Untitled record

140

Combinations with positive fractional kinetics (metabolites) or stereotaxic agonists of type 2 glutamate receptor receptor and its use

Summary

5 The present invention relates to combinations comprising a positive (prognostic) affirmative axis (PAM) and of a mutant glutamate receptor from an admixture 2 (mGluR2) or a pharmaceutically acceptable salt or solubility therefrom, or a stereotaxic agonist inhalers for a wanted transformational glutamate receptor of type 2 or a pharmaceutically acceptable or dissolved salt thereof. SV2A (2Α) synthetic vesicle protein lignin.

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M1 AKA S.

Combinations containing positive helix lozenges (agonists) or stereotaxic agonists for a transformational glutamate receptor from lymph2 and its use

Sorry, full

5 Area of deception

The present invention relates to combinations comprising a positive differential (modified) (PAM) erasure of a transformational glutamate receptor of type 2 (mG! UR2) or a pharmaceutically acceptable salt or solubility therefrom, or a stereotaxic agonist inhalers agonist inhalers from a type 2 mutant glutamic receptor compound or pharmaceutically acceptable salt Or dissolve from it, and the protein protein gut (2Α) SV2A.

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Epilepsy describes a condition in which someone experiences frequent seizures as a result of an underlying chronic illness. The course of epilepsy to a clinical phenomenon as well as a singular disease entity, because there are many forms and causes of epilepsy. Using the definition of epilepsy as sleeping without two or more agitators, the incidence of epilepsy is estimated to be between 15 and 0.3 to 0.5 per cent in different peoples around the world, and the prevalence of epilepsy D is estimated to 5 to 10 people out of every 1,000.

One of the basic steps in assessing and managing a patient with a seizure is to determine the type of seizure that has occurred. The main feature that defines the shells. Various seizures are if the seizure activity is 20 bold (focal with focal) or generalized.

Running seizures are those in which seizure activity is limited to separate areas of the cerebral cortex. If consciousness is fully preserved in Nubia, then the secret manifestations are considered relatively simple, and we call the Nubia a simple running nubia. And with poor awareness, the seizure is called a partial partial complication. A significant addition subgroup includes seizures that start as partial seizures and then spread amply across 25 chaffs, which are stripped by running seizures with a secondary generalization.

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Generalized seizures simultaneously include areas of the brain spreading in a binomial pattern. Absence or epileptic seizures are characterized by sudden consciousness, and lime without loss of postural control. Abnormal absence nuclei usually include a longer period in consciousness lapses, less sudden onset and stops, and a more pronounced misalignment that can include focal or lateral mirrors. Tension-parasitic or 5 generalized seizures, the major type of generalized seizure, are characterized by a sudden onset, without warning.

The initial phase of a seizure is usually a sign of tense muscle contractions, poor breathing, a noticeable improvement in the tunes that lead to rapid heart damage, blood pressure, and a right-to-size right. After 10-20 seconds, the tension phase of the seizure usually develops into a grazing phase, produced by the action of a composition that relaxes the muscles on the muscle contracting tension. We gradually want to relax periods until the end of the metastatic phase 10, which usually does not last more than 1 minute. The following phase) is characterized by the reaction after the muscle response, the muscular flaccidity, the seductive saliva nausea, which may cause squamous breathing and airway obstruction.

We are characterized by vomiting episodes of sudden loss of postural muscle tension lasting up to 1-2 seconds. Consciousness weakens and reduces lime, but there is usually no post confounding of the injury. Muscle rent spells are characterized by a sudden and brief muscle contraction that can include part and part of the body or the entire body.

15

Pronen synaptic vesicle SV2A (is) has been defined as a broad anticonvulsant target in circular and generalized epilepsy models. Studies in animal models and human tissue suggest that the eposodes of SV2A are included in epilepsy (for general consideration see for example: (a) Mendoza-Torreblanca et al. Synaptic vesicle 20 protein 2Α: basic facts and role in synaptic function European Journal

1-11 .of Neuroscience 2013, pp. (B) Kaminski RM, et al. Targeting SV2A for Discovery of Antiepileptic Drugs. In:, Noebels JI, Avoil M, Rogawski MA, et al., Editors. Jasper's Basic Mechanisms of the Bethesda (MD): National Center for .Epilepsies [Internet]. 4^th edition 25 2012; (Biotechnology Information (US.) Available at:

/http://www.ncbi.nlm.nih.gov/books/NBK8183).

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43291Α1 is not clear, but studies suggest that the change in SV2A's hurricane is what dictates the specific role of Nowack et al. Levetiracetam reverses) affects the SV2A synaptic deficits produced by overexpression of SV2A PLoS One 2011, is a key factor in SV2A emesis, as I have also suggested that (volume 6 (12), Θ29560 5

Crowder et al. Abnormal neurotransmission in) is associated with mice lacking synaptic vesicle protein 2Α (SV2A) Proc Nat Acad Sci) and we suggest studies in the genetically modified inactivity mice (USA 1991, Vol. 96, pp. 15268-15273 GABA leads to a mismatch between neurotransmission Glutamate and for SV2A related to Venkatesan et al. Altered balance between excitatory and inhibitory) 10 inputs onto CA pyramidal neurons from SV2A deficient but not SV2B it may be. (Deficient mice for Neurosci res 2012, 90, pp. 2317-2327 van Vliet) as a result of seizure activity and can be linked in the introduction of epilepsy S72A decreasing cyclone d et al. Decreased expression of synaptic vesicle protein 2Α, the binding site for levetiracetam, during epileptogenesis and chronic epilepsy 15

Feng et al. Down-regulation of; Epilepsia 2009, 50, pp. 422-433 synaptic vesicle protein 2Α in the anterior temporal neocoitex of patients; with intractable epilepsy for Mol Neuorosci 2009, 39, pp. 354-359 Toering et al. Expression patterns of synaptic vesicle protein 2Α in focal cortical dysplasia and TSC-cortical tubers Epilepsia 2009, 50, pp. 20 de Groot et al. (1418-1409) Epilepsy in patients with Expression of synaptic vesicle protein 2Α in epilepsy-associated brain tumors and in the peritumoral cortex Neuro-Oncology 2010, 12, pp.

