is still a need to provide effective treatments in which the effective dose of levetiracetam is lower and the side effect profile for the treatment of epilepsy and related disorders is more favorable, not only in adults but also in the pediatric population.</p>

<p> The present invention relates to (a) synaptic vesicle protein 2A ("SV2A") ligands and (b) metabotropic glutamate receptor subtype 2 ("mGluR2") positive allosteric modulator ("PAM") compounds. Or a combination thereof comprising a pharmaceutically acceptable salt or solvate thereof, or an orthosteric agonist compound of a metabotropic glutamate subtype 2 or a pharmaceutically acceptable salt or solvate thereof.</p>

<figref num="1">Co.No.2 and LEV single and combined administration ED at 6Hz 44mA₅₀Dose response to determine.</figref><figref num="2">Isobologram analysis of the combination of Co. No. 1 and levetiracetam (LEV) in a 6 Hz (44 mA) assay. Initial ED for both Co.No.1 and LEV₅₀The values (shown below) were calculated (data points on the x and y axes; filled diamonds). ED of two compounds in the theoretical straight line of additivity₅₀Associate the calculated value (solid black line). Theoretical ED on the combination of three fixed dose ratios (LEV: Co.No.1)₅₀Plotting (+ SEM): 1: 3-Filled Square / Black Solid Line, 1: 1-Filled Upward Triangle / Black Solid Line, and 3: 1-Filled Downward Triangle / Black Solid Line .. The experimental therapeutic dose was initially derived from theoretical values and adjusted according to the observed effects. Experimentally determined ED for each fixed dose ratio combination₅₀(+ SEM) values are also shown: 1: 3'-white square / dotted line, 1: 1'-white upward triangle / dotted line, and 3: 1'-white downward triangle / dotted line. Theory ED₅₀Value and experimentally determined ED₅₀Comparison with the value is a t-test (^***Comparison was made using P &lt;0.001). N = 8 per group. In Fig. 2, the ratio of LEV to Co.No.1 is shown as follows.</figref><tables num="1"><img file="JP2019123723A_D0004.tif" /></tables><figref num="3">Combination study of Co.No.25-a with levetiracetam (LEV) in 6Hz assay (44mA). At a dose of 10 mg / kg sc, Co.No.25-a improved the efficacy of LEV and its ED₅₀Shifts about 70 times. This suggests a positive pharmacodynamic relationship.</figref><figref num="4">Combination study of Co.No.2-a and levetiracetam (LEV) in 6Hz assay (44mA). At a dose of 10 mg / kg sc, Co.No.2-a improves the efficacy of LEV and its ED₅₀Shifts about 35 times. This suggests a positive pharmacodynamic relationship.</figref><figref num="5">Combination study of Co.No.6-b with levetiracetam (LEV) in 6Hz assay (44mA). At a dose of 10 mg / kg po, Co.No.6-b improved the efficacy of LEV and its ED₅₀Shifts about 100 times. This suggests a positive pharmacodynamic relationship.</figref><figref num="6">Combination study of LY-404039 with levetiracetam (LEV) in 6Hz assay (44mA). At a dose of 5 mg / kg sc, LY-404039 improved the efficacy of LEV and its ED₅₀Shifts about 27 times. This suggests a positive pharmacodynamic relationship.</figref>

In certain embodiments, the invention described herein is a pharmaceutical combination, in particular (a) with a synaptic vesicle protein 2A ("SV2A") ligand; (b) metabotropic glutamate agonists. Positive allosteric modulator ("PAM") compounds of receptor subtype 2 ("mGluR2") or pharmaceutically acceptable salts or solvates thereof, or metabotropic glutamate agonist subtype 2 orthosteric With respect to a pharmacological combination product comprising an agonist compound or a pharmaceutically acceptable salt or solvate thereof; (c) at least one pharmaceutically acceptable carrier.

In another embodiment, the invention relates to the combinations described herein for use as pharmaceuticals.

Another embodiment of the invention is described herein for producing a medicament or pharmaceutical for treating or preventing epilepsy and related disorders; neuropathic pain; migraine or resistant headache, and bipolar disorder and related disorders. Regarding the use of the described combinations.

Another embodiment of the invention relates to the use of a neuroprotective drug or combination described herein for producing a pharmaceutical product.

Another embodiment of the invention relates to the use of a medicament or combination described herein for the manufacture of a pharmaceutical or pharmaceutical product that prevents epileptigenicity.

Another embodiment is a method of treating or preventing epilepsy and related disorders in a subject; neuropathic pain; unilateral or resistant headaches; and bipolar disorders and related disorders, and synapses in the subject in need thereof. With a follicular protein 2A ("SV2A") ligand; a positive allosteric modulator ("PAM") compound of the metabotropic glutamate receptor subtype 2 ("mGluR2") or a pharmaceutically acceptable salt or solvent thereof. Effective for treatment when Japanese or metabotropic glutamate subtype 2 orthosteric agonist compounds or pharmaceutically acceptable salts or solvates thereof are administered together with SV2A ligand and mGluR2 compound. The present invention relates to a method comprising concomitant administration or sequential administration in an amount thereof.

Another embodiment relates to the combinations described herein for neuroprotection; or the combinations described herein used for neuroprotection.

Another embodiment relates to the combinations described herein for the prevention of epileptigenicity; or the combinations described herein for use in the prevention of epileptigenicity.

In another embodiment, the invention is a method of treating or preventing epilepsy and related disorders in a patient; neuropathic pain; unilateral or resistant headaches; bipolar disorders and related disorders, (a) small synapses. With a follicular protein 2A ("SV2A") ligand; (b) a positive allosteric regulator ("PAM") compound of the metabotropic glutamate receptor subtype 2 ("mGluR2") or a pharmaceutically acceptable salt thereof. Alternatively, a fixed dose combination of a solvate, or a metabotropic glutamate subtype 2 orthosteric agonist compound or a pharmaceutically acceptable salt or solvate thereof, together with the SV2A ligand and the mGluR2 compound. It relates to a method comprising administering in an amount effective for treatment when administered.

In another embodiment, the invention relates to a neuroprotective method using the combinations described herein.

In another embodiment, the invention relates to a method of suppressing epileptigenicity using the combinations described herein.

Another embodiment is a method of treating or preventing epilepsy and related disorders; neuropathic pain; unilateral or resistant headaches; bipolar disorders and related disorders, (a) synaptic vesicle protein 2A ("SV2A"). With a ligand; (b) A positive allosteric modulator ("PAM") compound of the metabotropic glutamate receptor subtype 2 ("mGluR2") or a pharmaceutically acceptable salt or admixture thereof, or A therapeutically effective amount of a combination or combination product containing an orthosteric agonist compound of the metabotropic glutamate receptor subtype 2 or a pharmaceutically acceptable salt or solvate thereof is required. The subject relates to a method comprising administering to a subject, eg, a warm-blooded animal, particularly a human.

Another embodiment is a neuroprotective method, in which (a) synaptic vesicle protein 2A ("SV2A") ligand and (b) metabotropic glutamate agonist subtype 2 ("mGluR2") are positive. Allosteric modulator ("PAM") compounds or pharmaceutically acceptable salts or solvates thereof, or metabotropic glutamate-operated receptor subtype 2 orthosteric agonist compounds or pharmaceutically acceptable salts or solvents thereof. The present invention relates to a method comprising administering a combination or concomitant product containing a Japanese product in a therapeutically effective amount to a subject in need thereof, for example, a warm-blooded animal, particularly a human.

Another embodiment is a method of suppressing epileptigenicity, in which (a) a synaptic vesicle protein 2A ("SV2A") ligand and (b) a metabotropic glutamate receptor subtype 2 ("mGluR2"). Positive allosteric modulator ("PAM") compounds or pharmaceutically acceptable salts or solvates thereof, or metabotropic glutamate receptor subtype 2 orthosteric agonist compounds or pharmaceutically acceptable salts thereof Alternatively, the method relates to a method comprising administering a combination or concomitant product containing a metabotropic glutamate in a therapeutically effective amount to a subject in need thereof, such as a warm-blooded animal, in particular a human.

In other embodiments, the invention combines the combinations of the invention described herein, in particular epilepsy and related disorders; neuropathic pain; migraine or resistant headache bipolar disorder; and treatment of related disorders or With respect to a medicinal or over-the-counter package that includes instructions for its simultaneous, separate, or sequential use in prophylaxis.

In other embodiments, the invention comprises a pharmaceutical or commercial package that comprises a combination of the inventions described herein, in particular with instructions for simultaneous, separate, or sequential use of it in neuroprotection. Regarding.

In other embodiments, the invention comprises a combination of the inventions described herein, particularly with instructions for simultaneous, separate, or sequential use of it in the suppression of epileptigenicity. Regarding commercial packaging.

In another embodiment, the invention relates to epilepsy and related disorders; neuropathic pain; unilateral or resistant headaches; amounts that are therapeutically effective in combination with bipolar disorders and related disorders; (a) small synapses. With a follicular protein 2A ("SV2A") ligand; (b) a positive allosteric modulator ("PAM") compound of the metabotropic glutamate receptor subtype 2 ("mGluR2") or a pharmaceutically acceptable salt thereof. Alternatively, it comprises a solvent or an orthosteric agonist compound of the metabotropic glutamate subtype 2 or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier. , Regarding combinations.

In another embodiment, the invention presents in therapeutic amounts with (a) synaptic vesicle protein 2A ("SV2A") ligands; (b) metabotropic glutamate receptor subs. A positive allosteric modulator ("PAM") compound of type 2 ("mGluR2") or a pharmaceutically acceptable salt or solvate thereof, or a metabotropic glutamate receptor subtype 2 orthosteric agonist compound or It relates to a combination comprising the pharmaceutically acceptable salt or solvate and at least one pharmaceutically acceptable carrier.

In another embodiment, the invention comprises (a) synaptic vesicle protein 2A ("SV2A") ligands and (b) metabotropic glutamate agonistic receptors in amounts that are therapeutically effective when used in combination for the prevention of epileptigenicity. A positive allosteric modulator ("PAM") compound of body subtype 2 ("mGluR2") or a pharmaceutically acceptable salt or solvate thereof, or an orthosteric agonist of metabotropic glutamate receptor subtype 2. With respect to a combination comprising a compound or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable carrier.

In another embodiment, the invention comprises (a) a synaptic vesicle protein 2A ("SV2A") ligand and (b) a metabotropic glutamate receptor subtype 2 for producing the concomitant product of the invention. A positive allosteric modulator ("PAM") compound ("mGluR2") or a pharmaceutically acceptable salt or solvate thereof, or a metabotropic glutamate receptor subtype 2 orthosteric agonist compound or pharmaceutical thereof. With respect to use with qualifyingly acceptable salts or solvates.

The component (b) of the combination of the present invention is generally referred to herein as "mGluR2 compound" or "mGluR2 PAM / agonist compound", or "positive allosteric regulator of mGluR2 / orthosteric agonist compound of mGluR2". , The compound is predominantly active in the metabotropic glutamate subtype 2, in particular the positive allosteric regulator (PAM) of the metabotropic glutamate subtype 2, and the metabotropic glutamate receptor. Means selected from body subtype 2 orthosteric agonists. Those skilled in the art will appreciate that mGluR2 and mGluR3 are highly homologous, as some mGluR2 orthosteric agonists also exhibit activity as mGluR3 orthosteric agonists. This means, for example, (-)-(1R, 4S, 5S, 6S) -4-amino-2-sulfonylbicyclo [3.1.0] -hexane-4,6-dicarboxylic acid (LY-404,039 [CAS 635318-]. Also known as 11-5]), K_i= 149nM (mGlu2 receptor) and K_i= 92 nM (mGlu3 receptor), mGlu2 and mGlu3 are 100-fold more selective than mGlu4a, mGlu6, mGlu7a, and mGlu8a and show no activity in mGlu1a and mGlu5a (Rorick-Kehn et al. (Rorick-Kehn et al. 2007) The Journal of Pharmacology and Experimental Therapeutics Vol.321, No.1, pp.308-317). Therefore, the terms "mGluR2 compound" or "mGluR2 PAM / agonist compound", or "positive allosteric modulator of mGluR2 / mGluR2 orthosteric agonist compound" have some other additional activity in vitro or in vivo. It does not exclude the compounds shown.

The combination of mGluR2 PAM compounds of the present invention is selected in particular from those disclosed in WO 2010/130424. Specific subgroups of the compounds disclosed in WO 2010/130424 are described in Formula (I):<chemistry num="4"><img file="JP2019123723A_D0005.tif" /></chemistry>Or its stereoisomer (in the formula, R¹Is (C_3~7Cycloalkyl) C_1~3Alkyl-, mono- or polyhalo C₁_~4Alkyl, and (C_1~4Alkyl) -O- (C_1~4Selected from the group consisting of (alkyl); R²Is halo or polyhalo C_1~4Alkyl; A is covalent or -CH₂-And L is the group (a), (b) and (c):<chemistry num="5"><img file="JP2019123723A_D0006.tif" /></chemistry>(In the formula, R^3aIs selected from unsubstituted phenyl, or phenyl substituted with one or two halo substituents; R^4aIs hydrogen, C_1~3Selected from the group of alkyl, and halo; or R^3a-CR^4aTogether with equation (a-1)<chemistry num="6"><img file="JP2019123723A_D0007.tif" /></chemistry>(In the formula, R^5aIndicates a group (which is hydrogen or halo); R^3bIs a phenyl substituted with one or two halo substituents, a pyridinyl substituted with one or two halo substituents, an unsubstituted pyrimidinyl, and one or two Cs._1~₃It can be defined by (selecting from the group of pyrimidinyls substituted with alkyloxy substituents)) or its pharmaceutically acceptable salts or solvates.

Thus, according to a particular embodiment of the invention, the positive allosteric modulator ("PAM") compound of the metabotropic glutamate receptor subtype 2 ("mGluR2") is the formula ("PAM") described herein. It is a compound of I).

In certain embodiments, the compound of formula (I) is the compound described above (in the formula, R).¹Cyclopropylmethyl-, 2,2,2-trifluoroethyl, and CH₃-O-CH₂-Selected from the group consisting of; R²Is chloro or CF₃Is; A is a covalent bond or -CH₂-And L is the group (a), (b) and (c):<chemistry num="7"><img file="JP2019123723A_D0008.tif" /></chemistry>(In the formula, R^3aIs selected from unsubstituted phenyl, or phenyl substituted with one or two fluorosubstituted groups; R^4aIs selected from the group consisting of hydrogen, methyl, and fluoro; or R^3a-CR^4aTogether with equation (a-1)<chemistry num="8"><img file="JP2019123723A_D0009.tif" /></chemistry>(In the formula, R^5aIndicates a group (which is hydrogen or fluoro); R^3bIs substituted with phenyl substituted with one or two fluoro substituents, pyridinyl substituted with one or two fluoro substituents, unsubstituted pyrimidinyl, and one or two methoxy substituents. (Selected from the group consisting of pyrimidinyl)) or a pharmaceutically acceptable salt or solvate thereof.

In certain embodiments, the compound of formula (I) is the compound described above (in the formula, (i) A is CH.₂And R²If is trifluoromethyl; R¹Is cyclopropylmethyl-; L is<chemistry num="9"><img file="JP2019123723A_D0010.tif" /></chemistry>Selected from; (ii) A is CH₂And R₂If is chloro; R¹Is cyclopropylmethyl-; L is<chemistry num="10"><img file="JP2019123723A_D0011.tif" /></chemistry>(Iii) A is a covalent bond and R²If is trifluoromethyl; R¹Is cyclopropylmethyl; L is<chemistry num="11"><img file="JP2019123723A_D0012.tif" /></chemistry>Selected from; (iv) A is a covalent bond and R²If is Cl; (iv-a) R¹Is cyclopropylmethyl and L is<chemistry num="12"><img file="JP2019123723A_D0013.tif" /></chemistry>Is; or (iv-b) R¹Is 2,2,2-trifluoroethyl and L is<chemistry num="13"><img file="JP2019123723A_D0014.tif" /></chemistry>Selected from; (v) A is CH₂And R¹Is-CH₂-O-CH₃If; R²Is -CF₃And L is<chemistry num="14"><img file="JP2019123723A_D0015.tif" /></chemistry>Or a pharmaceutically acceptable salt or solvate thereof.

The compound of formula (I) is disclosed in Pamphlet International Publication No. 2010/130424 and can be prepared by the method described therein, which is hereby incorporated by reference in its entirety. Will be done.

Specific compounds of formula (I) include:<chemistry num="15"><img file="JP2019123723A_D0016.tif" /></chemistry><chemistry num="16"><img file="JP2019123723A_D0017.tif" /></chemistry>

In one embodiment of the invention, the compound of formula (I) is<chemistry num="17"><img file="JP2019123723A_D0018.tif" /></chemistry>Co. No. 1; or its pharmaceutically acceptable salt, preferably its hydrochloride salt.

In another embodiment of the invention, the compound of formula (I) is<chemistry num="18"><img file="JP2019123723A_D0019.tif" /></chemistry>Co. No. 2; or a pharmaceutically acceptable salt thereof, preferably its hydrochloride salt (.HCl).

The combinations of mGluR2 PAM compounds of the present invention are also selected, in particular, from those disclosed in WO 2009/033704. The compound disclosed in International Publication No. 2009/033704 pamphlet has the following formula (IA):<chemistry num="19"><img file="JP2019123723A_D0020.tif" /></chemistry>And its stereoisomers (in the formula, R¹Is C_1~6Alkyl; or C_3~7C substituted with cycloalkyl_1~3It is phenyl, trifluoromethyl, or trifluoromethoxy substituted with alkyl, phenyl, or halo; R²Is halo, trifluoromethyl, C_1~3Alkyl, or cyclopropyl; R³Hydrogen, Fluoro, Hydroxy, Hydroxy C_1~3Alkyl, hydroxy C_1~3Alkyloxy, fluoro C_1~3Alkyl, Fluoro C_1~3Alkyloxy, or cyano; Ar is an unsubstituted phenyl; or n Rs⁴A phenyl substituted with a group (where n is 1, 2 or 3); R⁴Is hydrogen, halo, C_1~3Alkyl, hydroxy C_1~3Alkyl, polyhalo C₁_~3Alkyl, cyano, hydroxyl, amino, carboxyl, C_1~3Alkyloxy C_1~3Alkyl, C_1~3Alkyloxy, polyhalo C_1~3Alkyloxy, C_1~₃Alkylcarbonyl, mono- and di (C)_1~3Selected from the group consisting of alkyl) amino, and morpholinyl; or two adjacent Rs⁴Together, the groups are of the formula -N = CH-NH- (I), -CH = CH-NH- (ii), or -O-CH.₂-CH₂-Does form a divalent group of NH- (iii); or R³And R in the ortho position⁴Together with the group, the formula, -CH₂-O- (iv) or -O-CH₂-(V) forms a divalent group) and its pharmaceutically acceptable salts and solvates can be defined.