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43291Α1 lynch et al. The synaptic vesicle protein (SV2A) contains the SV2A is the binding site for the antiepileptic drug levetiracetam Proc. Natl. Pregarcetam and Celestretam, (Acad. Sci USA 2004, Vol. 101, pp. 9861-9866 Kaminski RM, et al. Targeting SV2A for Discovery of Antiepileptic) Noebels JL, Avoli M, Rogawski MA, et al., Editors. Jasper's: In .Drugs 5 Basic Mechanisms of the Epilepsies [Internet]. 4^th edition. Bethesda (MD): Available at National Center for Biotechnology Information (US) 2012 Nowack et al. ; Http: //www.ncbi.nml.nih.gov/books/NBK98183/ levetiracetam reverses synaptic deficits produced by overexpression of. (SV2A PloSone December 2011, Vol. 6 (12), 529560 10

Ligetizetam, (-) - (a- (s— enel-2-oxo-aperolidine acetamide or (2) -2_ (s-oxo-pyrrolidine!! Y) butota n-amide,

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15th It fend off anti-epilepsy. No activity was seen in conventional acute models (maximum trauma tests and a quinol ZnPin shift) but was found to be effective in decorated epilepsy models and genotypes for generalized epilepsy. A safety margin has demonstrated a high denatured level with other antiepileptic drugs (Klitgaard Levetiracetam: the preclinical profile of a new class of 13-18. Antiepileptics drugs Epilepsia 2001, 42 (Supplement 4), pp). Complete

20 Trade under the Keppra® trademark, available as a disc, as a to be the mouthpiece, and as a terrifying form made as a solution for impregnation. Keppra® has been approved in Europe as a postmenopausal treatment for patients 16 years of age with newly diagnosed epilepsy in the treatment of running-off episodes (nuclei) with or without secondary generalization and as an adjunctive treatment for use with antiepileptic drugs

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Others in the treatment of run-off episodes with or without generalization in patients with a 1-month disorder; seizures of myoclonus in 12-year-old patients with juvenile epilepsy; and major generalized tonic-parasitic episodes in a 12-year-old patients with unknown generalized epilepsy The reason (www.ema.erjropa.eu). Keppra® has also been approved in the United States of America 5 as an adjunct therapy for the treatment of running-off seizures in patients from 1 month of age;

Myocardial seizures in Marysa from the age of 12 years and older with severe juvenile myoclonic seizures; generalized quarterly tonic attacks in a patient of 6 years of age and older with generalized idiopathic epilepsy. Available as extended release tablets, Keppra XR® has been approved in the United States of America for adjuvant therapy for running seizures in patients 10 to 16 years of age and older with epilepsy.

(l6ttp: //www.accessdata.fda.gov/scripts/cder/dugsatfdaindex.cfm). Prevalacetam, a 4-a-a-propyl isotope from levetizetam, (R4)] - 2— (S2) - hypropyl udder^— Pyrrolidine-a-yl butane amide,

0 νη₂

15th Within clinical trials, it is studied as a monotherapy in running-off episodes and post-mash neuralgia, and as an adjunct therapy in partial-onset partial seizures, the Ungericht disease - Lundburg in adolescents and adults, and in photosensitive epilepsy (www.clinicaltrials.gov).

Celetetetam, (2c) -2 - [(4s) -4- (2,2, Pseudo-fodo-Feethel) -2-oxo-pyrrolidine-1-

20 Yl butane amide,

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C

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2. the

It has been tested in clinical trials.

The three gait preparations are known in the printed materials. For example, Done

5 For example, the detection of manufacturing processes for levetiracetam, in European invasive patent No. 036 162 0 EP and in British patent No. 2 225 225 322 GB. A process for preparing pre-acetam, for example, was disclosed in WB 01/62726. A practical barrier for the preparation of Celitzetam, for example, from WB2005 / 121082. Alternative processes for manufacturing the metabolites have been detected

10 The three are in European patent number 801806339.

Antiepileptic drugs have had a benefit in neurological and psychiatric disorders, including pain in neuropathy, migraine, tremor of idiopathic and anxiety, vertigo and antipolar disorder (.landmarck Antiepileptic drugs in ηοη-epilepsy disorders 15 Relations between mechanisms of action and clinical efficacy of CNS

27-47 .Drugs 2008, Vol. 22 (1), pp. Calabresi et al. Antiepileptic drugs in migraine: from clinical aspects to cellular meclianisms Trends in 188-195. Pharmacological Sciences 2007, Vol. 28 (4), pp; Rogawski and loscher, The neurobiology of antiepileptic drugs for the treatment of 20 685-692 .. (nonepileptic conditions, Nat Med, 2004, Vol. 10, pp

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43291Α1 It has been regretted that levetiracetam is effective or may be effective in a wide range of neurological disorders (Muralidharan and Bfiagwagar potential of). Mental disorders have been sold in levetiracetam in mood disorders: a preliminary review, CNS Drugs 2006, Mula et al. The role of anticonvulsant drugs in; Vol. 20, pp. 969-979 anxiety disorders: a critical review of the evidence for Clin 5 Kinrys et (anxiety disorders), (Psychopharmacol 2007, Vol. 27, pp. 263-272 al. levetiracetam as adjunctive therapy for refractory anxiety disorders Zhang et al. L; Clin Psychiatry 2007, Vol. 68, pp. 1010-1013 levetiracetam in social phobia: a placebo controlled pilot study for Kinrys et al. Psychopharmacol 2005, Vol. 19, pp. 551-553 10 levetiracetam for treatment-refractory posttraumatic stress disorder for Enggaard et al. Pain, Clinicaliatiatry 2006, Vol. 67, pp. 221-214 Specific effect of levetiracetam in experimental human pain models Eur Dunteman levetiracetam as an for; Pain 2006, Vol. 10, pp. 193-198 adjunctive analgesic in neoplastic plexopathies: case series and 15 commentary: for Pain Palliative Care Pharmacother 2005, Vol. 19, pp. Price levetiracetam in the treatment of neuropathic pain: three 43-35; movement disorders, (case studies Clin for Pain 2004, Vol. 20, pp. 33-36 Bushara et al. The effect of levetiracetam on essential tremor) McGavin et al. Neurology 2005, Vol. 64, pp. 1078-1080 20 Levetiracetam as a treatment for tardive dyskinesia: a case report Woods et al. Effects le: Neurology 2003, Vol. 61, pp. 419 Levetiracetam on tadive dyskinesia: a randomized, double-blind,; placebo-controlled study for Clin Psychiatry 2008, Vol. 69, pp. 546-554 Zivkovic et al. Treatment of tardive Dyskinesia with levetiracetam in a 25; transplant patient Acta Neurol Scand 2008, Vol. 117, pp. 351-353

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43291Α1 striano et al. Dramatic response to levetiracetam in post-ischaemic Holmes' tremor by Neurol Neurosurg Psychiatry 2007, Vol. 78, pp. 438Pizzini et al. (439) Le7etiracetam: An improvement of attention and of oral fluency on patients with partial epilepsy epilepsy research, 2006, vol. 68, pp. 5 De Groot et al. levetiracetam improves verbal memory in 188-181; high-grade glioma patients Neuro-oncology 2013, Vol. 15 (2), pp. 216 Bakker et al. Reduction of hippocampal meds, OK? improves 223; cognition in amnestic mild cognitive impairment Neuron 2012, Vol. 74, Eddy et al. The cognitive impact of: for general consideration pp. 467-474 10 antiepileptic drugs Ther Adv Neurol Disord 2011, Vol. 4 (6), pp. 385Wheless levetiracetam in the treatment of 407 and for reference cited in it: childhood epilepsy Neuropsychiatrie Disease and treatment 2007, Vol. Dolder and Nealy The (4) 3). 409-421 efficacy .and safety of newer anticonvulsants in patients with dementia 15 We propose data on biology. (Drugs Aging 2012, Vol. 29 (8), pp. 627-637, and some preliminary clinical trials - that levinensetam may have efficacy in suppressing Post-traumatic epilepsy, such as that caused by an epileptic condition, traumatic brain injury and ischemic stroke, and appears to have neuroprotective effects. What sends Legendzetetam's effectiveness in relieving epilepsy formation or comforting functional dysfunction must be demonstrated through critical animal and clinical studies (for general consideration:

loscher and Branndt: Prevention or modification of epileptogenesis after brain insults: expermintal Approaches and recent edition of research Shetty Prospects of; Pharmacol Rev 2010, Vol. 62, pp. 668-700 Levetiracetam as a neuroprotictive drug against status epilepticus, traumatic brain injury and stroke Front. Neur. 2013, 4: 172. Doi: 25 since it showed anti-epileptic activity in the model (lO.3389 / fneur.2O13.OO172

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43291Α1 lee) irritation of groats and mice. It has also been suggested that ligetizetetam inhibits the release of glutamate et al. levetiracetam inhibits glutamate transmission though presynaptic Ρ / Q-type calcium cliannels on the granule cells of dentate gyrus British. (Journal of Pharmacology 2009, Vol. 158, ΡΡ.1753-1762

It has been discovered that selenacetametam and yrega ricetam reduce the severity of dystonia in a dt-hamster model and may be beneficial for some patients with dysfunctional or dysfunctional warfare disorders (Hamann et al. Brivaracetam and seletracetam, tow new SV2A ligands, improve paraoxysmal). dystonia in the dt mutant hamster

10 99--102 .. (European Journal of Pharmacology 2008, Vol. 601, pp

Recent positive mGluR2 prognostic modules have emerged as new and several treatment approaches to treat many CNS disorders, including epilepsy, and some mGluR2 (positive prophylactic modules) have been subjected to clinical trials for treating schizophrenia and anxiety disorders.

15th (wwwclinicaltrials.gov, see example example: JNJ-4O411813 / ADX71149 by Addex Therapeutics and Janssen Pharmaceuticals, Inc.) The initial suggestion was that drugs that suppress the transmission of endotamias could have an effect in the treatment of epilepsy from acute non-clinical studies with mGlu2 / 3 mixing agonists (Moldrich et al. Glutamate metabotropic receptors as targets for drug therapy in

20 3-16 .Pharmacol. 2003, Vol. 476, pp for epilepsy (Eur). And you discover that my year

92379268, mGlu2 / 3 and 89389795, were ineffective in preventing MES dices up to doses that produced kinetic impairment but were found to be effective in a 6 Hz model in a dose-dependent manner (Barton et al. Comparison of the effect of glutamate receptor modulators in the 6 Ήζ and , maximal electroshock seizure models

25 17-26. Epilepsy Research 2003, Vol. 56, pp). The constant giving of Nahedah

mGlu2 / 3 has inconsistently stimulated seizure activity in long-acting toxicology pathways

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Dunayevich et al. Efficacy and tolerability of an mGlu2 / 3 agonist inhalers in the), treatment of generalized anxiety disorder Neuropsychopharmacology 1603-10. 2008, Vol. 33 (7), PP). This eutrophic ether may be associated with the changes induced by the Agonist inhalers in the sensitivity of the receptor system (accelerated immunity), but it has not yet been reported.