In certain embodiments, the compound of formula (IA) is the compound described above (in the formula, R).¹Is C_1~6Alkyl; or C_3~7C substituted with cycloalkyl_1~3It is phenyl, trifluoromethyl, or trifluoromethoxy substituted with alkyl, phenyl, or halo; R²Is halo, trifluoromethyl, C_1~3Alkyl, or cyclopropyl; R³Hydrogen, Fluoro, Hydroxy, Hydroxy C_1~3Alkyl, hydroxy C_1~3Alkyloxy, fluoro C_1~3Alkyl, Fluoro C_1~3Alkyloxy, or cyano; Ar is an unsubstituted phenyl, or n Rs.⁴A phenyl substituted with a group (where n is 1, 2 or 3); R⁴Is hydrogen, halo, C_1~3Alkyl, hydroxy C_1~3Alkyl, polyhalo C₁_~3Alkyl, cyano, hydroxyl, amino, carboxyl, C_1~3Alkyloxy C_1~3Alkyl, C_1~3Alkyloxy, polyhalo C_1~3Alkyloxy; C_1~₃Alkylcarbonyl, mono- and di (C)_1~3Selected from the group consisting of alkyl) amino, and morpholinyl; or two adjacent Rs⁴Group together, formula, -N = CH-NH- (I), -CH = CH-NH- (ii), or -O-CH₂-CH₂-Forms a divalent group of NH- (iii)) and its pharmaceutically acceptable salts and solvates.

In certain embodiments, the compound of formula (IA) is the compound described above (in the formula, R).¹Is C_1~6Alkyl; or C_3~7C substituted with cycloalkyl_1~3It is phenyl, trifluoromethyl, or trifluoromethoxy substituted with alkyl, phenyl, or halo; R²Is halo, trifluoromethyl, C_1~3Alkyl, or cyclopropyl; R³Hydrogen, Fluoro, Hydroxy, Hydroxy C_1~3Alkyl, hydroxy C_1~3Alkyloxy, fluoro C_1~3Alkyl, Fluoro C_1~3Alkyloxy, or cyano; Ar is an unsubstituted phenyl) and its pharmaceutically acceptable salts and solvates.

In other embodiments, the compound of formula (IA) is the compound described above (in the formula, R).¹Is 1-butyl, 2-methyl-1-propyl, 3-methyl-1-butyl, (cyclopropyl) methyl, or 2- (cyclopropyl) -3-ethyl; R³Is hydrogen, fluoro, or cyano; Ar is an unsubstituted phenyl) and its pharmaceutically acceptable salts and solvates.

In other embodiments, the compound of formula (IA) is the compound described above (in the formula, R).¹Is 1-butyl, 3-methyl-1-butyl, (cyclopropyl) methyl, or 2- (cyclopropyl) -1-ethyl; R²Is chloro; R³Is hydrogen or fluoro; Ar is an unsubstituted phenyl) and its pharmaceutically acceptable salts and solvates.

In another embodiment, the compound of formula (IA) is the compound described above (in the formula, R).¹Is C_1~6Alkyl; or C_3~7C substituted with cycloalkyl_1~3It is phenyl, trifluoromethyl, or trifluoromethoxy substituted with alkyl, phenyl, or halo; R²Is halo, trifluoromethyl, C_1~3Alkyl, or cyclopropyl; R³Hydrogen, Fluoro, Hydroxy, Hydroxy C_1~3Alkyl, hydroxy C_1~3Alkyloxy, fluoro C_1~3Alkyl, Fluoro C_1~3Alkyloxy, or cyano; Ar is n R⁴A phenyl substituted with a group (where n is 1, 2 or 3); R⁴Is halo, C_1~3Alkyl, hydroxy C_1~3Alkyl, C_1~3Alkyloxy, polyhalo C_1~3Alkyloxy, C_1~3Alkylcarbonyl, mono- and di (C)_1~3Selected from the group consisting of alkyl) amino, and morpholinyl; or two adjacent Rs⁴Group together, formula, -N = CH-NH- (I), -CH = CH-NH- (ii), or -O-CH₂-CH₂-Does form a divalent group of NH- (iii); or R³And R in the ortho position⁴Together with the group, the formula-CH₂-O- (iv), -O-CH₂-(V), forming a divalent group) and its pharmaceutically acceptable salts and solvates.

In other embodiments, the compound of formula (IA) is the compound described above (in the formula, R).¹Is 1-butyl, 2-methyl-1-propyl, 3-methyl-1-butyl, (cyclopropyl) methyl, or 2- (cyclopropyl) -1-ethyl; R³Is hydrogen, fluoro, or cyano; Ar is halo-substituted phenyl, trifluoromethyl, morpholinyl, or hydroxy C._1~3Alkyl) and its pharmaceutically acceptable salts and solvates.

In other embodiments, the compound of formula (IA) is the compound described above (in the formula, R).¹Is 1-butyl, 3-methyl-1-butyl, (cyclopropyl) methyl, or 2- (cyclopropyl) -1-ethyl; R²Is chloro; R³Is hydrogen or fluoro; Ar is a phenyl substituted with at least one halo group) and its pharmaceutically acceptable salts and solvates.

In other embodiments, the compound of formula (IA) is the compound described above (in the formula, R).¹Is 1-butyl, 3-methyl-1-butyl, (cyclopropyl) methyl, or 2- (cyclopropyl) -1-ethyl; R²Is chloro; R³Is hydrogen or fluoro; Ar is a phenyl substituted with at least two fluorogroups) and its pharmaceutically acceptable salts and solvates.

Compounds of formula (IA) are disclosed in Pamphlet International Publication No. 2009/033704 and can be prepared by the methods described therein, the patent document of which is incorporated herein by reference in its entirety. Will be done.

Specific compounds of formula (IA) include<chemistry num="20"><img file="JP2019123723A_D0021.tif" /></chemistry><chemistry num="21"><img file="JP2019123723A_D0022.tif" /></chemistry><chemistry num="22"><img file="JP2019123723A_D0023.tif" /></chemistry><chemistry num="23"><img file="JP2019123723A_D0024.tif" /></chemistry>And pharmaceutically acceptable salts and solvates thereof.

In one embodiment of the invention, the compound of formula (IA) is<chemistry num="24"><img file="JP2019123723A_D0025.tif" /></chemistry>Alternatively, it is a pharmaceutically acceptable salt or solvate thereof.

The combination of mGluR2 PAM compounds of the present invention is also selected, in particular, from those disclosed in PCT / European Patent Application Publication No. 2014/068676. The compound disclosed in PCT / European Patent Application Publication No. 2014/068676 has the following formula (IB):<chemistry num="25"><img file="JP2019123723A_D0026.tif" /></chemistry>And its stereoisomers (in the formula, R¹Is C_1~6Alkyl, (C_3~8Cycloalkyl) C_1~3Alkyl, and (C_1~3Alkyloxy) C_1~3Selected from the group consisting of alkyl; each R²Is F, Cl, C_1~3Alkyl, C_1~3Alkyloxy, mono-or polyhalo C_1~3Alkyl and mono-or polyhalo C_1~3Selected independently of alkyloxy; n is an integer selected from 1, 2, and 3) and its pharmaceutically acceptable salts and solvates can be defined.

The combinations of mGluR2 PAM compounds of the present invention are, in particular, the compounds of formula (IB) described above and their stereoisomers (in the formula, R).¹Is CH₃CH₂, CH₃CH₂CH₂, (Cyclopropyl) methyl, (cyclobutyl) methyl, ethyloxymethyl, and methyloxymethyl; the remaining variables are as described above), and their pharmaceutically acceptable salts and solvates. Selected from things.

In another embodiment, the combination of mGluR2 PAM compounds of the invention is, in particular, the compound of formula (IB) described above, and its stereoisomers (in the formula, R).¹Is CH₃CH₂, (Cyclopropyl) methyl, (cyclobutyl) methyl, and methyloxymethyl; the remaining variables are as described above), and its pharmaceutically acceptable salts and solvates. To.

In another embodiment, the combination of mGluR2 PAM compounds of the invention is, in particular, the compound of formula (IB) described above, and its stereoisomers (in the formula, R).¹Is CH₃CH₂, (Cyclopropyl) methyl, (cyclobutyl) methyl, and ethyloxymethyl; the remaining variables are as described above), and pharmaceutically acceptable salts and solvates thereof. To.

Thus, according to a particular embodiment of the invention, the positive allosteric modulator ("PAM") compound of the metabotropic glutamate receptor subtype 2 ("mGluR2") is the formula ("PAM") described herein. It is a compound of IB).

In other embodiments, the compound of formula (IB) is the compound described above (in the formula, each R).²Is F, Cl, CH₃, CH₃O and CF₃(Selected independently of) and its pharmaceutically acceptable salts and solvates.

In another embodiment, the compound of formula (IB) is of formula (I-Ba).<chemistry num="26"><img file="JP2019123723A_D0027.tif" /></chemistry>The aforementioned compounds having (in the formula, the variables are as described in formula (IB) herein), as well as pharmaceutically acceptable salts and solvates thereof.

In another embodiment, the compound of formula (IB) is of formula (I-Bb).<chemistry num="27"><img file="JP2019123723A_D0028.tif" /></chemistry>The aforementioned compounds having (in the formula, the variables are as described in formula (IB) herein), as well as pharmaceutically acceptable salts and solvates thereof.

Specific compounds of formula (IB) include 3- (cyclopropylmethyl) -7- [1- (4-fluorophenoxy) ethyl] -8- (trifluoromethyl) [1,2,4] triazolo- [ 4,3-a] Pyridine; 3- (Cyclopropylmethyl) -7-[(1^*R) -1- (4-fluorophenoxy) ethyl] -8- (trifluoromethyl) [1,2,4] triazolo [4,3-a] pyridine; 3- (cyclopropylmethyl) -7-[( 1^*S) -1- (4-fluorophenoxy) ethyl] -8- (trifluoromethyl) [1,2,4] triazolo [4,3-a] pyridine; 3- (cyclopropylmethyl) -7-[( 1S) -1- (2,4-difluorophenoxy) ethyl] -8- (trifluoromethyl) [1,2,4] triazolo [4,3-a] pyridine; 3- (cyclopropylmethyl) -7- [(1R) -1- (2,4-difluorophenoxy) ethyl] -8- (trifluoromethyl) [1,2,4] triazolo [4,3-a] pyridine; 3- (cyclopropylmethyl)- 7- [1- (2,4-difluorophenoxy) ethyl] -8- (trifluoromethyl) [1,2,4] triazolo- [4,3-a] pyridine; 3- (cyclopropylmethyl) -7 -[(1S) -1- (3,5-difluorophenoxy) ethyl] -8- (trifluoromethyl) [1,2,4] triazolo [4,3-a] pyridine; 3- (cyclopropylmethyl) -7-[(1S) -1- (3,4-difluorophenoxy) ethyl] -8- (trifluoromethyl) [1,2,4] triazolo [4,3-a] pyridine; 3- (Cyclopropylmethyl) -7-[(1S) -1- (2,3-difluorophenoxy) ethyl] -8- (trifluoromethyl) [1,2,4] Triazolo [4,3-a] Ppyridine; 3- (cyclopropylmethyl) -7-[(1S) -1- (2,5-difluorophenoxy) ethyl] -8- (trifluoromethyl) [1,2,4] triazolo [4,3- a] pyridine; 3- (cyclopropylmethyl) -7-[(1S) -1- (2,6-difluorophenoxy) ethyl] -8- (trifluoromethyl) [1,2,4] triazolo [4, 3-a] pyridine; 3- (cyclopropylmethyl) -7-[(1S) -1- (4-fluoro-2-methoxyphenoxy) ethyl] -8- (trifluoromethyl) [1,2,4] Triazolo [4,3-a] pyridine; 3- (cyclobutylmethyl) -7- [1- (2,4-difluorophenoxy) ethyl]

-8- (Trifluoromethyl) [1,2,4] triazolo- [4,3-a] pyridine; 7-[(1S) -1- (2-chloro-4-methylphenoxy) ethyl] -3- (Cyclopropylmethyl) -8- (trifluoromethyl) [1,2,4] triazolo [4,3-a] pyridine; 3- (cyclopropylmethyl) -7-[(1S) -1- (4- (4-) Fluoro-2-methylphenoxy) ethyl] -8- (trifluoromethyl) [1,2,4] triazolo [4,3-a] pyridine; 3- (cyclopropylmethyl) -8- (trifluoromethyl)- 7-[(1S) -1- (2,4,6-trifluorophenoxy) ethyl] [1,2,4] triazolo [4,3-a] pyridine; 7- [1- (2,4-difluoro) Phenoxy) ethyl] -3- (ethoxymethyl) -8- (trifluoromethyl) [1,2,4] triazolo- [4,3-a] pyridine; 3-ethyl-8- (trifluoromethyl) -7 -[1- (2,4,6-trifluorophenoxy) ethyl] [1,2,4] triazolo [4,3-a] pyridine; 7- [1- (2,4-difluorophenoxy) ethyl] -3-ethyl-8- (trifluoromethyl) [1,2,4] triazolo [4,3-a] pyridine; 3- (cyclobutylmethyl) )-7-[(1^*R) -1- (2,4-difluorophenoxy) ethyl] -8- (trifluoromethyl) [1,2,4] triazolo [4,3-a] pyridine; 3- (cyclobutylmethyl) -7- [(1^*S) -1- (2,4-difluorophenoxy) ethyl] -8- (trifluoromethyl) [1,2,4] triazolo [4,3-a] pyridine; 3- (ethoxymethyl) -8-( Trifluoromethyl) -7-[(1^*R) -1- (2,4,6-trifluorophenoxy) ethyl] [1,2,4] triazolo [4,3-a]

Pyridine; 3- (ethoxymethyl) -8- (trifluoromethyl) -7-[(1^*S) -1- (2,4,6-trifluorophenoxy) ethyl] [1,2,4] triazolo [4,3-a]

Pyridine; 7-[(1^*S) -1- (2,4-difluorophenoxy) ethyl] -3- (ethoxymethyl) -8- (trifluoromethyl) [1,2,4] triazolo [4,3-a] pyridine; 7- [ (1^*R) -1- (2,4-difluorophenoxy) ethyl] -3- (ethoxymethyl) -8- (trifluoromethyl) [1,2,4] triazolo [4,3-a] pyridine; 7- [ (1^*R) -1- (2,4-difluorophenoxy) ethyl] -3-ethyl-8- (trifluoromethyl) [1,2,4] triazolo- [4,3-a] pyridine; 7-[(1^*S) -1- (2,4-difluorophenoxy) ethyl] -3-ethyl-8- (trifluoromethyl) [1,2,4] triazolo- [4,3-a] pyridine; 7- [1- (2,4-difluorophenoxy) ethyl] -3-propyl-8- (trifluoromethyl) [1,2,4] triazolo [4,3-a] pyridine; 3-ethyl-8- (trifluoromethyl) -7-[(1^*R) -1- (2,4,6-trifluorophenoxy) ethyl]-[1,2,4] triazolo- [4,3-a] pyridine; 3-ethyl-8- (trifluoromethyl) -7 -[(1^*S) -1- (2,4,6-trifluorophenoxy) ethyl]-[1,2,4] triazolo- [4,3-a] pyridine; 7-[(1)^*R)-(2,4-difluorophenoxy) ethyl] -3-propyl-8- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine; and 7-[(1)^*S)-(2,4-difluorophenoxy) ethyl] -3-propyl-8- (trifluoromethyl)-[1,2,4] triazolo [4,3-a] pyridine can be mentioned.

Stereoisomers, their pharmaceutically acceptable salts and solvates are included within the scope of this list.

In other embodiments, the compound is 3- (cyclopropylmethyl) -7-[(1S) -1- (2,4-difluorophenoxy) ethyl] -8- (trifluoromethyl) [1,2,4. ] Triazolo [4,3-a] Pyridine hydrochloride can be selected.

Examples of the orthosteric agonist of mGluR2 / mGluR2 / 3 of the combination of the present invention include LY-404039; LY-2969822; LY-2934747; LY-379268; DCG-IV; LY-354740; LY-314582; LY-544344. LY-2140023; LY-181837; LY-389795; LY-446433; LY-450477; LY-395756; LY-566332; LY-541850; LY-2300559; LY-404040; LY-281223; LY-2979165; Gourmet Tad; MGS008; MGS0022; MGS0028; MGS0039; (-)-2-oxa-4-aminobicyclo [3.1.0] hexane-4,6-dicarboxylate; (+)-4-amino-2-sulfonylbicyclo [3.1.0] hexane-4,6-dicarboxylic acid; (+)-2-amino-4-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid; 1S, 2R, 5S, 6S-2- Amino-6-fluoro-4-oxobicyclo [3.1.0] hexane-2,6-dicarboxylic acid; 1S, 2R, 4S, 5S, 6S-2-amino-6-fluoro-4-hydroxybicyclo [3.1.0] ] Hexane-2,6-dicarboxylic acid; 1S, 2R, 3R, 5S, 6S-2-amino-3-fluorobicyclo [3.1.0] Hexane-2,6-dicarboxylic acid; 1S, 2R, 3S, 5S, 6S-2-amino-6-fluoro-3-hydroxybicyclo [3.1.0] hexane-2,6-dicarboxylic acid; (+)-4-amino-2-sulfonylbicyclo [3.1.0] hexane-4,6 -Dicarboxylic acid; (+)-2-amino-4-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid; 1S, 2R, 5S, 6S-2-amino-6-fluoro-4-oxobicyclo [3.1.0] hexane-2,6-dicarboxylic acid; 1S, 2R, 4S, 5S, 6S-2-amino-6-fluoro-4-hydroxybicyclo [3.1.0] hexane-2,6-Dicarboxylic acid; 1S, 2R, 3R, 5S, 6S-2-amino-3-fluorobicyclo [3.1.0] Hexane-2,6-dicarboxylic acid; or 1S, 2R, 3S, 5S, 6S-2- Amino-6-fluoro-3-hydroxybicyclo [3.1.0] Hexane-2,6-dicarboxylic acid includes, but is not limited to.