5 In preclinical epilepsy models. A positive erosive nucleus, on the other hand, modulates but does not directly stimulate an ongoing neurotransmitter, thereby reducing the risk of accelerated immunity.

Prior to the activity of a seizure, the measures of extracellular glutamate are measured in the fissure of the human hippocampus and the hands are stabilized during the activity of epilepsy (During and Spencer Extracellular hippocampal glutamate and spontaneous seizure in the conscious 10 1607-10. Human brain Lancet 1993, Vol. 341 (8861), PP), which supports the

A decrease in glutamate levels may be of benefit in treating epilepsy. In fact, glutamate levels during nucleus activity have decreased to potentially neurotoxic levels. Nubia activity leads to progressive structural damage to the human brain, which stimulates additional abnormalities in the metabolism of glutamate (Petroff et al. Glutamate-glutamine cycling in the epileptic).

15th 703-10 .the human hippocampus: Epilepsia 2002, Vol. 43 (7), pp). Subsequently,

It can be expected that a positive asymptotic axis d mGluR2 or a stereotaxic agonist inhalers for mGluR2 will protect against nerve damage caused by a seizure.

The publication of the global patent Inventories with the numbers W02009 / 033704 and 20W02010 / 10424 reveals a positive Naqari d mGluR2, its uses and the synthesis process

Desires The publications of the global patent holders with numbers W01997 / 18199 and W02003 / 104217 reveal the triggers of an amino acid receptor modulator that subsequently appeared to possess a stereotaxic agonist inhalers activity d mGlu2 / 3 (see, for example, Rorick-Kehn et al. (2007) The Journal of Pharmacology and Experimental therapeutics 25 (308-317 (Vol. 321, No. 1, pp)).

Additional examples of triggers having a stereotaxic agonist inhalers activity for mGlu2 / 3; are revealed

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WB2008 / 150233 Publication on Hypothalamic parabolic activity mGluR2.

The currently available antiepileptic drugs do not only affect the transmission of glutamate. Generally imagined

5 That its mechanism of action is that it alters the balance between the arousal transfer (mediated by glutamate) and to be discouraged (mediated by Johannessen landmark Antiepileptic drugs in non-) (GABA epilepsy disorders: relations between mechanisms of action and clinical 27-47 .. (efficacy of CNS Drugs 2008, Vol. 22 (1), pp

10 An important limiting factor in the use of the SV2A host is its durability and side-effect tolerance. For example, the effective dose of ligetiracetam for starting starting nuclei is dosed at 1,000 mg, 2000 mg, and 3000 mg, given twice daily. Included are reported side effects of lignerecetam, aggressive and angry behavior, anxiety, personality change, chills, cough or hoarseness, crying, personality dissipation, diarrhea, dryness of cloudiness, darkness, fever, general feeling after rest or lamentation.

15th Headache, vomiting, irregular heartbeats, irritability (agitation), joint pain, loss of appetite, lower back or side pain, mental depression, muscle aches and pains, nausea, painful or difficult urination, paranoia, rapid reaction or unique reaction Emotional, rapidly changing meadow, restlessness, tremors, tremors, shortness of breath, drowsiness or unusual tooth, sore throat, stuffed or swollen nose, sweating, trouble sleeping, unusual tiredness or weakness and vomiting. Hence, there is still a need for effective treatment

20 With a lower effective dose of leveneracetam and present a more favorable side effect to treat epilepsy and related disorders, and it is not only prescribed to the adult population but also to children.

And his religion ¹ No fees

Figure 1: Dosage response to determine 6 EDjq Hz 44 mAh for NO 2 and LEV alone

25 It is issued jointly.

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Figure 2: Analysis of exponential radial recording of the fishy rosemate synthesis 1 with leveteretetam (IEV) in a 6 hr assay (44 mA). ED values were determined_SInitial O (shown below) for the suspender 1 and IEV (data points on the X and y The Bloody axes; filling aids). The theory of purification theory connects calculated EDso values to suspenders (solid black line). Theoretical ED50 5 (SEM) is planned for three combinations with a fixed dose ratio (LEV: fishy No. 1): 3: 1 - fill-in planes / solid black line, 1: 1 - filled-towards-oriented / solid black-line triangles, and 1: 3 filled-in triangles Destined to turn on a solid black line. Initial experimental treatment doses were derived from theoretical values and adjusted according to the observed parameters. We also show experimentally determined tSEM values (ED5Q) for each combination with a fixed dose ratio: 3: 1 '- invading squares / dotted line, 1: 1' - 10 open open bound vectors / dotted line, and 1: 3'- open vector triangles For Busy / Dotted Line. And I have been

The gamblers gamut between theoretically and empirically defined the EDq values using t-news (8 = Ρ0000000 for each group. In Figure 2, the ratio of the LEV to the compound # 1 is depicted as follows:

<td></td><td>Attachment 1</td><td>LEV ratio</td>

<td></td><td> 3:1</td><td> ٠</td>

<td></td><td> 1:1</td><td>H</td>

<td></td><td> 1:3</td><td>a</td>

<td></td><td> ’3:1</td><td> -0—</td>

<td></td><td> ’1:1</td><td>—A—</td>

<td>345 = (LEV) ED50 coil / kg (211-485) (intraperitoneal, .ip)</td><td> ’1:3</td><td>-V-</td>

<td>EDso (compound No. 1) = 10.2 mg / kg (3.1-12.4) (subcutaneously (.SC))</td><td></td><td></td>

15th Figure 3: Combination studies of suspicious No. 25-a with leviteretetam (LEV) in a 6 Hz (44 mA) assay. At a dose of 10 mg / kg subcutaneously, fishy No. 25-A increases the potency of LEV, resulting in approximately 70 fold changes in ED50. This suggests a positive pharmacodynamic relationship.

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Figure 4: Twelve studies of RM-2a compound with levetizetam (LEV) in a 6 hr (44 mA) assay. At a dose of 10 mg / kg subcutaneously, the promoter Raem 2-A increases the potency of LEV, resulting in an approximation of a 35-fold changes in EDso. This suggests a positive pharmacodynamic relationship.

Figure 5: Twiffin lessons for RHM 6B with Leviteretam (LEV) in a 6 hr assay (5 44 mA). At an inventory of 10 mg / kg in the mouth, the terrible number 6b increases the potency of LEV, resulting in an approximation of a 100-fold exchange in ED._SO. This suggests a positive pharmacodynamic relationship.

Figure 6: LY-4O4O39 d-coupling studies with ligetetam (LEV) in a 6 hr assay (44 mAh). At a dose of 5 mg / kg subcutaneously, LY-4O4O39 increases the efficacy of LEV, leading to an asymptotic change of 27 fold in 1555. This suggests a positive pharmacodynamic relationship.

10

Paving disreputation

The present invention relates to a composition comprising

Lujain Bruin vesicle fixative SV2A (2Α); and

(B) A positive differential axis (ΡΑΜ) of a glutamate receptor-containing form 2 (15 'mGluR2) or pharmaceutically acceptable salt or soluble salt, or a stereotaxic agonist inhalers of a type 2 glutamate receptor compound or pharmaceutically acceptable or dissolved salt thereof.

In a specific embodiment, the invention as described herein relates to a pharmaceutical blend, specifically a pharmaceutical blend product, including

20 (A) Jane Bruin vesicular vesicle SV2A (2Α); and

(B) a positive affinity index (PAM) for a type 2-containing glutameric receptor antigen (mGluR2) or a salt acceptable for hay or dissolving from it, or a stereotaxic agonist inhalers of a type 2-containing glutamate receptor or a pharmaceutically acceptable or dissolved salt thereof; and

(C) At least one pregnant woman - pharmaceutically acceptable.

25

In an additional embodiment, the invention relates to the craving described herein for use as a medicine.

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An additional embodiment of deception relates to the use of the combination described herein to manufacture a drug or pharmaceutical product for the treatment or prevention of epilepsy and related disorders; neuropathic pain; migraine or resisting headache and isotropic disorders and related disorders.

5

An additional embodiment of the alkhenra is related to the use of the combination described here to manufacture a buffer or pharmaceutical product for neuroprotection.

An additional embodiment of required relates to the use of the combination described here to manufacture a drug or pharmaceutical product 10 to prevent epilepsy.

An additional embodiment relates to the treatment or prevention of epilepsy and related disorders; neuropathic pain; migraines or resistant headaches; isotropic and related compulsive disorder in a muric condition and includes the administration of gene Bern clamp vesicle SV2A (2Α) to the pathological condition that it needs 15 simultaneously or sequentially; A positive coupling index (PAM) for a GLT monitor

Of Type 2 (mGIuRZ¹"Or a pharmaceutically acceptable salt or soluble thereof, or a stereotaxic agonist inhalers for a compound containing the type 2 glutamate containing or a pharmaceutically acceptable salt or soluble thereof, in quantities that will be therapeutically effective when administering both the SV2A gene and the mG! UR2 monitor together.

20 A further embodiment relates to a combination as described herein. Neurological protection; or a combination as described here for use in neuroprotection.

An additional embodiment is related to a combination of as described here to prevent epilepsy formation; or an combination of as described herein for use in preventing epilepsy formation.

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The invention comprises an additional embodiment of a method for treating or preventing epilepsy and related disorders; pain of neuropathy; migraine or resistant headache; bipolar and related disorders when

The walker includes a fixed dose combination

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For the protein gland parasympathetic vesicle SV2A (2Α); and

5 (B) Positive pyrotechnic index (PAM) for a wanted glutamate receptor receiver of type 2

(mGluR2) or a pharmaceutically acceptable salt or soluble thereof, or agonist inhalers stereotaxic agonist inhalers of a suspicious transformation glutamate receptor of type 2 or a pharmaceutically acceptable or soluble salt thereof, in quantities that will be therapeutically effective when administering the SV2A gene and desired mGluR2 together.

10 The invention in an additional embodiment of a neurological protection method relates to a combination as defined here.

Invention in an additional embodiment of the anti-epilepsy method relates to a combination as defined here.

An additional embodiment relates to a method for treating or preventing epilepsy and related disorders; neuropathic pain; migraine or resistant headache; bipolar and related disorders. Method 15 includes the administration of a therapeutically effective amount of tween or a combination product comprising

(A) Lattice proteinase gene S72A (2Α); and

(B) a positive differential axis (PAM) for a type 2 mutant glutameric receptor (mG! UR2) or a pharmaceutically acceptable soluble or soluble salt, or a stereotaxic agonist inhalers for a transformational glutamate receptor of Type 2 or a pharmaceutically acceptable or dissolved salt from it,

20 To a situation of gaiter that needs it, such as a spotted blooded sperm, and a long-lived human.

An additional embodiment relates to a neurological protection method. The masculine method includes administering a therapeutically effective amount of a combination or combination product comprising

L2 protein synthesis of the vesicular vesicle SV2A (2Α); and

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(B) Positive differential erasure (PAM) and of a mutant glutamian receptor modifier from type 2 (“mGluR2) or a pharmaceutically acceptable salt or soluble salt thereof, or a stereotaxic agonist inhalers of a transformational glutamate receptor requester of type 2 or a pharmaceutically acceptable or dissolved salt from it, to a pathological condition He needs it, like a spotted blooded sperm, specifically humans.

An additional embodiment relates to an antiepileptic method. The aforementioned method involves administering a therapeutically effective amount of a combination or combination product comprising:

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L2 protein synthesis of the vesicular vesicle SV2A (2Α); and

(B) a positive differential axis (PAM) of a transformer glutamate receptor modulator of type 2 10 (mG! UR2) or a pharmaceutically acceptable or dissolved salt thereof, or a riser of a stereotaxic denominator of a receiving descriptor.