Specific groups of mGluR2 agonists include LY-379268; DCG-IV; LY-354740; LY-404039; LY-2969822; LY-2934747; LY-544344; and LY-2140023.

The metabotropic glutamate-operated receptor subtype 2 orthosteric agonists of the combinations of the present invention are, in particular, further incorporated herein by WO 1997/18199 and WO 2003/104217. It is selected from those disclosed in the issue pamphlet. The specific compound disclosed therein is as (-)-(1R, 4S, 5S, 6S) -4-amino-2-sulfonylbicyclo [3.1.0] hexane-4,6-dicarboxylic acid (LY-404039). Also known)<chemistry num="28"><img file="JP2019123723A_D0029.tif" /></chemistry>Or its salt or solvate, and (1R, 4S, 5S, 6S) -4-[[(2S) -2-amino-4- (methylthio) -1-oxobutyl] amino] -2-thiabicyclo [3.1. 0] Hexane-4,6-dicarboxylic acid 2,2-dioxide (also known as LY-2140023 [CAS 635318-55-7]),<chemistry num="29"><img file="JP2019123723A_D0030.tif" /></chemistry>Or a salt or solvate thereof, for example, a monohydrate thereof.

The compounds of the present invention are named using Advanced Chemical Development, Inc., software (ACD / Name product version 0.01.0.14105, October 2006) in accordance with the nomenclature rules agreed by the Chemical Abstracts Service (CAS). Described. In the case of a tautomer, the name of the tautomer whose structure is shown is described. However, it should be clear that other tautomers not shown are also included within the scope of the invention.

As used herein, "C" as a group or part of a group._1~3Alkyl "," C_1~₄Alkyl ", or" C_1~6The notation "alkyl" refers to a linear or branched saturated hydrocarbon group having 1-3 or 1-4 or 1-6 carbon atoms, such as methyl, ethyl, 1-propyl, 1-methylethyl, butyl, 1-. Methylpropyl, 2-methyl-1-propyl, 1,1-dimethylethyl, 3-methyl-1-butyl, 1-pentyl, 1-hexyl and the like are defined.

"C" as a group or part of a group_3~7Cycloalkyl "or" C_3~8The notation "cycloalkyl" defines cyclic saturated hydrocarbon groups with 3-7 or 3-8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The notation "halo" or "halogen" as used herein as a group or as part of a group refers to fluoro, chloro, bromo, or iodine, preferably fluoro or chloro.

"Mono-and Polyhalo C_1~3Alkyl "or" Mono-and Polyhalo C_1~4The notation "alkyl" is the aforementioned C substituted with one, two, three, or, if possible, more of the aforementioned halo atoms, respectively._1~3Alkyl or C_1~4It shall indicate alkyl.

Whenever the term "replaced" is used in the present invention, it shall be one on the atom or group indicated in the expression using "replaced" unless otherwise noted or not apparent from the context. Indicates that the above hydrogens, preferably 1 to 3 hydrogens, more preferably 1 to 2 hydrogens, more preferably 1 hydrogen, have been replaced by those selected from the group shown. However, in the step of isolating a chemically stable compound as a result of substitution without exceeding the usual valence, that is, the step of isolating it from the reaction mixture to a useful degree of purity, and the step of formulating it into a therapeutic agent. It is assumed that a compound that is sufficiently robust to withstand is obtained.

As used herein, the term "antiepileptic drug" and the abbreviation "AED" are used interchangeably with the term "anticonvulsant" as used herein. A drug that can treat, suppress, or prevent seizure activity or ictogenesis when administered to a subject or patient.

As used herein, the term "synaptic vesicle protein 2A ligand" and the abbreviation "SV2A ligand" are used interchangeably unless otherwise noted. Examples of SV2A ligands are Gazette, UK Pat. No. 1,039,113; UK Pat. No. 1,309,692; European Patent No. 1262036; European Patent No. 1806339; International Publication No. 2001/062726; US Patent Application Publication No. 2002/094787; International Publication No. 2004/087658 Pamphlet; International Publication No. 2005/121082 Pamphlet; International Publication No. 2005/054188 Pamphlet; International Publication No. 2006/128692 Pamphlet; International Publication 2006/128693 Pamphlet; International Publication No. 2007/065595 Pamphlet; International Publication No. 2008/132139 Pamphlet, and International Publication No. 2008/132142 Pamphlet; International Publication No. 2011/047860 Pamphlet; International Publication No. 2012/143116 Pamphlets; and the compounds described in WO 2012/143117, but are not limited to these. Suitable specific examples of SV2A ligands include, but are not limited to, levetiracetam, bribalacetam and celetrasetam.

Therefore, in one embodiment of the invention, the SV2A ligand is selected from levetiracetam, bribalacetam and celetrasetam.

In certain embodiments, the SV2A ligand is levetiracetam.

In certain embodiments, the SV2A ligand is bribalacetam.

The method for producing the above SV2A ligand is known from the literature, for example, European Patent No. 1806339; European Patent No. 0162036, and British Patent No. 2225322 (Levetiracetam); International Publication No. 01/62726. (Brivalacetam); as well as WO 2005/121082 (Celetracetam); such methods are incorporated herein by reference in their entirety.

In other embodiments, the combinations of the invention are (a) with an SV2A ligand selected from levetiracetam or bribalacetam; (b).<chemistry num="30"><img file="JP2019123723A_D0031.tif" /></chemistry>Alternatively, it comprises a pharmaceutically acceptable salt thereof, preferably a hydrochloride salt thereof, or a solvate thereof.

In other embodiments, the pharmaceutical compositions of the invention are (a) with a pharmaceutically effective amount of levetiracetam or bribalacetam; (b) of a pharmaceutically effective amount.<chemistry num="31"><img file="JP2019123723A_D0032.tif" /></chemistry>Alternatively, it comprises a pharmaceutically acceptable salt thereof, preferably a hydrochloride salt thereof, or a solvate thereof.

In other embodiments, the combinations of the invention are (a) with a pharmaceutically effective amount of levetiracetam or bribalacetam; (b) of a pharmaceutically effective amount.<chemistry num="32"><img file="JP2019123723A_D0033.tif" /></chemistry>Or the pharmaceutically acceptable salt or solvate thereof.

In other embodiments, the pharmaceutical compositions of the invention are (a) with a pharmaceutically effective amount of levetiracetam or bribalacetam; (b) of a pharmaceutically effective amount.<chemistry num="33"><img file="JP2019123723A_D0034.tif" /></chemistry>Or the pharmaceutically acceptable salt or solvate thereof.

In other embodiments, the combinations of the invention are (a) with a pharmaceutically effective amount of levetiracetam or bribalacetam; (b) of a pharmaceutically effective amount.<chemistry num="34"><img file="JP2019123723A_D0035.tif" /></chemistry>Or the pharmaceutically acceptable salt or solvate thereof.

In other embodiments, the pharmaceutical compositions of the invention are (a) with a pharmaceutically effective amount of levetiracetam or bribalacetam; (b) of a pharmaceutically effective amount.<chemistry num="35"><img file="JP2019123723A_D0036.tif" /></chemistry>Or the pharmaceutically acceptable salt or solvate thereof.

In other embodiments, the combinations of the invention are (a) with a pharmaceutically effective amount of levetiracetam or bribalacetam; (b) of a pharmaceutically effective amount.<chemistry num="36"><img file="JP2019123723A_D0037.tif" /></chemistry>Or the pharmaceutically acceptable salt thereof, particularly the hydrochloride salt thereof, or a solvate thereof.

In other embodiments, the pharmaceutical compositions of the invention are (a) with a pharmaceutically effective amount of levetiracetam or bribalacetam; (b) of a pharmaceutically effective amount.<chemistry num="37"><img file="JP2019123723A_D0038.tif" /></chemistry>Or the pharmaceutically acceptable salt thereof, particularly the hydrochloride salt thereof, or a solvate thereof.

In other embodiments, the combinations of the invention are (a) with a pharmaceutically effective amount of levetiracetam or bribalacetam; (b) a pharmaceutically effective amount of LY-404039 or a pharmaceutically acceptable salt thereof, particularly its hydrochlorides. Includes salts or solvates thereof.

In other embodiments, the pharmaceutical compositions of the invention are (a) with a pharmaceutically effective amount of levetiracetam or bribalacetam; (b) a pharmaceutically effective amount of LY-404039 or a pharmaceutically acceptable salt thereof, particularly It contains the hydrochloride or a solvate thereof.

In other embodiments, the combinations of the invention are (a) a pharmaceutically effective amount of levetiracetam or bribalacetam; (b) a pharmaceutically effective amount of LY-2140023 or a pharmaceutically acceptable salt or solvate thereof. In particular, it includes its monohydrate.

In other embodiments, the pharmaceutical compositions of the invention are (a) with a pharmaceutically effective amount of levetiracetam or bribalacetam; (b) a pharmaceutically effective amount of LY-2140023 or a pharmaceutically acceptable salt or solvate thereof. Includes, especially with its monohydrate.

The concomitant products of the present invention, in particular the pharmaceutical compositions of the present invention, are particularly suitable for the treatment of epilepsy and related disorders.

Some of the mGluR2 compounds, in particular the mGluR2 PAM / agonist compounds of the invention and their pharmaceutically acceptable addition salts and solvates thereof, contain one or more chiral centers and are present as stereoisomers. You will find that you get.

As used herein, the term "compound of the invention" refers to mGluR2 PAM compounds, in particular compounds of formula (I) / (IA) / (IB), and mGluR2 agonist compounds disclosed herein, It shall contain the salt and solvate.

As used herein, it has a bond that is shown only as a solid line and is not shown as an unbroken wedge or broken bond, or otherwise in a particular arrangement around one or more atoms. Any chemical formula shown as being (eg, R, S) considers a possible stereoisomer or a mixture of two or more stereoisomers, respectively.

In the above and below, the terms "mGluR2 compound" and "mGluR2 PAM / agonist compound" shall include their stereoisomers and their tautomers. "Stereoisomers", "stereoisomeric forms" or "stereochemically isomeric" The term "forms)" is used interchangeably above and below. The present invention includes all stereoisomers of the compounds of the invention as pure stereoisomers or as mixtures of two or more stereoisomers. Enantiomers are three-dimensional isomers that are mirror images of each other that cannot be superimposed. A 1: 1 mixture of a pair of enantiomers is a racemate or a racemic mixture. Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e. they are not in a mirror image relationship. If the compound contains a double bond, the substituents may be in the E or Z configuration. Substituents on divalent cyclic (partial) saturated groups may have a cis- or trans-configuration; for example, if the compound contains a disubstituted cycloalkyl group, the substituents. May be in the cis arrangement or in the trans arrangement. Thus, the invention includes enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof whenever chemically possible. The meaning of all these terms, namely enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof, is known to those skilled in the art. Absolute configuration is specified according to the Cahn-Ingold-Prelog system. The arrangement at the position of the asymmetric atom is specified by R or S. Divided stereoisomers of unknown absolute configuration can be indicated by (+) or (-), depending on the direction in which they rotate the plane polarized light. For example, split enantiomers of unknown absolute configuration can be indicated by (+) or (-), depending on the direction in which they rotate the plane polarized light.

When a particular steric isomer has been identified, it is this that the steric isomer is substantially free of other isomers, i.e. less than 50%, preferably less than 20% of the other isomers coexisting. It means that it is more preferably less than 10%, even more preferably less than 5%, particularly less than 2%, and most preferably less than 1%. Thus, when the mGluR2 compound is specified, for example, (R), this means that the compound is substantially free of the (S) isomer; the mGluR2 compound is specified, for example, E. When, this means that the compound is substantially free of the Z isomer; when the mGluR2 compound is specified, for example, cis, this means that the compound is substantially free of the trans isomer. Means that.

Some of the mGluR2 compounds may exist as their tautomers. Such forms are included within the scope of the present invention as long as they exist, even if they are not explicitly stated in the above equation.

Therefore, a single compound can exist as both a stereoisomer and a tautomer.

For pharmaceutical use, a salt of a compound of the invention refers to a non-toxic "pharmaceutically acceptable salt" (a salt of a compound of the invention whose counterion is pharmaceutically acceptable). However, other salts may be useful in the production or purification of the compounds of the invention or their pharmaceutically acceptable salts and may include pharmaceutically unacceptable acids and bases. All salts, whether pharmaceutically acceptable or not, are within the scope of the invention.

The pharmaceutically acceptable acid and base salts described above or below are intended to include the form of therapeutically active, non-toxic acid and base salts that the compounds of the invention can form. Suitable pharmaceutically acceptable salts of the compound include, for example, a solution of the compound to a pharmaceutically acceptable acid, such as an inorganic acid, such as a hydrohalogen acid such as hydrochloric acid or hydrobromic acid, sulfuric acid. , Nitrate, and acids such as phosphoric acid; or organic acids such as acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvate, oxalic acid (ie ethanediic acid), malonic acid, succinic acid (ie buthanic acid), Solutions of acids such as maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, and pamonic acid Contains acid addition salts that can be formed by mixing with. Conversely, the salt form can be converted to the free base form by treating it with an appropriate base. Furthermore, when the compounds of the invention have acidic moieties, suitable pharmaceutically acceptable salts thereof can include organic and inorganic bases. Suitable base salt forms include salts with organic bases such as, for example, ammonium salts, alkali metal salts and alkaline earth metal salts, such as lithium salts, sodium salts, potassium salts, magnesium salts, and calcium salts. , Primary, secondary and tertiary aliphatic and aromatic amines, such as methylamine, ethylamine, propylamine, isopropylamine, four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, Salts with diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; Includes benzathine salts, N-methyl-D-glucamine salts, hydrabamine salts, and salts with amino acids such as arginine, lysine and the like. Conversely, the salt form can be converted to the free acid form by treating with an acid.

The term "solvate" includes solvent addition forms in which the compound of formula (I) can be produced, and salts thereof. Examples of such solvent-added forms include, for example, hydrates, alcoholates and the like.

Preparation of Compound of Formula (IB) The compound of formula (IB) of the present invention can generally be prepared by a series of steps, each of which is known to those skilled in the art. In particular, the compound can be produced according to the following synthetic method.

The compounds of formula (IB) can be synthesized in the form of racemic mixtures of enantiomers that can be separated from each other according to division methods known in the art. The racemic compound of formula (IB) can be converted to the corresponding diastereomeric salt form by reaction with a suitable chiral acid. The form of the diastereomeric salt is then separated by, for example, selective crystallization or fractional crystallization, from which the enantiomers are liberated with alkali. Alternative methods for separating enantiomers of compounds of formula (IB) include liquid chromatography or supercritical fluid chromatography (SFC) using a chiral stationary phase. If the reaction occurs stereospecifically, the pure stereoisomer can also be derived from the corresponding pure stereoisomer of the appropriate starting material.

A. Preparation of the final compound of formula (IB) The final compound of formula (IB) is an intermediate compound of formula (II) according to the reaction skim (1), which is a reaction carried out under conventional Mitsunobu reaction conditions. It can be produced by reacting with a compound of formula (III). The reaction is preferably carried out in tetrahydrofuran, 1,4-dioxane, diethyl ether, toluene, benzene, dichloromethane, or a mixture thereof, using phosphine and an azodicarboxylate or amide, at -30 to 150 ° C. It is carried out by heating method or under microwave irradiation. The most commonly used phosphines are triphenylphosphine and tributylphosphine, which are usually dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, di- (4-chlorobenzyl) azodicarboxylate, azo. Combined with dibenzyl dicarboxylate, di-tert-butyl azodicarboxylate, bis- (dimethylylamide) azodicarboxylate, dipiperidide azodicarboxylate, or dimorphholide azodicarboxylate. In the reaction scheme (1), all variables are as defined in equation (IB).<chemistry num="38"><img file="JP2019123723A_D0039.tif" /></chemistry>

B. Preparation of Intermediates Experimental Procedure 2 The intermediate compound of formula (II) can be prepared by exposing the intermediate of formula (IV) to conditions known to those skilled in the art. This is shown in reaction scheme (2) (all variables are defined as described above in the equation). Methods of achieving these transformations are well known to those of skill in the art. The compound of formula (II) is obtained by treating the aldehyde of formula (IV) with an organometallic such as methyllithium bromide or methylmagnesium bromide. A suitable solvent for this reaction is an ether such as tetrahydrofuran, and the reaction is usually carried out at a temperature of 78 ° C to 40 ° C. In reaction scheme (2), all variables are defined as in equation (IB).<chemistry num="39"><img file="JP2019123723A_D0040.tif" /></chemistry>

Experimental Procedure 3 The intermediate compound of formula (IV) can be carried out using, for example, oxone, osmium tetroxide, an intermediate of formula (V) under dihydroxylation and oxidative cleavage conditions known to those of skill in the art. Can be produced by reacting. This process can optionally be carried out in a solvent such as 1,4-dioxane, water, at a temperature generally from about -100 oC to about 100 ° C. An overview of such methods can be found in "Comprehensive Organic Transformations", VCH Publishers, (1989), RCLarock, pp.595-596. This is shown in reaction scheme (3) (all variables are defined as described above in the equation).<chemistry num="40"><img file="JP2019123723A_D0041.tif" /></chemistry>

Experimental procedure 4 The intermediate compound of formula (V) is subjected to a coupling reaction between the intermediate of formula (VI) and the compound of (VII), for example, a Still coupling reaction or a Suzuki coupling reaction. It can be produced by carrying out under known conditions. This process can optionally be carried out in a solvent such as 1,4-dioxane, water, generally at a temperature of around room temperature to about 200 ° C. in the presence of a base. This is defined in Reaction Scheme (4) (in the equation, all variables are defined as described above, M is trialkyltin, boronic acid or boronic acid ester, and palladium catalyst, halo is chloro, bromo, or iodine. ).<chemistry num="41"><img file="JP2019123723A_D0042.tif" /></chemistry>

Experimental Procedure 5 For the intermediate compound of formula (VI), use the intermediate compound of formula (VIII) according to a procedure known in the art, for example, phosphorus (V) oxychloride (POCl).₃) In the presence of a halogenating agent, for example, in a suitable solvent such as dichloroethane, under microwave irradiation, for a suitable time during which the reaction can be completed, for example, for 5 minutes, at a temperature of 140 to 200 ° C. It can be manufactured by cyclizing with. In reaction scheme (5), R¹Is defined as in formula (IB) and the halo is chloro, bromo, or iodine.<chemistry num="42"><img file="JP2019123723A_D0043.tif" /></chemistry>

Experimental Procedure 6 The intermediate compound of formula (VIII) can be produced by reacting the hydrazine intermediate of formula (IX) with the acid halide of formula (X) according to a procedure known in the art. The reaction can be carried out, for example, using an inert solvent such as DCM in the presence of a base such as triethylamine, for example at room temperature, for a suitable time during which the reaction can be completed, for example 20 minutes. In reaction scheme (6), R¹Is defined as Equation (IB).<chemistry num="43"><img file="JP2019123723A_D0044.tif" /></chemistry>

Experimental Procedure 7 The intermediate compound of formula (IX) is a reaction of the intermediate compound of formula (XI) with hydrazine according to scheme (7), i.e., a suitable reaction failure such as, for example, ethanol, THF or 1,4-dioxane. Reactions carried out under thermal conditions in an active solvent, for example, by heating the reaction mixture at 160 ° C. for 30 minutes under microwave irradiation, or heating at 70 ° C. for 16 hours using conventional heating methods. It can be produced by reacting according to the above. In reaction scheme (7), the halo is chloro, bromo, or iodine.<chemistry num="44"><img file="JP2019123723A_D0045.tif" /></chemistry>

Experimental Procedure 8 The intermediate compound of formula (XI) is a reaction of the intermediate compound of formula (XII) with benzyl alcohol according to reaction scheme (8), ie, a suitable reaction-inert solvent such as, for example, N, N-dimethylformamide. It can be produced by reacting in the presence of a suitable base such as sodium hydride at room temperature for a suitable time during which the reaction can be completed, for example, according to the reaction carried out for 1 hour. In reaction scheme (8), the halo is chloro, bromo, or iodine.<chemistry num="45"><img file="JP2019123723A_D0046.tif" /></chemistry>

Experimental Procedure 9 The intermediate compound of formula (XII) reacts the intermediate of formula (XIII) with a suitable trifluoromethylating agent, such as, for example, fluorosulfonyl (difluoro) methyl acetate ester, according to reaction scheme (9). It can be manufactured by allowing it to be produced. This reaction is carried out, for example, in a suitable reaction-inert solvent such as N, N-dimethylformamide, in the presence of a suitable coupling agent such as copper (I) iodide, under thermal conditions, for example. The reaction mixture is heated, for example, under microwave irradiation at 160 ° C. for 45 minutes. In reaction scheme (9), the halo is chloro, bromo, or iodine.<chemistry num="46"><img file="JP2019123723A_D0047.tif" /></chemistry>

The starting material of formulas (II), (VII), (X) or (XIII) is a compound that is commercially available or can be prepared according to conventional reaction procedures known to those skilled in the art.