Transformational glutamate of Type 2 or pharmaceutically acceptable soluble or dissolved salt thereof,

To a condition he needs, boil a hot blooded animal, specifically humans.

In an additional embodiment, the present invention relates to a pharmaceutical product or commercial rice with a combination

15th According to the invention as described herein, specifically with instructions, for use in a unified time, separately or consecutively in the treatment or prevention of epilepsy and related disorders; neuropathic pain; migraine or bipolar resistant headache; and related disorders.

In an additional embodiment, the present invention relates to a pharmaceutical product or a commercial package comprising a combination

20 According to the required as described here, specifically with instructions, to be used at the time of unit, separate or successive in neurological protection.

In an additional embodiment, the present invention relates to a pharmaceutical product or a commercial package comprising a combination according to the pore as described herein, specifically with instructions, for use at a single time, separate or 25 consecutive anti-epilepsy.

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The invention relates to an additional embodiment; a mixture comprising a therapeutically effective amount of anti-epileptic and related disorders; neuropathic pain; migraine or resistant headache; bipolar and related disorders;

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Ligine protein synthesis by vesicular SV2A ”(2Α); and

5 (B) A positive differential axis (PAM) and of a mutant glutamate metabolism receptor type 2

(“MGluR2) or a pharmaceutically acceptable soluble salt or soluble thereof, or a stereotaxic agonist inhalers for a transformational glutamate receptor compound of Type 2 or a pharmaceutically acceptable soluble or dissolved salt from it, and at least one pharmaceutically acceptable carrier.

10 The invention relates to an additional embodiment of a combination comprising a therapeutically effective amount of purchaser as neurotransmitter

(A) Ligamentosome protein protein gene SV2A (2Α '); and

(B) Positive Differential Erasing (“PAM”) of a suspicious GLM receptor of Type 2

(mGluR2) or a pharmaceutically acceptable salt or soluble thereof, or agonist inhalers stereotaxic agonist inhalers for a suspicious acceptance of 15 transformational glutamate of Type 2 or a pharmaceutically acceptable salt or soluble therefrom, and at least a pharmaceutically acceptable limit carrier.

The invention relates to an additional embodiment of a combination comprising a therapeutically effective amount of antiepileptic formation

20 (A) Lattice proteinase gene S72A (2Α)); and

(B) a positive differential axis (PAM) for a mutant glutamate receptor-type receiver of the type 2 (mGIR) or a pharmaceutically acceptable salt or soluble salt thereof, or a stereotaxic agonist inhalers for a suspicious metabolite of type 2 metabolites or pharmaceutically acceptable salt from it, and at least one carrier Pharmaceutically acceptable.

In an additional embodiment, the invention relates to the use of

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43291Α1

18

(A) Ljen Bronin papillary vesicle SV2A (2Α); and

(B) Positive coupled erasure (PAM) modulation of type 2 glutamate receptor acceptor

(mGluR2) or a pharmaceutically acceptable soluble salt or soluble thereof, or agonist inhalers, a stereotaxic ingredient for a suspicious transformational glutamate receptor from the proxy 2 or a pharmaceutically acceptable salt or soluble from it,

5 To prepare a bleach product according to the present invention .

The components (b) of the combination of the invention are generally referred to here as mGluR2 or parasites

PAM / mGluR2 astringent, or suspicious positive affective axis of 2 ^ 0 abnormal stereotaxic component d mGluR2 which means that the ranps have a reactively active activated glutamate receptor 10 of type 2; and they are specifically chosen from positive affinity agonizers (PAMs) for a receptor

Transformational glutamate from type 2, and protruding stereotoxic modifiers for a transformational glutamate receptor

2. A skilled person would be familiar with the large homogeneity d mGluR2 and mGluR3, which is why some of the agonists of the stereotaxic ingredient, mGluR2, have been activated as the stereotonic rectifiers of mGluR3. That is the case, for example, d-acid (-) - (4, RI c, 5 c, 15 6 c) -4-amytho-2-dicyclochlorodylase [1.3 0] -hexane-6,4 cryoxylation (known)

Also with 404,039-CAS 635318-11-5] ΙΥ]), with Ki (inhibitory constant) = 149 nm molar (nM) (mGlu2 receptor) and 92 = Kj nano molar (mGlu3 receptor) selective 00'1 the fold of rnGlu2 and mGlu3 at 7a, _6, mG, u4a-, and 8a_, and inactive at mGlula and Rorick-Kehn et al. (2007) The Journal of Pharmacology and) mGlu5a20 308-317. Experimental Therapeutics Vol. 321, No 1, pp). So it is

The term mGluR2 suspenders or AM agonists are mGluR2 risers, or a positive asymptotic axis is a suspicion of 5-L ^ / mGlur2 a stereotaxic ingredient of mGluR2 that does not exclude suspiciously does not expose some other secondary secondary activity in the laboratory or in vivo.

25 The selection of mGluR2 PAM suspenders is precisely the combination of the invention that was disclosed in WB2010 / 130424. A specific subgroup can be defined

Wk

43291Α1

19

Of the aforementioned pathogens that are disclosed in the global invention part No. No.

W02010 / 130424 through the following summer (I)

<img file="MA43291A1_D0009.tif" />

Or Zeer form Vzgih of it, as that

5 R is chosen from the group consisting of (7_3 cycloalkyl) 3_etylalkyl-, mono - or poly (antagonist) halo alkyl, and (Ch alkyl) -0- (4Calkyl);

R is halo or poly halo 4 to 0kyl;

A is covalent bonding or-C-;

L is chosen from the roots (b), (a) and (: (C

<img file="MA43291A1_D0010.tif" />

whereas .