As used herein, the term "composition" is optionally derived directly or indirectly from a product containing a specified amount of the specified ingredient, as well as a combination of the specified amount of the specified ingredient. Products shall be included.

As used herein, the term "subject" refers to an animal that is or was a subject of treatment, observation or experiment, preferably a mammal, most preferably a human adult, child or infant.

As used herein, the term "therapeutically effective amount" includes reducing one or more of the symptoms of the disease or disorder being treated; and / or reducing the severity of one or more of the symptoms of the disease being treated. , Means the amount of pharmacologically active compound or pharmaceutical agent that elicits a biological or medical response in a tissue system, animal or human as required by a researcher, veterinarian, physician or other clinician.

Compound (a) SV2A ligand and (b) metabotropic glutamate receptor subtype 2 ("mGluR2") positive allosteric modulator ("PAM") or pharmaceutically acceptable salt or solvate thereof , Or in combination with metabotropic glutamate subtype 2 orthosteric agonists or pharmaceutically acceptable salts or solvates thereof, compounds (a) and (b) are administered simultaneously or separately. Whether administered to or sequentially, it may be beneficial compared to the effects of compound (a) or (b) administered alone. In particular, there may be at least one beneficial effect, eg, a mutual enhancement of the effects of compounds (a) and (b), an effect that outweighs the additive effect, in particular a synergistic effect; For example, a significantly lower effective amount of the combination of (a) and (b); additional therapeutic effects not observed with either compound (a) or (b) alone, a more beneficial side effect profile, or with (a). The combined therapeutic effect of (b) one or both ineffective doses can be mentioned.

As used herein, "ED of individual compounds (a) and (b)"₅₀The term "(a) synaptic vesicle protein 2A ligand and (b) compound of formula (I)" with a fixed dose ratio of 1: 1 calculated based on the values refers to the individual compounds (a) and (b). Each ED₅₀Refers to a composition comprising a dose of compounds (a) and (b) corresponding to 50% of a dose, or a multiple of this fixed dose ratio. "ED of individual compounds (a) and (b)₅₀The term "(a) Synaptic vesicle protein 2A ligand: compound of formula (I)" with a fixed dose ratio of 3: 1 calculated based on the values is (b) each ED.₅₀Compound (b) of formula (I) and each ED of compound (a) in a dose corresponding to a dose of 75%₅₀Refers to a dose of compound (a) corresponding to 25% of the dose, or a composition comprising a multiple of this fixed dose ratio, and so on.

Therefore, in another embodiment of the invention, the (a) SV2A ligand and the compound of formula (b) (I) are contained in the pharmaceutical composition in a fixed dose ratio of (a): (b) from about 1: 10 to about. 10: 1, preferably about 1: 5 to about 5: 1, more preferably about 1: 3 to about 3: 1, in another embodiment about 1: 1 to about 3: 1; in an alternative embodiment 1 : 3; 1: 1 in yet another embodiment; 3: 1 in other embodiments; fixed dose ratios are ED for individual compounds (a) and (b)₅₀Calculated based on the value.

The present invention relates to (a) synaptic vesicle protein 2A ("SV2A") ligands and (b) mGluR2 PAM / agonist compounds, particularly of the formulas (I) / (IA) / (IB) described herein. When it comes to co-therapy or combination therapy, which involves administration with a compound, the pharmaceutically effective or therapeutically effective amount is such that the combination effect elicits the desired biological or medical response. Means the amount of combination of drugs taken together with. For example, administration of (a) an SV2A ligand described herein and (b) an mGluR2 PAM / agonist compound, in particular a compound of formula (I) / (IA) / (IB) described herein. Therapeutically effective amounts of the combination therapy, including, have a therapeutically effective combination effect when taken together or sequentially, (a) the amount of SV2A ligand described herein and (b) mGluR2 PAM / agonist compounds, in particular. , Can be the amount of compound of formula (I) / (IA) / (IB). In addition, those skilled in the art will be given mGluR2 when performing combination therapy with a therapeutically effective amount as in the above example. The amount of PAM / agonist compounds, in particular the compounds of formula (I) / (IA) / (IB), and / or the amount of suitable SV2A ligand, may or may not be therapeutically effective amounts individually. You will find that it is okay.

The present invention provides a combination therapy of a therapeutically effective amount of SV2A ligand and a therapeutically effective amount of mGluR2 PAM / agonist compound, particularly the compounds of formulas (I) / (IA) / (IB) described herein. Provide prophylactic or therapeutic methods, including administration to subjects in need. To this end, the compounds or compositions of the invention must be used in the appropriate therapeutically effective amounts or therapeutically effective doses described above.

One of ordinary skill in the art can easily determine the optimal dose and dosing schedule, which will vary depending on the particular compound used, the method of administration, the strength of the formulation, the method of administration, and the progression of the disease state. In addition, the dose should be adjusted according to factors related to the particular patient being treated, including the patient's age, weight, diet, and duration of administration.

Those skilled in the art will appreciate that therapeutically effective doses of the compounds of the invention may include repeated doses in long-term treatment schemes with clinically significant results.

MGluR2 in a combination of the invention administered daily The amount of PAM / agonist compound, in particular the amount of compound of formula (I) / (IA) / (IB), may range from about 0.01 to about 2000 mg. Examples of daily doses of compounds of formula (I) / (IA) / (IB) are 0.01 mg, 0.05 mg, 0.1 mg, 0.5 so that the dose to the patient to be treated can be adjusted according to the symptoms. mg, 1.0 mg, 2.5 mg, 5.0 mg, 10.0 mg, 15.0 mg, 25.0 mg, 50.0 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 750 mg, and 1000 mg. The effective amount of the drug is usually supplied at a dose level ranging from about 0.01 mg / kg body weight to about 150.0 mg / kg body weight per day, or any range thereof. Preferably, the range is from about 0.1 to about 100.0 mg / kg body weight per day, more preferably from about 0.5 mg / kg body weight to about 50 mg / kg body weight, more preferably from about 1.0 to about 25.0 mg / kg body weight per day. is there. Compounds can be administered once, twice, three or four times daily. The amount of SV2A ligand administered daily may range from about 0.01 to about 7000 mg, preferably 250 to 5000 mg, more preferably 500 to 3000 mg. Examples of daily doses of SV2A ligand are 2.5 mg, 5.0 mg, 10.0 mg, 15.0 mg, 25.0 mg, 50.0 mg, 100 mg, 150 mg, so that the dose to the patient to be treated can be adjusted according to the symptoms. 200 mg, 250 mg, 500 mg, 750 mg, 1000 mg, 1500 mg, and 3000 mg. The effective amount of the drug is usually supplied at a dose level ranging from about 0.01 mg / kg body weight to about 150.0 mg / kg body weight per day, or any range thereof. Preferably, the range is from about 0.1 to about 100.0 mg / kg body weight per day, more preferably from about 0.5 mg / kg body weight to about 50 mg / kg body weight, more preferably from about 1.0 to about 25 per day. It has a body weight of 0 mg / kg. Compounds can be administered once, twice, three or four times daily. All quantities described in this paragraph and in the following paragraphs refer to the free form (ie, the non-salt form). The above value represents the equivalent of the free form, that is, the amount when the free form is administered. When the salt is administered, the amount needs to be calculated based on the relationship between the molecular weight ratio of the salt and the free form.

The daily doses mentioned above have been calculated for an average body weight of approximately 70 kg and must be recalculated for pediatric use or for patients with significantly different body weights.

Dosages may be provided as 1, 2, 3, or 4 or more partial doses administered at appropriate intervals throughout the day. The dose used is preferably the daily dose of mGluR2 PAM / agonist compound, in particular the daily dose of the compound of formula (I) / (IA) / (IB) described above, or the daily dose of SV2A ligand described above. Corresponds to an amount, or a partial dose thereof, eg, 1/2, 1/3, 1/4 of it. The dosage form contains the mGluR2 PAM / agonist compound, in particular compound (I) / (IA) / (IB), and / or the SV2A ligand, together in the same amount as the range or amount described in the previous paragraph. For example, the dosage form may be mGluR2 PAM / agonist compound, in particular compound (I) / (IA) / (IB) 10 mg, 25 mg, 50 mg, 100 mg, 150 mg, or 200 mg, SV2A ligand 10 mg, 25 mg, 50 mg. , 100 mg or 250 mg may be contained in separate formulations or combinations. In one embodiment, mGluR2 PAM / agonist compounds, in particular compounds of formula (I) / (IA) / (IB), are administered once daily (qd), especially as a daily dose, and SV2A ligands are administered once or twice daily. (qd or bid), especially given as one or two doses per day. When both compounds are administered once daily, this is 2 for mGluR2 PAM / agonist compounds, in particular those with compounds of formula (I) / (IA) / (IB) and those with SV2A ligand. Administer two separate doses or a combined dose containing the mGluR2 PAM / agonist compound, in particular the compound of formula (I) / (IA) / (IB) and the SV2A ligand. This can be achieved.

The combination of the present invention can be administered once, twice, three times, four times a day, or multiple times as needed. In one embodiment, the combination is administered once daily. In another embodiment, the combination is administered twice daily, or three times daily. Dosage forms contain separate dosage forms, ie, dosage forms containing only the mGluR2 PAM / agonist compound, in particular compounds of formula (I) / (IA) / (IB), or SV2A ligand only. It may be carried out in a dosage form; or in a combination dosage form containing the active ingredient mGluR2 PAM / agonist compound, in particular a compound of formula (I) / (IA) / (IB) and an SV2A ligand. Also, a mixture of a combination dosage form and a separate dosage form can be used. The dosage forms that can be administered will be described later, and oral dosage forms, particularly tablets or capsules, are preferable.

The active ingredient may be formulated into the pharmaceutical composition separately or as a combined pharmaceutical composition. In the latter case, therapeutically effective amounts of mGluR2 PAM / agonist compounds, in particular therapeutically effective amounts of compounds of formula (I) / (IA) / (IB), or pharmaceutically acceptable salts thereof, and SV2A ligands (the former). Is described herein) and a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

In another aspect, the invention presents a therapeutically effective amount of a therapeutically effective amount of mGluR2 PAM / agonist compound, particularly a therapeutically effective amount of a compound of formula (I) / (IA) / (IB), or a therapeutically effective amount thereof. A method for producing a pharmaceutical composition according to the present specification, which comprises a step of homogenically mixing a pharmaceutically acceptable salt or solvate with a therapeutically effective amount of at least one SV2A ligand.

The combinations provided herein are epilepsy and related disorders; neuropathic pain; migraine or resistant headache; for prevention or treatment of bipolar disorder and related disorders; for neuroprotection; or for epilepogenic prevention at the same time. It can also be formulated as a concomitant formulation that is used separately or sequentially. In such cases, the mGluR2 PAM / agonist compound, in particular the compound of formula (I) / (IA) / (IB), is formulated into a pharmaceutical composition containing other pharmaceutically acceptable excipients. , SV2A ligands are separately formulated into pharmaceutical compositions containing other pharmaceutically acceptable excipients. Conveniently, these separate pharmaceutical compositions may be part of a kit that is used simultaneously, separately or sequentially.

The individual components of the combination of the invention can be administered simultaneously or separately at different times during treatment, or in combination in divided or single combination forms.

Therefore, mGluR2 PAM / agonist compounds, in particular compounds of formula (I) / (IA) / (IB) and SV2A ligands, can be formulated individually or in combination into various pharmaceutical compositions suitable for the purpose of administration. .. Among these, a therapeutically effective amount of a particular compound, or a therapeutically effective amount of both of the two compounds, is combined with a pharmaceutically acceptable carrier, and the carriers vary widely depending on the form of the formulation desired for administration. Can take form. Pharmaceutical compositions are oral, parenteral (including subcutaneous (sc), intramuscular (im), and intravenous (iv)), rectal, transdermal, buccal, or nasal. It can be manufactured as a medicine to be used. The pharmaceutical composition is administered by intracranial or intravertebral needles and / or catheters in routes including the intracerebral, intraventricular (intraventricular), intraventricular (intracerebroventricular), intrathecal, intracisternal, intraspinal and / or perispinal routes It can also be manufactured to be administered directly to the nervous system by delivery with or without a pumping device, but is not limited thereto. Compositions suitable for oral administration include powders, granules, aggregates, tablets, compressed or coated pills, dragees, sachets, hard or gelatin capsules, syrups and suspensions. Compositions suitable for parenteral administration include aqueous or non-aqueous solutions or emulsions, while compositions suitable for administration in rectal administration include suppositories with hydrophilic or hydrophobic bases. Can be mentioned. A suitable transdermal delivery system can be used for topical administration and a suitable aerosol delivery system can be used for nasal delivery.

For example, in the production of compositions for oral administration, in the case of oral liquid compositions such as suspensions, syrups, elixirs, emulsions, and solutions, for example, water, glycols, oils, alcohols, etc .; or solids. In the case of compositions, any of the usual pharmaceutical media such as solid carriers such as starch, sugars, kaolin, lubricants, binders, and disintegrants can be used. In parenteral compositions, the carrier will usually contain at least most of the sterile water, to which other components, such as lysis aids, emulsifiers, or other aids, may be added. Injectable solutions may be prepared in which the carrier comprises saline, glucose solution, or a mixture thereof. Injectable suspensions may be prepared, in which case suitable liquid carriers, suspending agents and the like may be used. Also included are solid formulations intended to be liquid formulations immediately prior to use, such as powders that are dissolved / suspended. In compositions suitable for transdermal administration, the carrier optionally comprises a skin penetration enhancer and / or wetting agent in combination with a small amount of a suitable skin-compatible additive. mGluR2 PAM / agonist compounds, in particular compounds of formula (I) / (IA) / (IB), or SV2A ligands, or combinations thereof, are also suitable for this type of administration, eg, by oral inhalation or injection. , Solution, suspension, or dry powder. Suitable pharmaceutical compositions for administration in the form of aerosols or sprays include, for example, mGluR2 PAM / agonist compounds, in particular compounds of formula (I) / (IA) / (IB), or SV2A ligands, or both. A pharmaceutically acceptable liquid carrier, such as ethanol or water, or a suspending agent suspended in a mixture thereof. If desired, the formulation can also further contain other pharmaceutical aids such as surfactants, emulsifiers, and stabilizers as well as propellants. Such formulations typically contain a pharmacologically active compound in a concentration of about 0.1-50% by weight, particularly about 0.3-3% by weight.

The pharmaceutical composition comprises the active ingredient mGluR2 PAM / agonist compound, particularly a compound of formula (I) / (IA) / (IB), or an SV2A ligand, or a combination of both, from about 0.1% to about 50%. Alternatively, it can be contained at a concentration of about 1% to about 30%, or about 3% to about 20%, or about 5% to about 20%, all percentages being weight%, all in the pharmaceutical composition. The total of the ingredients of is not more than 100%. In compositions containing both mGluR2 PAM / agonist compounds, in particular compounds of formula (I) / (IA) / (IB) and two compounds with SV2A ligands, mGluR2 PAM / agonist compounds, in particular formula The compounds of (I) / (IA) / (IB) are about 0.1% to about 50%, or about 1% to about 30%, or about 3% to about 20%, or about 5% to about 20%. Present in concentration; SV2A ligands are about 3% to about 50%, or about 5% to about 50%, or about 10% to about 50%, or about 10% to about 40%, or about 10% to about. It is present at a concentration of 30% and the sum of all the ingredients in the pharmaceutical composition does not exceed 100%.

The pharmaceutical composition can conveniently be provided in unit dosage form so that it is easy to administer and the dose is uniform. Examples include tablets (including scored tablets and coated tablets), capsules, pills, suppositories, powder sachets, cashiers, and injectable solutions or suspensions, and the like, and a plurality of these. There are segregated multiples thereof. Solid dosage forms for oral administration, such as tablets or capsules, are covered.

The solid dosage form can be packaged in any known packaging in the form of unit doses, with blister packaging being preferred for tablets and capsules in particular. When mGluR2 PAM / agonist compounds, especially compounds of formula (I) / (IA) / (IB) and SV2A ligands are formulated separately, they can be packaged in separate blister, one blister It can also include mGluR2 PAM / agonist compounds in the form of unit doses, in particular compounds of formula (I) / (IA) / (IB) in the form of unit doses and SV2A ligands in the form of unit doses, eg , One row has multiple units of mGluR2 PAM / agonist compounds, in particular multiple units of compounds of formula (I) / (IA) / (IB), and another row has SV2A ligands. Other means may be possible.

Can the combinations of the invention be used to treat or prevent epilepsy and related disorders; neuropathic pain; migraine or resistant headaches; and bipolar disorders and related disorders; or they, as neuroprotective agents, Alternatively, it can be used to prevent epileptigenicity.

As used herein, the term "treatment" refers to any process that can slow, prevent, prevent or stop the progression of a disease, or alleviate symptoms, but not necessarily all symptoms. It does not indicate that it will be completely eliminated.

As used herein, unless otherwise stated, the term "epilepsy and related disorders" or "epilepsy or related disorders" refers to one or more convulsions and / or tremors in a subject (preferably a human adult, child or infant). It shall mean any obstacle that causes a war. Suitable examples include, but are not limited to, localized-related epilepsy, generalized epilepsy, and epilepsy with both generalized and localized seizures, with or without generalization. Partial seizures, myochrony seizures, primary general tonic seizures, especially primary general tonic seizures in patients with idiopathic generalized epilepsy, convulsions associated with Rennox-Gasteau syndrome, convulsions as a complication of disease or pathology (eg) , Encephalopathy, phenylketonuria, juvenile Gaucher's disease, Lundvork progressive myocrony epilepsy, stroke, head trauma, stress, hormonal changes, drug use or withdrawal, alcohol use or withdrawal, sleep deprivation, fever, and infections, etc. (Convulsions associated with), epileptic seizures (convulsive or non-convulsive), essential tremor, and limb immobility syndrome, but are not limited to these. Preferably, the disorder is selected from epilepsy (regardless of type, root cause or origin), essential tremor or limb immobility syndrome. More preferably, the disorder is epilepsy (regardless of type, root cause or origin) or essential tremor. Specific examples of epilepsy include refractory epilepsy, also referred to as treatment or refractory epilepsy. The term is often used when a patient is unable to be treated with three or more antiepileptic drugs (AEDs). Refractory epilepsy also includes refractory partial epilepsy and refractory generalized epilepsy (including idiopathic or symptomatic epilepsy).

As used herein, the term "neuropathic pain" includes pain resulting from a chronic or debilitating condition or disorder. Chronic or debilitating pathologies or disorders that can cause neuropathic pain include painful diabetic peripheral neuropathy, post-herpes zoster neuropathy, trigeminal neuropathy, post-stroke pain, pain associated with multiple sclerosis, and neuropathy. Pain associated with, for example, idiopathic or post-traumatic neuropathy and pain in mononeuritis, HIV-related neuropathic pain, cancer-related neurogenic pain, carpal canal-related neuropathic pain, pain associated with spinal cord injury, complex These include local pain syndrome, neuropathic pain associated with fibromyalgia, lower back and cervical pain, reflex sympathetic dystrophy, phantom limb syndrome and pain syndrome associated with other chronic and debilitating conditions. It is not limited to.

As used herein, the term "migraine" refers to the presence of moderate to severe unilateral beating headaches lasting 4 to 72 hours, including migraine without aura and migraine with aura. It shall mean a chronic, episodic and debilitating clinical condition diagnosed by. As used herein, "migraine without aura" is based on the following criteria: (a) Headache attacks lasting 4 to 72 hours, with the following characteristics: unilateral site, pulsatile, Has moderate to severe intensity that has a direct impact on daily activities, and at least two exacerbations due to actions such as climbing stairs: and (b) during headache, next: nausea and / or vomiting, And shall mean at least 5 seizures that satisfy that at least one of photophobia and phonophobia occurs. As used herein, "aura migraine" is as follows: (a) one or more completely reversible aura symptoms: (b) at least one aura symptom that gradually appears over more than 4 minutes, Or two or more consecutive symptoms; (c) no aura lasting more than 60 minutes; (d) headache before, at the same time as, or after the aura, between the aura and the headache It shall mean at least two auras with at least three of the four characteristics of having a time of less than about 60 minutes.

As used herein, the term "bipolar disorder and related disorders" refers to bipolar disorder type I (eg, single-manic episode, most recent episode is mild manic, most recent episode is manic, unless otherwise noted. The most recent episode shall be mixed, the most recent episode may be depressed, and the most recent episode may not be identifiable), bipolar disorder type II, mood circulatory disorder and bipolar disorder (these terms are the Diagnostic and Statistical manual of). Mental Disorders 4th Edition, Text Revision, American Psychiatric Association, 2000 (DSM-IV-TR) or 5th Edition, Text Revision, American Psychiatric Association, 2013 (DSM-5)^TM) Is defined by the diagnostic criteria in. Preferably, bipolar disorder is characterized by a depressive and manic (or hypomanic) cycle. Preferably, the bipolar disorder is bipolar disorder type I or bipolar disorder type II. As used herein, "mania" shall include mania or manic mood phase, regardless of the underlying cause. As used herein, the term "bipolar mania" shall mean mania associated with, characteristic of, or symptomatic of bipolar disorder. Therefore, the method of treating bipolar mania of the present invention relates to a method of treating mania and / or the mania stage of bipolar disorder. As used herein, the term "bipolar depression" shall mean depression associated with, characteristic of, or symptomatic of bipolar disorder. Therefore, the method of treating bipolar depression of the present invention relates to a method of treating depression and / or depressive phase of bipolar disorder. As used herein, unless otherwise stated, "alternate" or "bipolar alternation". The term "cycling)" shall refer to mood swings during the depressive and mania stages that are characteristic of bipolar disorder. Accordingly, the present invention includes, but is limited to, methods of stabilizing said shifts, including reducing the frequency of shifts and / or reducing the size of the manic and / or depressive stages. It's not a thing.

Therefore, in one embodiment, the pharmaceutical composition of the present invention can be used for mood stabilization, especially for manic-depressive mood stabilization.

As used herein, the term "epileptic origin" refers to the gradual process by which epilepsy develops. Can this process occur after a variety of conditions, including brain injury, or neurodegenerative diseases, traumatic brain injury, stroke, brain tumors, central nervous system infections, and status epilepticus; or it is a gene mutation It can happen later.

As used herein, the term "anxiety" specifically refers to generalized anxiety disorder.

As used herein, the term "about" has its usual meaning. In certain embodiments, when it comes to numbers, it can be interpreted to mean numbers ± 10%, or ± 5%, or ± 2%, or ± 1%, or ± 0.5%, or ± 0.1%. .. In other embodiments, the exact value is indicated by removing the term "about".

"And / or" means that each or both of the listed components or features, or all of them, is a possible variant, among other things, an alternative or accumulation of two or more of them.

As used herein, the terms "one (a)", "one (an)", "the" and similar terms used in connection with the present invention (especially in the claims). Should be construed as including both the singular and the plural, unless otherwise noted or explicitly inconsistent with the context.