R³³ Choose from non-replaceable vinyl, or replaceable vinyl D1 or 2 from the Halo alternatives;r4 is chosen from the hydrogen group, 3_Cjalkyl and halo; or that RCR represents the root together of the summer (1-a)

<img file="MA43291A1_D0011.tif" />

Where R is hydrogen or halo;

r3 is chosen from the phenyl group substituting D1 or 2 from the Halo alternatives, pyridinyl replacing the D1 or 2 from the Halo alternatives, the non-replaceable pyrimidynil and the pyramidinil replacing the D1 or 2 alternatives to the 3C alkyl oxy;

20 Or pharmaceutically acceptable salt or melt from it.

Mk

43291Α1

Consequently, according to a specific embodiment of the invention, the positive GPC for the type 2 mutant glutamate receptor modulator (mGLuR2) is a desirable summer (I) as defined here.

In a specific embodiment, the summer ideologies (I) are defined as here

whereas

Ri is chosen from the group composed of propyl Miguel cyclo-, 2; 2; 2 for trichlorethyl, and

-coc;

R² Is chloro or CF3;

A is covalent bonding or - ^ GH—;

L is chosen from the roots (b), (a) and (: (C

<img file="MA43291A1_D0012.tif" />

Ν '

<img file="MA43291A1_D0013.tif" />

whereas

R is chosen from a non-substituted vinyl or a substituted vinyl 1 or 2 from fluoro alternatives; r4 is chosen from a group of hydrogen, methyl and fluoro;

Or that R^3a-CR^4a They represent a root of summer (1-a)

<img file="MA43291A1_D0014.tif" />

(3-1)

Where is R5^a Is hydrogen or fluoro;

r3 is chosen from the phenyl group substituting D1 or 2 'of the fluoro substitutes, pyridinyl substituting the D1 or 2 fluoro substitutes, the non-replaceable pyrimidynil and the pyrimidyl substituting the D1 or 2. of the alternatives to methoxy;

MA

43291Α1

Or a pharmaceutically acceptable salt or a solution.

In a specific embodiment, the summer ideologies (I) are as defined herein

(i) When A is? CH; R is TRF; then Ri is the cyclo-propyl -; and

I picks who

<img file="MA43291A1_D0015.tif" />

C-a.,

(!!!) When A is covalent bonding; R is trifluoro Miguel; then Ri is cyclopropyl methyl; and

I picks who

(La); (lb); (lc);

(il) When A is CH; and R02 is chloro

R¹ He is a cyclamenoprilyl -; and

Oh

Zam,

0

Mk

43291Α1

<img file="MA43291A1_D0016.tif" />

M00

9-i) or (9-1);

IV) When A is a covalent bond and R is an E, then

(iv— a) Ri is propyl cyclic methyl and L is

<img file="MA43291A1_D0017.tif" />

La) F);

or

(7ab) Ri is 2.2.2 trifluorimethyl and L is chosen from

<img file="MA43291A1_D0018.tif" />

<img file="MA43291A1_D0019.tif" />

<img file="MA43291A1_D0020.tif" />

(A-a); and

(V) When A is CH and R1 is CH2-O-CH3 - then R2 is 3 CF - and I is

\ ١٩

Dora ....

H

Zsimie- (A 230, (3aa, 3α

(Li);

Or pharmaceutically acceptable salt or melt from it.

Mk

43291Α1

23

The summer jewels (I) are detected in WB2010 / 130424 and can be prepared according to the process described here, which has been incorporated as a whole mantle.

5 Includes specific nuns from summer (I)

<td>0 The aphid bud 2; or a hydrochloride salt thereof (HCI) (compound No. 2A)</td><td>Propeller REM 1, or a hydrochloride salt thereof (compound A)</td>

<td>CFa 0 y 0 Nudity No. 4</td><td>CF3 Mother F Al-Marri No. 3</td>

<td>CF3 Sinfulness of monk number 6; or of hydrochloride salt thereof (compound No. 6a)</td><td>Hey. Nudity No. 5</td>

<td>Coming; &lt;- &lt;) Nudity No. 8</td><td>Free of charge Al-Marri No. 7</td>

Mk

43291Α1

<td>F-CK} 0 Awful support 10</td><td>M0 M1 Complex number 9</td>

<td>Complex number 12</td><td>Your stump Complex number 11</td>

<td>Skj 'h Resegue- (No 3, 3aa, 3α) Awesome despite 14</td><td>CFs 9 dunums Complex number 13</td>

In one embodiment of the required, the compound, the summer (I) is

<img file="MA43291A1_D0021.tif" />

Compound number A, or a pharmaceutically acceptable salt thereof, is preferably a hydrochloride salt thereof.

5 In an additional embodiment of the invention, the compound of summer (I) is

<img file="MA43291A1_D0022.tif" />

Compound No. 2, or a pharmaceutically acceptable salt thereof, is preferably HCI.

The mGluR2 PAM relaxants are specifically selected from the combination of the invention from those disclosed in the GNR WO2009 / 033704 publication. The aforementioned relaxants 10 that are exposed in the global patent publication W02009 / 033704 can be identified by summer (-1

A) The following

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43291Α1

<img file="MA43291A1_D0023.tif" />

R (Ι-Α)

And chemical forms of riri 'from the stereoisomer of it, where that

R is alkyl alkylate; or 3-C1 alkyl substituted in the 7-C3 cycloalkyl, phenyl or vinyl substituted with HALO, trichloro-amylase or tetrahydro methoxy;

5 R is halo, a tetrahydrofluoride, 3_Cialkyl or cyclopropyl;

R is hydrogen, fluoro, hydroxyl, hydroxy 3A0kyl, hydroxy 3A0kyloxy, zero 3A0kyl, fluoro 3A0kyl oxy or cyato; and