<p> The following examples are described to aid in the understanding of the present invention, but they should be understood as limiting the present invention and not limiting the invention as described in the claims below. Absent.</p><p>A) Compounds of formula (IB) -Chemical properties and IN VITRO tests Several methods for producing compounds of formula (IB) of the present invention will be described in the following examples. Unless otherwise stated, all starting materials were obtained from the supplier and used without further purification.</p><p> Hereinafter, "aq." Means aqueous; "DCE" means 1,2-dichloroethane, "DCM" means dichloromethane; "DIPE" means diisopropyl ether; "DIPEA" means N, Means N-diisopropylethylamine; "DMF" means N, N-dimethylformamide; "ES" means electrospray; "Et₃"N" means triethylamine; "Et₂"O" means diethyl ether; "EtOAc" means ethyl acetate; "h" means time; "HPLC" means high performance liquid chromatography; "HRMS" means high resolution mass spectrometry / mass "L" or "L" means liter; "LRMS" means low resolution mass spectrometry / mass spectrometry; "MeOH" means methanol; "min" means minutes Means; "mp" means melting point; "Pd (PPh)₃)₄Means tetrakis (triphenylphosphine) palladium (0); "RP" means reverse phase; "rt" means room temperature; "s" means seconds; "sat." Means saturated Means; "SFC" means supercritical fluid chromatography; "sol." Means solution; "THF" means tetrahydrofuran.</p><p> Microwave assisted reaction is a single-mode reactor: Initiator^TMIt was performed in a Sixty EXP microwave reactor (Biotage AB) or in a multimode reactor: MicroSYNTH Labstation (Milestone, Inc.).</p><p> Thin layer chromatography (TLC) was performed on silica gel 60 F254 plate (Merck) with reagent solvent. Open column chromatography was performed on silica gel with a particle size of 60 Å and mesh = 230-400 (Merck) using standard techniques. Automatic flash column chromatography uses Merck's ready-to-connect cartridges, crushed silica gel, particle size 15-40 μm (disposable flash column for normal phase), and Armen Instrument's SPOT. Or it was done with the LAFLASH system.</p><p> The absolute stereochemical configuration of some compounds was determined using vibrational circular dichroism (VCD). They are CDs₂Cl₂Was placed in a KBr liquid cell as a solvent and measured with a Bruker Equinox 55 equipped with PMA 37 (PEM: 1350 cm).^-1, LIA: 1mV, resolution: 4cm^-1). A description of the use of VCDs to determine absolute configuration is given in Dyatkin ABet.al, Chirality, 14: 215-219 (2002).</p><p> Whenever the notation "RS" is used herein, it means that the compound is a racemic mixture, unless otherwise noted. When the mixture is separated, the stereochemical configuration of some compounds is indicated as "R" or "S"; for some compounds, the compounds themselves are isolated as a single stereoisomer and are mirror images. If the isomer is pure, but the absolute stereochemistry is not specified, the stereochemical configuration is "^*R "or"^*S "was shown. The enantiomeric excess of the compounds reported herein was determined by analysis of the racemic mixture by performing SFC comparisons of the separated enantiomers after supercritical fluid chromatography (SFC).</p><p>Intermediate Manufacturing Description 1-Intermediate 1<chemistry num="47"><img file="JP2019123723A_D0048.tif" /></chemistry> CH cyclopropyl acetic acid ([CAS 5239-82-7], 50 g, 500 mmol)₂Cl₂SOCl after dissolving in (300 mL)₂(100 mL) was added. After stirring the reaction mixture at 60 ° C. for 2 hours, the solvent was evaporated to give Intermediate 1 (53 g, 90%), which was used without further purification.</p><p>Description 2-Intermediate 2<chemistry num="48"><img file="JP2019123723A_D0049.tif" /></chemistry> Methyl 2,2-difluoro-2- (fluorosulfonyl) acetate ([CAS 680)) in a solution of 2,4-dichloro-3-iodopyridine ([CAS 343781-36-2], 290 g, 1058 mmol) in DMF (1.7 L). After adding -15-9], 403 g, 2098 mmol) and CuI (403 g, 2.13 mol), the reaction was heated at 100 ° C. for 5 hours. The reaction was cooled and filtered. H₂Dilute with O and Et₂Extract with O, NH₃Washed with solution. Dry the organic layer (Na₂SO₄), Filtered and concentrated under reduced pressure to give Intermediate 2 (160 g), which was used without further purification.</p><p>Description 3-Intermediate 3<chemistry num="49"><img file="JP2019123723A_D0050.tif" /></chemistry> Benzyl alcohol (35 g, 325 mmol) was added to a solution of NaH (60% oil dispersion, 24 g, 600 mmol) in DMF (2 L) (0 ° C), and the reaction was stirred for 2 minutes. Intermediate 2 (160 mg, 741 mmol) was added all at once and stirred at 0 ° C. for 1 hour. Reaction H₂Dilute by adding O, Et₂Extracted with O. Dry the organic layer (Na₂SO₄), Filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / EtOAc = 20/1). The pure fraction was recovered and the solvent was evaporated to give Intermediate 3 (100 g, 38%).</p><p>Description 4-Intermediate 4<chemistry num="50"><img file="JP2019123723A_D0051.tif" /></chemistry> In a solution of Intermediate 3 (100 g, 277 mmol) in 1,4-dioxane (1.5 L), NH₂NH₂After adding hydrate (85% aqueous solution, 300 g, 9.11 mol), the reaction was heated in a sealed tube at 160 ° C. for 2 hours. The mixture is concentrated under reduced pressure, dissolved in DCM and LVDS.₃Washed with. Dry the organic layer (Na₂SO₄), Filtered and concentrated under reduced pressure to give Intermediate 4 (90 g, 90%), which was used without further purification.</p><p>Description 5-Intermediate 5<chemistry num="51"><img file="JP2019123723A_D0052.tif" /></chemistry> CH of Intermediate 4 (90 g, 318 mmol)₂Cl₂After adding triethylamine (64.3 g, 636 mmol) to the (1.5 L) solution and cooling the mixture to 0 ° C, CH of Intermediate 1 (53 g, 449 mmol)₂Cl₂The solution was added. The solution was stirred at room temperature for 1 hour. Saturate the reaction mixture LVDS₃Wash with solution and CH₂Cl₂Extracted with. Dry the organic layer (Na₂SO₄), Filtered and concentrated under reduced pressure to give Intermediate 5 (104.4 g, 90%).</p><p> The following intermediates were synthesized according to a synthesis procedure similar to that reported in Description 5 (D5).</p><p><tables num="2"><img file="JP2019123723A_D0053.tif" /></tables></p><p>Description 6 (a) Intermediate 9<chemistry num="52"><img file="JP2019123723A_D0054.tif" /></chemistry> CH of Intermediate 5 (101 g, 277 mmol)₃Phosphoryl oxychloride (V) (84.7 g, 553 mmol) and N, N-diisopropylethylamine (71.3 g, 553 mmol) were added to the CN (1.2 L) solution. The reaction mixture was stirred at 90 ° C for 38 hours. The reaction is then diluted with DCM and Na₂CO₃Washed with solution. Dry the organic layer (Na₂SO₄), Filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / EtOAc = 4/1). The pure fraction was recovered and the solvent was evaporated to give Intermediate 9 (31.39 g, 41%).</p><p>(b) Intermediate 10<chemistry num="53"><img file="JP2019123723A_D0055.tif" /></chemistry> After the reaction was performed in 4 batches, they were combined for work-up and purification. N, N-diisopropylethylamine (3.96 mL, 22.69 mmol) followed by phosphorus oxychloride (2.12 mL, 22.69 mmol) was added to a solution of intermediate 6 (7 g, 20.6 mmol) in DCE (50 mL) to add 150 reaction mixture. Heated in a ° C microwave heating furnace for 5 minutes. The DCM is then added to saturate the organic layer.₃Wash with solution and dry (Na₂SO₄), Concentrate under reduced pressure to obtain the desired compound, which is column chromatographed (gradient elution: DCM 100% ~ MeOH.NH)₃Purification with 2% / DCM) gave Intermediate 10 (2.5 g, 49%).</p><p> The following intermediates were synthesized according to a synthesis procedure similar to that reported in Explanation 6 (a) or (b).</p><p><tables num="3"><img file="JP2019123723A_D0056.tif" /></tables></p><p>Description 7-Intermediate 13<chemistry num="54"><img file="JP2019123723A_D0057.tif" /></chemistry> (Ph₃P)₄Pd (2.096 g, 1.81 mmol), Intermediate 9 (10 g, 36.28 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxoborolane ([CAS 75927-49-0) ], 7.77 mL, 43.53 mmol) with oxygen scavenger dioxane (30 mL) and oxygen scavenger saturated LVDS₃It was added under nitrogen to a stirred solution dissolved in solution (30 mL). The mixture was stirred at 100 ° C. for 18 hours. The mixture was diluted with EtOAc / water and filtered through a pad of diatomaceous earth. The filtrate was treated with saturated brine and extracted with EtOAc. The organic layer is separated and dried (Na₂SO₄), The solvent was evaporated under reduced pressure. Flash column chromatography (silica; EtOAc / CH) of crude product₂Cl₂, 0/100 ~ 5/95). The desired fraction was collected and concentrated under reduced pressure to give Intermediate 13 (6.08, 63%) as a yellow solid.</p><p> The following intermediates were synthesized according to a synthesis procedure similar to that reported in Description 7.</p><p><tables num="4"><img file="JP2019123723A_D0058.tif" /></tables></p><p>Description 8 (a) Intermediate 17<chemistry num="55"><img file="JP2019123723A_D0059.tif" /></chemistry> A solution of osmium tetroxide (2.5% t-BuOH solution, 10.103 mL, 0.781 mmol) followed by a solution of sodium periodate 12.53 g, 58.58 mmol in water (48.5 mL) with intermediate 13 (6.08 g, 20.02 mmol) dioxane ( 192 mL) Added to suspension. The mixture was stirred at room temperature for 2 hours.</p><p> The mixture was treated with water and EtOAc and it was filtered off with a pad of diatomaceous earth. The filtrate was extracted with EtOAc. The organic layer is separated and dried (Na₂SO₄), The solvent was evaporated under reduced pressure. Crude product Et₂Washed with O, filtered and dried to give Intermediate 17 (4.25 g, 79%) as a brown solid.</p><p>(b) Intermediate 18<chemistry num="56"><img file="JP2019123723A_D0060.tif" /></chemistry> Suspension of distilled water (19 mL) of sodium periodate (5.04 g, 23.54 mmol) with osmium tetroxide (2.5% t-BuOH solution, 4.06 mL, 0.31 mmol) and intermediate 14 (2.08 g, 7.85 mmol) And was added to a stirring solution dissolved in dioxane (75 mL). After stirring the mixture at room temperature for 150 minutes, saturate the mixture.₃And treated with saturated brine and extracted with DCM. The organic layer is separated and dried (Na₂SO₄), Filtered and concentrated under reduced pressure. Et the product₂It was triturated with O, filtered under reduced pressure and finally placed in a desiccator at 50 ° C. for 18 hours to give Intermediate 18 (1.6 g, 80%) as a brown solid.</p><p> The following intermediates were synthesized according to a synthesis procedure similar to that reported in Explanation 8.</p><p><tables num="5"><img file="JP2019123723A_D0061.tif" /></tables></p><p>Description 9 (a) Intermediates 21a, 21b and 21c<chemistry num="57"><img file="JP2019123723A_D0062.tif" /></chemistry> Methylmagnesium bromide (1.4 M THF solution, 12.40 mL, 17.37 mmol) in a stirred suspension of intermediate 17 (4.25 g, 15.79 mmol) in THF (281.07 mL) at -20 ° C under nitrogen. Dropped. The mixture was stirred at -20 ° C for 45 minutes. Saturated crude product NH₄It was treated with Cl solution and extracted with EtOAc. The organic layer is separated and dried (Na₂SO₄), Filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica; MeOH / DCM, 0/100 ~ 4/96). The desired fraction was collected and concentrated under reduced pressure to give Intermediate 21a (racemic mixture) (2.96 g, 66%). Intermediate 21a (1.82g) chiral SFC: [Fixed phase: CHIRALPAK AD-H (5μm 250 × 20mm), Mobile phase: CO₂Purified with 80%, EtOH 20%], 21b (R-enantiomer) (0.453g, 10%) as a light gray solid, and intermediate 21c (S-enantiomer) (0.439g, 10%) Obtained.</p><p>(b) Intermediate 22<chemistry num="58"><img file="JP2019123723A_D0063.tif" /></chemistry> Methylmagnesium bromide (1.4 M THF solution, 3.97 mL, 5.56 mmol) in a stirred suspension of intermediate 18 (1.23 g, 5.06 mmol) in THF (90 mL) at -20 ° C, N.₂Dropped in the atmosphere. The mixture was stirred at -20 ° C for 45 minutes. Saturated crude product NH₄It was treated with Cl solution and extracted with EtOAc. The organic layer is separated and dried (Na₂SO₄), Filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica; MeOH / DCM, 0/100 ~ 4/96). The desired fraction was collected and concentrated under reduced pressure. The residue thus obtained is Et.₂Triturating with O gave Intermediate 22 (620 mg, 35%) as a pale yellow solid.</p><p> The following intermediates were synthesized according to a synthesis procedure similar to that reported in Description 9.</p><p><tables num="6"><img file="JP2019123723A_D0064.tif" /></tables></p><p> Intermediate 24a was further separated into intermediate 24b and intermediate 24c.</p><p><tables num="7"><img file="JP2019123723A_D0065.tif" /></tables></p><p>Production of final compound of formula (IB) Example 1 (a) Synthesis of compounds 4-b, 6-b and 5-b<chemistry num="59"><img file="JP2019123723A_D0066.tif" /></chemistry> DIAD (2.07 mL, 10.52 mmol), intermediate 21a (2 g, 7.01 mmol), 2,4-difluorophenol (1.00 mL, 10.52 mmol), and triphenylphosphine (2.76 g, 10.52 mmol) in THF (. It was added dropwise to a stirring solution dissolved in 74.18 mL) at 0 ° C. in a nitrogen atmosphere. The mixture was stirred at 100 ° C. for 10 minutes under microwave irradiation. The mixture is diluted with EtOAc and saturated with LVDS.₃Washed with solution. The organic layer is separated and dried (Na₂SO₄), Filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica; MeOH / DCM, 0/100 to 97/3). The desired fraction was collected and concentrated under reduced pressure. The residue was triturated with DIPE to give compound 4-b (1.46 g, 52%) as a white solid, which was obtained as a chiral SFC [stationary phase: Chiralpak AD (5 μm 250).^*30mm, mobile phase: CO₂Purification with 85%, iPrOH 15%)] gave compound 6-b (0.659 g, 24%) and compound 5-b (0.693 g, 25%).</p><p>(b) Alternative synthesis of compound 6-b<chemistry num="60"><img file="JP2019123723A_D0067.tif" /></chemistry> DIAD (31.06 μL, 0.16 mmol) with intermediate 21b (30 mg, 0.11 mmol), 2,4-difluorophenol (15.07 μL, 0.16 mmol) and triphenylphosphine (41.38 mg, 0.16 mmol) in THF ( It was added dropwise to a stirring solution dissolved in 1.11 mL) at 0 ° C. in a nitrogen atmosphere. The mixture was stirred at 100 ° C. for 10 minutes under microwave irradiation. The mixture is diluted with EtOAc and saturated with LVDS.₃Washed with solution. The organic layer is separated and dried (Na₂SO₄), Filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica; MeOH / DCM, 0/100 to 97/3). The desired fraction was collected and concentrated under reduced pressure. The residue was triturated with DIPE to give compound 6-b (40 mg, 96%) as a white solid.</p><p>(c) Synthesis of compound 6-b hydrochloride (.HCl) DIAD (207.06 μL, 1.05 mmol) with intermediate 21b (200 mg, 0.70 mmol) and 2,4-difluorophenol (100.45 μL, 1.05 mmol) , Triphenylphosphine (275.84 mg, 1.0516 mmol) was added dropwise to a stirring solution of THF (4 mL) at 0 ° C. under a nitrogen atmosphere. The mixture was stirred at 100 ° C. for 15 minutes under microwave irradiation. The mixture is diluted with EtOAc and saturated with LVDS.₃Washed with solution. The organic layer is separated and dried (Na₂SO₄), Filtered and concentrated under reduced pressure. RP HPLC the residue (stationary phase: C18 XBridge 30 × 100 mm 5 μm, mobile phase: 0.1% NH₄CO₃H / NH₄OH aqueous solution (pH 9) 60%, CH₃CN 40% to 0.1% NH₄CO₃H / NH₄OH aqueous solution (pH 9) 43%, CH₃Purification with (gradient to CN57%) to obtain a white solid residue, which is Et₂It was dissolved in O (8 mL) and 1,4-dioxane (0.5 mL). HCl (4M dioxane solution, 200 μL) was added dropwise to the solution thus obtained. Filter the white solid precipitate and Et₂Wash with O and dry (Na₂SO₄), Evaporated under reduced pressure. The white residue thus obtained is Et.₂Triturating with O gave compound 6-b.HCl (110 mg, 36%) as a white solid.</p><p> The following compounds were synthesized starting from Intermediate 21b and following a synthetic procedure similar to that reported in Example 1 (b).<chemistry num="61"><img file="JP2019123723A_D0068.tif" /></chemistry></p><p>Example 2 Synthesis of Compound 7-b<chemistry num="62"><img file="JP2019123723A_D0069.tif" /></chemistry> Procedure (a): DIAD (31.06 μL, 0.158 mmol) with intermediate 21b (30 mg, 0.105 mmol), 3,5-difluorophenol (20.52 mg, 0.158 mmol) and triphenylphosphine (41.38 mg, 0.158 mmol). ) And Was dissolved in THF (1.113 mL) and added dropwise to a stirring solution at 0 ° C. under a nitrogen atmosphere. The mixture was stirred at 100 ° C. for 10 minutes under microwave irradiation. The mixture is diluted with EtOAc and saturated with LVDS.₃Washed with solution. The organic layer is separated and dried (Na₂SO₄), Filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica; MeOH / DCM, 0/100 to 96/4). The desired fraction was collected and concentrated under reduced pressure. The residue was triturated with DIPE to give compound 7-b (21 mg, 50%) as a white solid.</p><p> Procedure (b): Alternatively, Compound 7 also started from Intermediate 21b and was synthesized according to a synthetic procedure similar to that reported in Example 1 (b).</p><p>Example 3 Synthesis of Compound 8-b<chemistry num="63"><img file="JP2019123723A_D0070.tif" /></chemistry> Procedure (a): DIAD (31.06 μL, 0.158 mmol) with intermediate 21b (30 mg, 0.105 mmol), 3,4-difluorophenol (20.52 mg, 0.158 mmol) and triphenylphosphine (41.38 mg, 0.158 mmol). ) And Was dissolved in THF (1.11 mL) and added dropwise to a stirring solution at 0 ° C. under a nitrogen atmosphere. The mixture was stirred at 100 ° C. for 10 minutes under microwave irradiation. The mixture is diluted with EtOAc and saturated with LVDS.₃Washed with solution. The organic layer is separated and dried (Na₂SO₄), Filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica; MeOH / DCM, 0/100 to 96/4). The desired fraction was collected and concentrated under reduced pressure. The residue was triturated with DIPE to give compound 8-b (10.6 mg, 25%) as a white solid.</p><p> Procedure (b): Alternatively, Compound 8-b also started from Intermediate 21b and was synthesized according to a synthetic procedure similar to that reported in Example 1 (b).</p><p>Example 4 Synthesis of Compound 15-b<chemistry num="64"><img file="JP2019123723A_D0071.tif" /></chemistry> Procedure (a): DIAD (155.3 μL, 0.789 mmol) with intermediate 21b (150 mg, 0.526 mmol), 2,4,6-trifluorophenol (116.8 mg, 0.789 mol) and triphenylphosphine (206.88 mg). , 0.789 mmol) was added dropwise to a stirring solution of THF (5.56 mL) at 0 ° C. under a nitrogen atmosphere. The mixture was stirred at 100 ° C. for 10 minutes under microwave irradiation. Dilute the mixture with DCM and saturate LVDS₃Washed with solution. The organic layer is separated and dried (Na₂SO₄), Filter, concentrate under reduced pressure, then flash column chromatography (silica; MeOH / NH₃Purified with 7N DCM solution 0/100 ~ 90/10). The desired fraction was collected and concentrated under reduced pressure. RP HPLC (stationary phase: C18 XBridge 30 × 100 mm 5 μm, mobile phase: 0.1% NH₄CO₃H / NH₄OH aqueous solution (pH 9) 54%, CH₃CN46% to 0.1% NH₄CO₃H / NH₄OH aqueous solution (pH 9) 64%, CH₃Purification with a gradient to 36% CN) gave a colorless oil, which crystallized on standing (2 days). The solid was triturated with heptane to give compound 15-b (129.8 mg, 59%) as a white solid.</p><p> Procedure (b): Alternatively, compound 15-b was also synthesized starting from intermediate 21b and following a synthetic procedure similar to that reported in Example 1 (b).</p><p>Example 5 Synthesis of Compounds 1-b, 2-b and 3-b<chemistry num="65"><img file="JP2019123723A_D0072.tif" /></chemistry> Compounds 1-b, 2-b and 3-b were synthesized according to the procedure described in Example 1 (a). Therefore, DIAD (500.05 μL, 2.54 mmol), intermediate 21a (483 mg, 1.69 mmol), 4-fluorophenol (227.77 mg, 2.03 mmol) and triphenylphosphine (666.14 mg, 2.54 mmol) in THF ( The residue was obtained by reacting in 17.91 mL) as described in Example 1 (a) and purified by flash column chromatography (silica; EtOAc / DCM 0/100 to 90/10). The desired fraction was collected and concentrated under reduced pressure. The resulting residue was triturated with DIPE to give compound 1-b (320 mg, 50%) as a white solid, which was obtained as a chiral SFC [stationary phase: Chiralpak AD (5 μm 250).^*30mm, mobile phase: CO₂Purification with 77%, MeOH 23%)] gave compound 2-b (131 mg, 20%) and compound 3-b (129 mg, 20%) as white solids.</p><p>Example 6 Synthesis of Compounds 24-b, 26-b, and 27-b<chemistry num="66"><img file="JP2019123723A_D0073.tif" /></chemistry> Compounds 24-b, 26-b, and 27-b were synthesized according to the procedure described in Example 1 (a). Therefore, DIAD (364.57 μL, 1.85 mmol), intermediate 22 (320 mg, 1.23 mmol), 2,4-difluorophenol (176.86 μL, 1.85 mmol), and triphenylphosphine (485.67 mg, 1.85 mmol) The residue was obtained by reacting in THF (13.06 mL) as described in Example 1 (a) and purified by flash column chromatography (silica; MeOH / DCM 0/100 ~ 96/4). The desired fraction was recovered and concentrated under reduced pressure to give a colorless oil, which was crystallized with DIPE to give compound 24 as a white solid, which was obtained by RP HPLC (stationary phase: C18 XBridge 30 × 100 mm 5 μm; Mobile phase: 0.1% NH₄CO₃H / NH₄OH aqueous solution (pH 9) 54%, CH₃CN46% to 0.1% NH₄CO₃H / NH₄OH aqueous solution (pH 9) 64%, CH₃Purification with (gradient to 36% CN) to give a colorless oil, which is triturated with heptane to crystallize to give compound 24-b, 240 mg (52%) as a white solid, which is then obtained as a chiral SFC (stationary phase:: CHIRALPAK AD-H 5 μm 250 × 20 mm; Mobile phase: CO₂85%, iPOH (0.3% iPrNH)₂) 15%) to give compound 26-b (103 mg, 22%) and compound 27-b (107 mg, 23%).</p><p> The following compounds were obtained according to a synthetic procedure similar to that reported in Example 1 (a).<chemistry num="67"><img file="JP2019123723A_D0074.tif" /></chemistry></p><p> The following compounds were synthesized starting from the intermediates shown and according to the synthetic procedure reported in Example 1 (b).<chemistry num="68"><img file="JP2019123723A_D0075.tif" /></chemistry></p><p> Table A below lists other compounds of formula (IB) produced in a manner similar to the above Example (Exp. No.).</p><p><tables num="8"><img file="JP2019123723A_D0076.tif" /></tables></p><p><tables num="9"><img file="JP2019123723A_D0077.tif" /></tables></p><p><tables num="10"><img file="JP2019123723A_D0078.tif" /></tables></p><p><tables num="11"><img file="JP2019123723A_D0079.tif" /></tables></p><p>Analytical partial optical rotation The optical rotation was measured with a Perkin-Elmer 341 optical meter equipped with a sodium lamp and reported as follows: [α] o (λ, cg / 100 ml, solvent, T ° C).</p><p>[α]_λ^T= (100α) / (l × c): In the equation, l is the path length (unit: dm), and c is the concentration of the sample at temperature T (° C) and wavelength λ (unit: nm) (unit: g). / 100 ml). If the wavelength of light used is 589 nm (sodium D line), the symbol D may be used instead. The sign of rotation (+ or-) shall always be stated. When using this formula, always state the concentration and solvent in parentheses after the rotation. Rotations are reported in degrees and the unit of concentration is not stated (it is assumed to be g / 100 ml).</p><p>LCMS The following method was used to assess the (LC) MS properties of the compounds of the invention.</p><p>General Procedures High Performance Liquid Chromatography (HPLC) measurements were performed using the LC pumps, diode array (DAD) detectors or UV detectors, and columns described for each method. Other detectors were also included as needed (see method table below).</p><p> The flow from the column was introduced into a mass spectrometer (MS) configured to include an atmospheric pressure ion source. It is within the knowledge of one of ordinary skill in the art to set adjustment parameters (eg, scan range, data acquisition time (dwell time), etc.) to obtain ions that allow the identification of the nominal monoisotopic molecular weight (MW) of the compound. Inside. Data was acquired using appropriate software. Compounds have their measured retention time (R)_t) And ions. Unless otherwise stated in the table of data, the reported molecular ions are [M + H].⁺(Protonated molecule) and / or [MH]^-Corresponds to (deprotonated molecule). If the compound was not directly ionizable, describe the type of adduct (ie, [M + NH].₄]⁺, [M + HCOO]^-etc). For molecules with multiple isotope patterns (Br, Cl ..), the reported values are those obtained for the lowest isotope mass. All of the results obtained were accompanied by experimental uncertainties usually associated with the method used. Hereinafter, "SQD" means a single quadrupole detector, "RT" means room temperature, "BEH" means a crosslinked ethylsiloxane / silica hybrid, and "HSS" means high-strength silica. , "DAD" means diode array detector.</p><p><tables num="12"><img file="JP2019123723A_D0080.tif" /></tables></p><p>The melting point value is the peak value, and the value obtained is accompanied by the experimental uncertainty usually associated with this method of analysis.</p><p>Mettler FP 81HT / FP90 Equipment For some compounds, the melting point was determined by the FP 81HT / FP90 equipment (Mettler-Toledo) in open capillaries. Melting points were measured with a temperature gradient of 1, 3, 5 or 10 ° C / min. The maximum temperature was 300 ° C. The melting point was read from a digital display.</p><p><tables num="13"><img file="JP2019123723A_D0081.tif" /></tables></p><p><tables num="14"><img file="JP2019123723A_D0082.tif" /></tables></p><p>SFC-MS General Procedures SFC measurements include FCM-1200 dual pump fluid control module for supplying carbon dioxide (CO2) and regulator, CTC Analytics automatic liquid sampler, TCM for columns heating from room temperature to 80 ° C- 20000 Performed using a Berger instrument analyzer with a thermal control module. An Agilent 1100 UV photodiode array detector with a high pressure flow cell that can withstand up to 400 bar was used. The flow from the column was split injected into the MS spectrometer. The MS detector was configured to include an atmospheric pressure ion source. The following ionization parameters for the Waters ZQ Mass Spectrophotometer are: Corona: 9 μa, Ion Source Temperature: 140 ° C, Cone: 30 V, Probe Temperature 450 ° C, Extractor 3 V, Desolvent Gas 400 L / H, Cone Gas 70 L / H. Is. Nitrogen was used as the nebulizer gas. Data were collected using the Waters-Micromass MassLynx-Openlynx data system.</p><p> Method 1: In addition to the general procedure: Analytical chiral separation by SFC-MS was performed on a CHIRALPAK AD DAICEL column (10 μm, 4.6 × 250 mm) at 35 ° C. and a flow rate of 3.0 ml / min. Mobile phase is CO₂85%, iPrOH (+ 0.3% iPrNH)₂) 15% and held in constant composition mode for 7 minutes.</p><p> Method 2: In addition to the general procedure: Analytical chiral separation by SFC-MS was performed on a CHIRALPAK AD DAICEL column (10 μm, 4.6 × 250 mm) at 35 ° C. and a flow rate of 3.0 ml / min. Mobile phase is CO2, 75%, iPrOH (+ 0.3% iPrNH)₂) 15% and held in constant composition mode for 7 minutes.</p><p> Method 3: In addition to the general procedure: Analytical chiral separation by SFC-MS was performed on a CHIRALPAK AD DAICEL column (10 μm, 4.6 × 250 mm) at 35 ° C. and a flow rate of 3.0 ml / min. Mobile phase is CO2, 80%, methanol 10% + iPrOH (+ 0.3% iPrNH)₂) 10% and held in constant composition mode for 7 minutes.</p><p><tables num="15"><img file="JP2019123723A_D0083.tif" /></tables></p><p>Nuclear Magnetic Resonance (NMR) For some compounds, using a standard pulse sequence on either the Bruker DPX-400 or Bruker AV-500 spectrometer operating at 400 MHz and 500 MHz, respectively,¹The 1 H NMR spectrum was recorded. Chemical shift (δ) reports the shift from tetramethylsilane (TMS) used as an internal standard to the low magnetic field side in parts per million (ppm). Co.No.6-b:¹1 H NMR (400MHz, CDCl₃) δ ppm 0.30-0.38 (m, 2H), 0.59-0.68 (m, 2H), 1.14-1.22 (m, 1H), 1.72 (d, J = 6.5Hz, 3H), 3.02-3.14 (m, 2H) , 5.84 (q, J = 6.3Hz, 1H), 6.67-6.73 (m, 1H), 6.80-6.89 (m, 2H), 7.30 (d, J = 7.4Hz, 1H), 8.11 (d, J = 7.4) Hz, 1H) Co.No.7-b:¹1 H NMR (400MHz, CDCl₃) δ ppm 0.30-0.39 (m, 2H), 0.59-0.68 (m, 2H), 1.11-1.23 (m, 1H), 1.70 (d, J = 6.5Hz, 3H), 3.01-3.14 (m, 2H) , 5.83 (q, J = 6.2Hz, 1H), 6.35-6.45 (m, 3H), 7.13 (d, J = 7.2Hz, 1H), 8.08 (d, J = 7.4Hz, 1H) Co.No.8 -b:¹1 H NMR (400MHz, CDCl₃) δ ppm 0.30-0.38 (m, 2H), 0.58-0.68 (m, 2H), 1.11-1.22 (m, 1H), 1.69 (d, J = 6.2Hz, 3H), 3.01-3.13 (m, 2H) , 5.79 (q, J = 6.2Hz, 1H), 6.53 (dtd, J = 9.2,3.1,3.1,1.7Hz, 1H), 6.72 (ddd, J = 11.6,6.5,3.1Hz, 1H), 6.95-7.04 (m, 1H), 7.15 (d, J = 7.4Hz, 1H), 8.07 (d, J = 7.4Hz, 1H) Co.No.15-b:¹1 H NMR (500MHz, CDCl₃) δ ppm 0.30-0.41 (m, 2H), 0.59-0.71 (m, 2H), 1.16-1.25 (m, 1H), 1.70 (d, J = 6.4Hz, 3H), 3.05-3.16 (m, 2H) , 5.80 (q, J = 6.4Hz, 1H), 6.62-6.70 (m, 2H), 7.45 (d, J = 7.5Hz, 1H), 8.16 (d, J = 7.2Hz, 1H) Co.No.13 -b:¹1 H NMR (500MHz, CDCl₃) δ ppm 0.27-0.39 (m, 2H), 0.58-0.67 (m, 2H), 1.12-1.21 (m, 1H), 1.73 (d, J = 6.4Hz, 3H), 2.22 (s, 3H), 3.06 (qd, J = 15.4,6.6Hz, 2H), 5.92 (q, J = 6.4Hz, 1H), 6.71 (d, J = 8.4Hz, 1H), 6.89 (dd, J = 8.4,1.4Hz, 1H) , 7.18 (d, J = 1.7Hz, 1H), 7.32 (d, J = 7.2Hz, 1H), 8.07 (d, J = 7.2Hz, 1H) Co.No.14-b:¹1 H NMR (500MHz, CDCl₃) δ ppm 0.28-0.39 (m, 2H), 0.57-0.69 (m, 2H), 1.12-1.21 (m, 1H), 1.70 (d, J = 6.6Hz, 3H), 2.31 (s, 3H), 3.01 -3.12 (m, 2H), 5.79 (q, J = 6.6Hz, 1H), 6.55 (dd, J = 9.0, 4.3Hz, 1H), 6.69 (td, J = 8.5, 3.0Hz, 1H), 6.87 ( dd, J = 9.0,2.9Hz, 1H), 7.17 (d, J = 7.5Hz, 1H), 8.06 (d, J = 7.2Hz, 1H) Co.No.20-b:¹1 H NMR (500MHz, CDCl₃) δ ppm 1.22 (t, J = 7.1Hz, 3H), 1.72 (d, J = 6.4Hz, 3H), 3.58 (q, J = 7.1Hz, 2H), 5.03-5.10 (m, 2H), 5.84 ( q, J = 6.5Hz, 1H), 6.67-6.74 (m, 1H), 6.81-6.88 (m, 2H), 7.34 (d, J = 7.2Hz, 1H), 8.40 (d, J = 7.5Hz, 1H) ) Co.No.22-b:¹1 H NMR (500MHz, CDCl₃) δ ppm 1.23 (t, J = 6.9Hz, 3H), 1.70 (d, J = 6.4Hz, 3H), 3.58 (q, J = 7.0Hz, 2H), 5.05-5.12 (m, 2H), 5.81 ( q, J = 6.6Hz, 1H), 6.62-6.70 (m, 2H), 7.48 (d, J = 7.5Hz, 1H), 8.45 (d, J = 7.2Hz, 1H) Co.No.31-b:¹1 H NMR (400MHz, CDCl₃) δ ppm 1.07 (t, J = 7.40Hz, 3H) 1.72 (d, J = 6.24Hz, 3H) 1.92 (sxt, J = 7.63Hz, 2H) 2.98-3.14 (m, 2H) 5.84 (q, J = 6.47Hz, 1H) 6.65-6.74 (m, 1H) 6.78-6.89 (m, 2H) 7.29 (d, J = 7.40Hz, 1H) 8.02 (d, J = 7.40Hz, 1H).</p><p>In vitro Testing of Compounds of Formula (IB) The compounds of formula (IB) provided in the present invention are positive allosteric modulators of mGluR2. These compounds appear to enhance the glutamate response by binding to allosteric sites other than the glutamate binding site. In the presence of the compound of formula (IB), the response of mGluR2 to the concentration of glutamate is increased. Since the compound of formula (I) can enhance the function of the receptor, it is expected that it exerts their action substantially at mGluR2. Suitable for identifying such compounds, more specifically compounds of formula (IB), described below [³⁵Table E shows the effects of the positive allosteric modulators tested on mGluR2 using the S] GTPγS binding assay.</p><p> [³⁵S] GTPγS binding measurement [³⁵S] GTPγS binding measurement is a non-hydrolyzed GTP, [³⁵S] GTPγS (γ release³⁵An assay with a functional membrane used to examine G protein-coupled receptor (GPCR) function, which measures the integration of S-labeled guanosine 5'triphosphate. The G protein subunit catalyzes and is an agonist of the exchange of guanosine 5'diphosphate (GDP) by guanosine triphosphate (GTP) [³⁵When GPCRs are activated by S] GTPγS, they are cleaved and unable to continue the exchange cycle due to incorporation (Harper (1998) Current Protocols in Pharmacology 2.6.1-10, John Wiley &amp; Sons, Inc.). Radioactive [³⁵The amount of S] GTPγS incorporated is a direct measure of G protein activity and therefore agonist activity can be determined. The mGlu2 receptor has been shown to preferentially bind to the Gαi protein, which is the preferred binding of this method, and thus it is the receptor activation of the mGlu2 receptor in both recombinant cell lines and tissues. Widely used to find out. Here, the human mGlu2 receptor has been transferred and adapted from Schaffhauser et al. (Molecular Pharmacology, 2003, 4: 798-810) for the detection of positive allosteric regulatory (PAM) properties of the compounds of the invention, derived from cells. Use the membrane of [³⁵S] Describes the use of GTPγS binding measurements.</p><p>Membrane Production CHO cells were cultured to preconfluent and stimulated with 5 mM butyrate for 24 hours. The cells were then harvested by scraping in PBS and the cell suspension was centrifuged (Benchip centrifuge at 4000 RPM for 10 minutes). The supernatant was discarded and the pellet was gently resuspended in 50 mM Tris-HCl, pH 7.4 by mixing using vortex and pipette operation. The suspension was centrifuged at 16,000 RPM (Sorvall RC-5C + Rotor SS-34) for 10 minutes and the supernatant was discarded. Again, the pellet was homogenized in 5 mM Tris-HCl, pH 7.4 using an ultra turrax homogenizer and centrifuged (18,000 RPM, 20 minutes, 4 ° C). The final pellet was resuspended in 50 mM Tris-HCl, pH 7.4 and stored in appropriate doses at -80 ° C before use. The protein concentration was measured by the Bradford method (Bio-Rad, USA) using bovine serum albumin as a standard substance.</p><p> [³⁵S] GTPγS binding measurement The positive allosteric regulatory activity of mGluR2, a test compound, was measured as follows. 10mM HEPES acid, 10mM HEPES salt, pH7.4, 100mM NaCl, 3mM MgCl₂And the test compound and glutamic acid were diluted in assay buffer containing 10 μM GDP. Human mGlu2 receptor-containing membranes were thawed on ice and diluted in assay buffer supplemented with 14 μg / ml saponin. Membrane with compound only or with compound (approx. EC)₂₀) Concentrations of glutamic acid (PAM assay) were pre-incubated at 30 ° C for 30 minutes. [³⁵After the addition of S] GTPγS (fc0.1nM), the assay mixture is shaken briefly, further incubated and activated.³⁵S] GTPγS was taken in (30 minutes, 30 ° C). The final assay mixture is 10 mM HEPES acid, 10 mM HEPES salt, pH 7.4, 100 mM NaCl, 3 mM MgCl.₂, 10 μM GDP and 2 μg / ml saponin contained 7 μg of membrane protein. The total reaction volume was 200 μl. The reaction was terminated by rapid filtration through a Unifilter-96 GF / B plate (Perkin Elmer, Massachusetts, USA) using a 96-well filtermate universal harvester. Filter with ice-cooled 10 mM NaH₂PO₄/ 10 mM Na₂HPO₄, Washed 6 times at pH 7.4. The filter was then air dried and 40 μl of liquid scintillation cocktail (Microscint-O) was added to each well. Membrane-bound radioactivity was counted with a Perkin Elmer Microplate Scintillation and Luminescence Counter.</p><p>Data analysis EC for investigating positive allosteric regulation (PAM)₂₀The concentration-response curve of the representative compound of the present invention obtained in the presence of the mGluR2 agonist glutamate was prepared using the Lexis software interface (developed by J &amp; J). The data were calculated as% of the control glutamate reaction, which is defined as the maximum reaction obtained when glutamate alone was added. Nonlinear regression analysis was used to analyze the sigmoid concentration response curve, which plots the logarithmic concentrations of these percentages versus the test compounds. Next, EC the concentration that shows half the effect of the maximum reaction.₅₀Calculate as. The following pEC₅₀The value is -logEC₅₀However, at this time, EC₅₀Is represented by M. E_maxIs defined as the relative maximum effect (ie, the maximum effect% on the control glutamate reaction).</p><p> Table E below shows the pharmacological data obtained for the compounds of formula (IB) and the current pharmacological data obtained for the compounds of formulas (I) and (IA).</p><p><tables num="16"><img file="JP2019123723A_D0084.tif" /></tables></p><p><tables num="17"><img file="JP2019123723A_D0085.tif" /></tables></p><p><tables num="18"><img file="JP2019123723A_D0086.tif" /></tables></p><p> If the concentration response curve does not reach the plateau level, pEC₅₀No value was calculated.</p><p> Prescribed EC to investigate positive allosteric regulation₂₀All compounds were tested in the presence of concentrations of the mGluR2 agonist glutamate. pEC₅₀Values were calculated from concentration reaction experiments at at least 8 concentrations.</p><p>B) Anticonvulsant test using mGluR2 compound (orthosteric agonist and compound of formula (I) / (IA) / (IB) General test Compound and solution preparation The test compound uses the optimum fluid volume to body fluid ratio. The test compound was administered to mice at a volume of 0.01 mL / g body weight (White HS, et al., General Principles: Experimental selection, quantification, and evaluation of antiepileptic drugs, in Antiepileptic Drugs, Fourth Edition, RH Levy). , RH Mattson, and BSMeldrum, Editors.1995, Raven Press, Ltd .: New York, pp.99-110). For subcutaneous (sc) administration, the test compound was administered into the sagging skin along the animal's back, except that compound 6-b was administered orally (po). In each test conducted on the test compound (excluding the test conducted on compound 6-b), the final compound concentration was administered as an aqueous solution dissolved in 20% Hp-β-CD. For compound 6-b, a 40% Hp-β-CD storage solution was first prepared and used to formulate compound 6-b at the desired concentration for testing by the oral route; the final compound concentration was 20% Hp. -It was administered as a suspension suspended in β-CD. A 20% Hp-β-CD solution was used as the solvent group.</p><p> In LY-404039, the final compound concentration was sc-administered as an aqueous physiological saline solution.</p><p> For compound CAS 1092453-15-0, the final compound concentration was administered after dissolving in a 10% Hp-β-CD (+ NaCl) solvent.</p><p> The final levetiracetam concentration was administered by dissolving in a 0.5% aqueous solution of methylcellulose (MC) administered by intraperitoneal (ip) injection.</p><p>Important Reagents a) Solvent Solution 0.5% Methyl Cellulose (MC) 40% Hydroxypropyl-β-Cyclodextrin (Hp-β-CD) Preservation Solution b) Other Solutions Tetrakine (0.5% Solution w / v) is instilled in plastic. After dropping from the container into the eyes of all animals, electrical stimulation was performed with a corneal electrode.</p><p>Animals and Animal Breeding Adult male CF No1 albino mice (26-35 g) were obtained from Charles River, Portage, Michigan. Animals were fed a sufficient diet (Prolab RMH 3000) and were given free food and water except for a short period of time when they were removed from their cages for testing. Newly received animals in the laboratory were given sufficient time to correct for food and water restrictions that may occur during migration prior to use in the test. All mice were housed in plastic cages in a specially constructed room with controlled humidity, ventilation, and controlled lighting (12 hours on -12 hours off). Animals were housed, fed, and handled in accordance with the recommendations of the National Council Publication, "Guide for the Care and Use of Laboratory animals".</p><p>Minimal Movement Disorder (MMI) Acute MMI was assessed by a combination of direct animal observations of the overt symptoms of neural or muscular function in the animal. In mice, the rotarod procedure was used to reveal minimal muscle or neuropathy. The animal can maintain its equilibrium for extended periods of time when the mouse is placed on a rod that rotates at a speed of 6 rpm. If an animal fell off this rotating rod three times a minute, it was considered addicted.</p><p>Average effective dose and addiction dose (ED₅₀And TD₅₀) Measurement ED of each test compound₅₀Or TD₅₀In the measurement of, the first dose administered is usually the same dose as the successful case used for TPE measurement. If the initial dose used was effective or toxic in more than 50% of the animals, the next dose should be half of the initial dose; the initial dose was effective or toxic in less than 50% of the animals. If so, the next dose should be twice the initial dose. The third and fourth doses were chosen to create evenly spaced dose-response lines. There must be at least 4 points that are included or are between 0 and 100%.</p><p>TPE measurement Generally, the test compound was administered to each group of 4 animals, and 5 time points: 1 test in each group at 0.25 hours, 0.5 hours, 1 hour, 2 hours, or 4 hours after treatment. (White et al. 1995). TPE was measured using a 6Hz (32mA) assay. The time at which maximum prevention was observed (0.25 hours, 0.5 hours, 1 hour, 2 hours, or 4 hours after treatment) was considered the maximum duration of effect (TPE).</p><p> With the TPE measured or pre-measured in this test, the compounds were tested in a 6 Hz assay (32 mA and / or 44 mA) at several doses, including doses that prevented little or no prevention.</p><p> ED₅₀And the 95% confidence interval (CI) was calculated using a computer program provided in the laboratory using Probit analysis (Finney "Probit Analysis" 34d Ed 1971, London: Cambridge University Press).</p><p>Serum collection for pK / pD analysis In various tests, animals were sacrificed after the test and trunk blood and / or brain tissue (whole brain) was collected to quantify drug levels. Immediately after the test, the animals were decapitated and trunk blood was collected in BD Vacutainer® tubes containing K2EDTA and cooled with ice until centrifugation. After centrifugation (13000 to 18000 rpm, 5 to 7 minutes), plasma was removed, transferred to a labeled microcentrifuge tube and stored at -80 ° C. Immediately after decapitation, the brain was removed and instantly frozen to collect brain tissue. Frozen samples were placed in labeled centrifuge tubes and stored at -80 ° C.</p><p>6Hz Psychomotor Seizures in Mice The 6Hz seizure test is used as a model for drug-resistant limbic attacks. 6Hz seizures show resistance to phenytoin, carbamazepine, lamotrigine, and topiramate (Barton et al. "Pharmacological characterization of the 6Hz psychomotor seizure model of partial epilepsy" Epilepsy Research 2001, Vol.47, pp.217-222).</p><p>6 Hz Psychomotor Attack Test Method Corneal stimulation (6 Hz, 0.2 ms square pulse, duration 3 seconds; Barton et al. 2001) induced focal epilepsy in mice. Mouse tests were performed at 32 mA or 44 mA. Prior to irritation, 0.5% tetracaine droplets were instilled in each eye. Seizures caused by corneal irritation in this assay include stereotyped automatistic behaviors, including fainting, forefoot clonus, whiskers monocontraction, and traub-tail, after minimal clonus. ) Occurs. Animals that did not exhibit these behaviors were considered prevented.</p><p>Example 1-Tests with Compounds 1 and 2 1.1. Combination test with Co.No.1, Co.No.2 and levetiracetam First, at the dose that showed the lowest TPE activity of each compound in the 6Hz 44mA test. Each compound was tested individually. When the mGluR2 PAM compound was used in combination with levetiracetam (at the same dose and time point as in the individual studies), almost complete prevention was observed in the 6Hz 44mA study (Table 2). In addition to recording efficacy and toxicity data for these compounds, either alone or in combination, both plasma and brain samples were taken from each group for pharmacokinetic / pharmacokinetic analysis. No pharmacokinetic interactions were observed based on compound concentrations in plasma and brain samples (data not shown). In summary, compounds 1 and 2 show a positive pharmacodynamic interaction with levetiracetam in the 6 Hz model, which does not appear to be due to pharmacokinetic interactions and there is no increase in movement disorders (Table 2, Table 2,). 2a, 2b). The effect of one dose of Compound 2 on the dose response of LEV was also tested. As shown in Table 3, the ED of LEV compared to the case where LEV was tested alone.₅₀Shifted about 200 times. LEV appeared to slightly improve the potency of Co No. 2 (Table 3).</p><p>Isobologram analysis of the interaction between Co. No. 1 and levetiracetam in the 1.2.6 Hz seizure model An isobologram study was performed on the combined administration of Co. No. 1 and LEV in the 6 Hz (44 mA) assay. The study was performed according to the method previously described (Madsen et al. 2011). Initial ED for both Co.No.1 and LEV₅₀Obtain a value and use it to theoretically ED for a combination of three fixed dose ratios (LEV: Co.No.1): 1: 3, 1: 1, and 3: 1.₅₀The (mean ± standard error, SEM) value was calculated. The dose used was ED₅₀It was proportional to the calculated value. For example, the dose ratio used for the 1: 1 paradigm is 0.5 x LEV ED₅₀And 0.5 × Co.No.1 ED₅₀Based on. Similarly, the 1: 3 paradigm is 0.25 x LEV ED₅₀And 0.75 × Co.No.1 ED₅₀It was used. 3: 1 dose ratio is 0.75 x ED₅₀LEV and 0.25 × Co.No.1 ED₅₀It was used. The experimental therapeutic dose (see Table 4) was based on theoretical values and adjusted according to the observed effects. Experimentally determined ED for each fixed dose ratio combination₅₀The (+ SEM) value was compared to the theoretical value (t-test) for statistical purposes. Experimentally determined ED₅₀Value is theoretical ED₅₀If it was significantly lower, the dose ratio was determined to outweigh the additive (synergistic). After that, the experimental combination dose was determined for the same paradigm in a 6 Hz seizure test (Table 4 below). Isobologram studies of Compound 1 and levetiracetam in the 6 Hz model show significant synergistic pharmacodynamic interactions at all dose ratios evaluated and closely correlate with plasma concentrations of Compound 1. Furthermore, no movement disorders were observed at any of the evaluated dose ratios, suggesting that synergistic pharmacodynamic interactions do not result in increased exercise toxicity.</p><p>1.3. Mouse corneal kindling model and test with compound 1 5 consecutive times as defined by Racine (Racine "Modification of seizure activity by electrical stimulation" II.motor seizure "Electroenceph Clin Neurophysiol 1972,32, pp.281-294) The mice were subjected to electrical stimulation kindling twice daily with 3 mA, 60 Hz stimulation for 3 seconds using corneal electrodes up to the criteria for stage 5 seizures. After the mice reached a stable kindling state, the test compound or solvent Was administered and each animal was given the aforementioned electrical stimulation with a pre-determined TPE. After stimulation, the animals were observed for the presence or absence of seizure activity scoring on a Racine scale (0-5), where 5 was rising and The highest stage of fall. For corneal kindling attacks, 1 dose of LEV and 2 doses of Co. No. 1 were tested individually and in combination. The combination of Compound 1 and levetyracetam in this model is positive. (Table 5 below) is suggested.</p><p> A summary of the data for the compounds tested alone is shown in Table 1, and the other results of the tests performed according to Example 1 are listed in Tables 2-5 below.</p><p><tables num="19"><img file="JP2019123723A_D0087.tif" /></tables></p><p><tables num="20"><img file="JP2019123723A_D0088.tif" /></tables></p><p><tables num="21"><img file="JP2019123723A_D0089.tif" /></tables></p><p><tables num="22"><img file="JP2019123723A_D0090.tif" /></tables></p><p><tables num="23"><img file="JP2019123723A_D0091.tif" /></tables></p><p><tables num="24"><img file="JP2019123723A_D0092.tif" /></tables></p><p><tables num="25"><img file="JP2019123723A_D0093.tif" /></tables></p><p><tables num="26"><img file="JP2019123723A_D0094.tif" /></tables></p><p> Isobologram analysis (Fig. 2) shows that the combined use of Co. No. 1 and levetiracetam has a significant positive synergistic effect.</p><p><tables num="27"><img file="JP2019123723A_D0095.tif" /></tables></p><p>Example 2-Tests with Compounds 25-a and 2-a 2.1. Combination test with Co. No. 25-a and levetiracetam Independent dose-response tests were performed on both compounds in a 6 Hz 44 mA test, and TPE 1 hour for levetiracetam. With ip, for Co.No.25-a, ED with TPE 1 hour sc₅₀The value was calculated. ED of Co.No.25-a₅₀The value is 25.9 mg / kg, ED for levetiracetam₅₀The value was estimated to be about 345 mg / kg. The dose-response of levetiracetam was repeated in combination with 10 mg / kg Co.No.25-a (a dose of Co.No.25-a that was not prevented alone in the 6 Hz 44 mA model). ED in levetiracetam dose-response by combined administration of 10 mg / kg Co. No. 25-a₅₀Was 4.9 mg / kg (about 70 times lower than levetiracetam alone), and importantly, the 6 Hz 44 mA seizure model provided complete prevention. These results suggest a positive pharmacodynamic interaction between Co. No. 25-a and levetiracetam in a 6 Hz seizure model.</p><p><tables num="28"><img file="JP2019123723A_D0096.tif" /></tables></p><p><tables num="29"><img file="JP2019123723A_D0097.tif" /></tables></p><p><tables num="30"><img file="JP2019123723A_D0098.tif" /></tables></p><p>2.2. Co.No.2-a and Levetiracetam Combination Test Dose-response studies include the 6Hz 32mA and 44mA tests (Table 9 below) and the combination test with levetiracetam (Co. for LEV dose-response in Table 10a). The effects of No. 2-a and the effects of LEV on the dose response of Co. No. 2-a in Table 10b below) describe the tests with Co. No. 25-a and levetiracetam above. I went in the same way.</p><p><tables num="31"><img file="JP2019123723A_D0099.tif" /></tables></p><p><tables num="32"><img file="JP2019123723A_D0100.tif" /></tables></p><p><tables num="33"><img file="JP2019123723A_D0101.tif" /></tables></p><p> At a dose of 10 mg / kg sc, Co.No.2-a improves the efficacy of LEV and its ED₅₀Shifts about 35 times. This suggests a positive pharmacodynamic relationship (Table 10a). At a dose of 350 mg / kg ip, LEV enhances the potency of Co.No.2-a and its ED₅₀Shifts about 14 times. This suggests a positive pharmacodynamic relationship (Table 10b).</p><p>Example 3-Test with Compound 6-b 3.1. Combination test with Co.No. 6-b and levetiracetam An independent dose-response test was performed on both compounds in a 6 Hz 44 mA test, with TPE 1 hour ip and for levetiracetam. For Co.No.6-b, ED with TPE 0.5 hours po₅₀The value was calculated. ED of Co.No.6-b₅₀The value is 16.1 mg / kg, ED for levetiracetam₅₀The value was estimated to be about 345 mg / kg. A 10 mg / kg Co.No.6-b (a dose of Co.No.6-b that was not prevented alone in the 6 Hz 44 mA model) was co-administered, and the dose-response of levetiracetam was repeated. ED in levetiracetam dose-response by co-administration of 10 mg / kg Co. No. 6-b₅₀Was 2.4 mg / kg (about 100 times lower than levetiracetam alone), and importantly, the 6 Hz 44 mA seizure model provided complete prevention. These results suggest a positive pharmacodynamic interaction between Co. No. 6-b and levetiracetam in a 6 Hz seizure model.</p><p> The results of the tests performed on Compound 6-b are shown in Tables 11-13 below.</p><p><tables num="34"><img file="JP2019123723A_D0102.tif" /></tables></p><p><tables num="35"><img file="JP2019123723A_D0103.tif" /></tables></p><p><tables num="36"><img file="JP2019123723A_D0104.tif" /></tables></p><p>Example 4-Test with compound LY404039 3.1. Combination test with LY404039 and levetiracetam LY-404039 was tested alone and in combination with levetiracetam according to the procedure described above. The results of the tests conducted with LY-404039 are shown in Tables 14 to 15.</p><p><tables num="37"><img file="JP2019123723A_D0105.tif" /></tables></p><p><tables num="38"><img file="JP2019123723A_D0106.tif" /></tables></p><p> At a dose of 5 mg / kg, LY404039 improved the efficacy of LEV, ED₅₀Shifts about 27 times. This suggests a positive pharmacodynamic relationship.</p><p>Example 4-Test with compound CAS 1092453-15-0 4.1.2,3-dihydro-7-methyl-5-[3- (1-piperazinylmethyl) -1,2,4-oxadiazole- 5-Il] -2-[[4- (trifluoromethoxy) phenyl] methyl] -1H-isoindole-1-one [CAS 1092453-15-0]</p><p>(Described in International Publication No. 2008150233 Pamphlet, International Publication No. 2011084098 Pamphlet) and combination test with levetiracetam<chemistry num="69"><img file="JP2019123723A_D0107.tif" /></chemistry> CAS 1092453-15-0 was tested alone and in combination with levetiracetam according to the procedure described above. The results of Example 5 are shown in Tables 16-17.</p><p><tables num="39"><img file="JP2019123723A_D0108.tif" /></tables></p><p> Low pharmacological activity was observed at the doses and time points tested. Maximum pharmacological activity at 0.25 to 1 hour at the tested dose. The combination test was performed in a 6 Hz (44 mA) assay using 20 mg / kg sc and TPE for 1 hour.</p><p><tables num="40"><img file="JP2019123723A_D0109.tif" /></tables></p><p> Current datasets show that mGlu2 PAM or agonist molecules have anticonvulsant activity in 6 Hz animal models. 150 nM EC₅₀efficacy([³⁵The test mGlu2 PAM, with appropriate PK parameters and brain permeability (as determined by the S] GTPγS assay), showed pharmacological activity in both the 32 mA and 44 mA 6 Hz paradigms. Furthermore, all the test molecules showed a synergistic effect with LEV. In contrast, it had weak pharmacological activity in vitro (EC).₅₀The 562nM) molecule CAS 1092453-15-0 showed no pharmacological activity in any of the 6 Hz tests and showed no synergistic effect with LEV.</p><p> Importantly, from the data, in vitro EC under conditions of comparable PK characteristics and appropriate brain permeability.₅₀Based on the values, the most potent mGlu2 PAM appears to be the most potent in vivo, suggesting that in vitro efficacy can be associated with in vivo efficacy. In addition, the ED obtained with the 32mA model₅₀ED similar to or found in the 44mA paradigm₅₀Synergistic effects with LEV are consistently seen at mGlu2 PAM doses that are at least 2-fold lower (ie, doses that show no pharmacological activity in the 44 mA test when the molecule is tested alone).</p><p> The mGlu2 / 3 agonist LY404039 also showed pharmacological activity in both 6 Hz tests and did not show pharmacological activity when tested alone, the ED determined in the 44 mA model.₅₀A synergistic effect was observed at doses three times lower.</p><p> Based on preclinical data available on the 6Hz 44mA model, the combined use of potent SV2A ligands with potent mGlu2 PAM results in an average effective amount of SV2A ligands such as LEV or ED.₅₀Seems to decrease 35 to 100 times.</p><p> Therefore, although not bound by theory, positive allosteric modulators (mGluR2 PAM) of metabotropic glutamate subtype 2 compounds, especially EC of 150 nM.₅₀efficacy([³⁵S] When determined by GTPγS assay) (EC₅₀Is EC₂₀The concentration of the combination of the present invention due to the concentration that produces the half-maximal effect of the concentration response curve obtained in the presence of glutamate), as well as the mGluR2 PAM compound with appropriate PK parameters and brain permeability. It is suggested that ineffective amounts of one or both of compound (a) and compound (b) should be used synergistically with SV2A ligands, especially levetiracetam.</p><p> Thus, in another embodiment, a metabotropic glutamate subtype 2 positive allosteric modulator (mGluR2 PAM) compound of the combination of the invention described herein has an EC of 150 nM.₅₀efficacy([³⁵S] When determined by GTPγS assay) (EC₅₀Is EC₂₀It is selected from mGluR2 PAM compounds having a concentration that produces the maximum half effect of the concentration reaction curve obtained in the presence of glutamic acid.</p><p>Predictive Example A) Dominance-inferiority relationship (DSR) in rat IN VIVO assay The DSR assay is divided into two models: reduction of the dominant behavior model of mania (RDBM) and reduction of the inferior behavior model of depression (RSBM). did. RDBM, which treats dominant animals with test compounds, predicts the ability of test compounds to treat mania. RSBM, which treats inferior animals with the test compound, predicts the ability of the test compound to treat depression.</p><p> Male Sprague Dawley rats (140-160 g) from Charles River Laboratories Wilmington, MA are used in this assay. Rat shipments are received every two weeks. Each shipment undergoes a 5-day quarantine, a 1-week acclimation period, and a 1-week selection process, followed by a 5-week drug or solvent treatment of the selected pairs.</p><p> The number of rats is 4 per cage. Access to food is limited to one hour per day after the test from Monday to Thursday. Allow rats free access to food after the test on Friday until they are fasted again on Sunday. Allow rats to have constant water intake. The fasting period used has little effect on weight gain, as the average rat weight will be approximately 300 g by the end of the study. At the end of the experiment, rats will be sacrificed by decapitation and trunk blood and brain will be collected for in vitro experiments and drug concentration measurements.</p><p> The basic test equipment consisted of two chambers connected by a tunnel that was only large enough for one rat to pass through at a time. Place a container of sweetened milk on the floor at the midpoint of the tunnel. This basic device can be replicated for simultaneous video tracking of a total of 4 pairs of rats. The camera can distinguish rats marked with different colors. Therefore, for video tracking, one cage is colored red and the other cage is colored yellow on the rat's head. Only one animal can comfortably access the feeder at a time, but both animals can drink milk for 5 minutes daily. Video tracking software records the time each rat spends in the feeder zone for this 5 minutes each day and saves it in a text file.</p><p> Randomly assign rats to a pair and start the test. Each member of the pair is placed in the opposite chamber of the test equipment. Record the time each rat spends in the feeder zone. During the first week (5 days) of the study, the animals will adapt to the new environment. If the three criteria are met, the animal with the highest score will be assigned the dominance in the second week of the study. First of all, there must be a significant difference (bilateral t-test, P &lt;0.05) in the mean daily lactation scores of both animals. Second, the dominant animal score must be at least 25% higher than the score of the inferior animal. Finally, there should be no "reversals" in the anti-selection week in which the presumed inferior rat scored more than its dominant partner when isolated. Ideally, the reversal is minimal during the habituation week. Only animal pairs that meet these criteria will continue to be tested.</p><p> Significant difference in time spent in feeders between dominant and inferior rats is determined by ANOVA using GraphPad Prism software (GraphPad Software, Inc. San Diego, Ca) followed by bilateral t-test (P &lt;0.05). To do. Comparisons between treatment groups are made using normalized dominance level values of paired animals. The superiority level is a value that determines the social relationship between paired objects. Dominance level (DL) = FTD-FTS (In the equation, FTD is the feeder time of the dominant rat and FTS is the feeder time of the inferior rat. Normalization is performed according to the following equation. Dominance level (week n) , Unit:%) = (Predominant level (Nth week)) / (Predominant level (2nd week))</p><p> The statistically significant difference in the level of dominance between the control group (a pair of rats in which both the dominant and inferior animals are treated with solvent) and the treatment group (the inferior rat is treated with a drug and the dominant rat is treated with a solvent). ANOVA, followed by t-test. The onset time value of pharmacological activity (AOT-50) in 50% of the reaction and the minimum and maximum response to the drug were performed using nonlinear regression analysis (GraphPad Software, Inc. San Diego, Ca) based on the reduction of the dominant level value. To calculate. The normalized DL value is used in this calculation, and the DL value of the treatment week is normalized as% of the value of the pair in the second week (before treatment) by the above formula. In these situations, the minimal response (DL) determines the positive pharmacological activity corresponding to efficacy, as the DL value decreases when the response to the drug is positive. If the response to the drug is negative (symptoms worsen), the DL value increases. If the drug does not have such pharmacological activity, the maximum response does not exceed 100%. A maximum DL value significantly higher than the control value (about 100%) indicates that the drug has negative pharmacological activity.</p><p> Levetiracetam and mGluR2 PAM / agonist compounds (eg, compounds 2,2-a, 25-a, 6-b or LY-404039) are evaluated in rat RDBM according to the procedure detailed below.</p><p> The dominant rat group consisted of levetylacetam 10 mg / kg and various concentrations from about 0.05 mg / kg (n 3), 0.5 mg / kg (n 3), 2.5 mg / kg (n 3), QD po treatment with 5.0 mg / kg (n 3) and 50.0 mg / kg (n 3) of mGluR2 PAM / agonist compound. The solvent control group of the dominant rat is treated with 0.5% methylcellulose (n 3) and the second control group of the dominant rat is treated with QD ip at 30 mg / kg sodium valproate (two of each n 3). From the test n 6).</p><p> All treatments should be given approximately 1 hour before the study. All treatments will start on Saturday after the second week of the study (selection week). Levetiracetam and mGluR2 PAM / agonist compounds are administered orally (po).</p><p> When dominant animals are treated with levetiracetam 10 mg / kg and mGluR2 PAM / agonist compounds, the difference between dominant and inferior rats disappears after 1 or 2 weeks of treatment, depending on the dose. Similarly, when dominant animals are treated with sodium valproate, the difference between dominant and inferior rats disappears after the first week of treatment. Increased tolerance can be seen in dominant rats treated with levetiracetam and mGluR2 PAM / agonist compounds or sodium valproate. Therefore, treatment of dominant rats allows for increased time in the feeder of their inferior partners.</p><p> Data are normalized to initial control week values to compare different drug and dose effects. Levetiracetam with mGluR2 PAM / agonist compound if there is a significant difference in predominant level (DL) values between solvent-treated and combination-treated rats that begins in the second week and continues for the duration of the 5-week treatment. The strongest effect of the combination is recognized. By comparison, animals treated with sodium valproate (30 mg / kg) consistently showed a decrease in predominant levels after the second week of treatment and increased efficacy the following week.</p><p> In order to estimate the onset time of pharmacological activity (AOT), the daily mean value of the pair of feeder time of the dominant animal and the inferior animal is plotted, and the significant difference between the two groups is calculated using the two-sided t-test.</p><p> To compare pharmacological activity onset time (AOT) between different treatments, pharmacological activity onset time is estimated from a non-linear regression fit. The non-linear regression model fits for each drug, combination, and dose-normalized daily DL value.</p><p> The effects of levetiracetam and mGluR2 PAM / agonist compounds on RDBM appear to be dose-dependent.</p><p> In this assay, the combination of levetiracetam and the mGlu2 PAM / agonist compound appears to reduce predominant behavior, indicating that this combination exhibits anti-manic activity.</p><p>B) Oral Tablets As a specific embodiment of the oral composition, 100 mg of mGluR2 PAM / agonist compound is formulated with well-ground lactose, the total amount is 580-590 mg, and a hard gel capsule of size O is filled.</p><p> Although the aforementioned specification teaches the principles of the invention and examples are described for illustrative purposes, the practice of the invention is usually within the scope of the following claims and their equivalents. It will be found that all variants, variants and / or modifications are included.</p>