En is a non-substituted vinyl; or a root-substituted vinyl η which is r4, where η is 1, 2 or 3;

R is selected from the group consisting of hydrogen, halo, 3A 0kyl, hydroxy 3A0kyl, 10 poly halo3_A0kyl, cyano, hydroxyl, amino, carboxyl, 3A 0kylkyl oxy 3_Ag alkyl, 3A 0kyl oxy, 3kA , Mono and titer (3-1 h. Alkyl) ametho, and moonyl; or

Two adjacent R4 roots taken from a double valence root from summer

(N = CH-NH- (i_,

15th (CH = CH-NH- (ii_, or

jti-OCC-NH- (iii

r3 and the root of R4 in a straight position are taken together from the mezzi root. C par of summer

(CH2-0- (iv-; or

(0-CH2- (V-)

20 And pharmaceutically acceptable salts and cyclists.

In a specific embodiment, the summer nuns are (Ι-Α) as defined here

whereas

MA

43291Α1

R. is 6_kyl alkyl; or 3_a 0 alkyl substituted D7b03 cycloalkyl, phenyl or vinyl substituted with HALO, trifluoro-methyl or tetrafluoroethoxy;

R is halo, trifluoro-methyl, 3_0alkyl or cycloidal speed;

R is hydrogen, fluoro, hydroxyl, hydroxy 3A 0kyl, hydroxy 3A0kyl5Oxy, fluoro 3A0kyl, fluoro 3A0kyl oxy or cyato; and

En is a non-substituted vinyl; or a root-substituted vinyl η which is r4, where η is 1, 2 or 3;

R4 is selected from the group consisting of hydrogen, halo, 3_Cj alkyl, hydroxy 3_Cj alkyl, poly-halo 3-C alkyl, cyato, hydroxyl, amino, creoxyl, 3_Cj alkyl oxy 3_Galkyl, 3_A 0 alkyl oxy, poly-halo 3_A0A C alkyl carbonyl, mono and 10 E. D technology (3-alkyl) ametho, and moleil; or

Two adjacent R4 roots taken together from a double-valence root of the summer (NCH-NH- (i-, CH = CH-NH_ (ii-; or-O-CH2-CH2-NH- (iii-)

15th And pharmaceutically acceptable salts and oprates from it.

In a specific embodiment, the summer nuns are (Ι-Α) as defined here

whereas

R is 6_a 0 alkyl; or 3_ [C alkyl substituted with 7-C3 cycloalkyl, phenyl or vinyl substituted with HALO, trifluoroethyl or trifluoroethoxy;

20 R² It is halo, trifluoroethyl, 3-Cj alkyl or cyclopropyl;

R is hydrogen, fluoro, hydroxyl, hydroxy 3-C alkyl, hydroxy 3_A 0 alkyl oxy, fluoro 3A 0 alkyl, fluoro 3g alkyl oxy or cyano; and

En is a non-replaceable vinyl;

The pharmaceutically acceptable salts and placentas thereof.

25

In an additional embodiment, the summer relaxants are (--1) as defined here

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43291Α1

27

whereas

Ri is abiotyl, 2-methyl-1brl, 3-methyl-abiotyl, (metallic propyl) methyl or 2 (metallic propyl) -3-ethyl;

R is hydrogen, fluoro or cyato; and

5 En is a non-replaceable vinyl;

The pharmaceutically acceptable salts and solvents thereof.

In an additional embodiment, the summation desires (Ι-Α) are defined as these

whereas

10 Ri is apiotyl, 3-MSL-1 butyl, (cyclopropyl) methyl or 2- (condensate beryl) -a-ESL;

R is chloro;

R³ It is hydrogen ofluoro; and

En is a non-replaceable vinyl;

And pharmaceutically acceptable salts and solvents thereof.

15

In an additional embodiment, the summer desires are Ι-Α as defined here

whereas

R is 0_6-alkyl; or-Cg alkyl substituted with C37 cycloalkyl, phenyl or vinyl substituted with HALO, triflu-methyl or triflu-methoxy;

20 R2 is halo, trifluoro-methyl, 3_a 0kyl or cyclopropyl;

R is hydrogen, fluoro, hydroxyl, hydroxy 3 C alkyl, hydroxy 3 C alkyl oxy, fluoro 3 alkyl, fluoro 3_0 alkyl oxy or cyano; and

Ar is a substituted vinyl with the roots with which is r4, where η is 1, 2 or 3;

R is selected from the group consisting of halo, 3_a 0kyl, hydroxy o 0kyl, 3-C1kyl

25 Oxy, poly-halo 3_a 0kyl oxy, 3_a 0kyl carbonyl, mono - and ammonary (3-alkyl) ametho, and morulinyl; or

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43291Α1

Two adjacent R roots are taken from the double valence of the root of the summer

(N-CH-NH- (i-,

(CH = CH-NH- (ii_, or

(OCC-NH- (iii-; or

R and R the root in a straight position are taken together from a double valence root from the summer

(CHO- (iv-; or

(7) -0-CH2-;

And pharmaceutically acceptable salts and cyclists.

In an additional embodiment, the summer suspensors (Ι-Α) are defined here

whereas

Ri is apiotyl, 2-methyl-appropyl, 3-methyl-abiotyl, (cyclic barbell) Miguel or 2 (cyclopril) -a-ethyl;

<img file="MA43291A1_D0024.tif" />

<img file="MA43291A1_D0025.tif" />

En hovinil is substituted with halo, trifluoro migil, morbolite or hydroxy 3_Cj alkyl; pharmaceutically acceptable salts and solvents thereof.

In an additional embodiment, the summer suspensors are (Ι-Α) as defined herein

Ri is abiotyl, 3-mes-a-butyl, (cyclopropyl) amel or 2- (cyclopril) -a-ethyl;

R² Is chlorine;

R³ Hydrogen or fluoro; and

En is vinyl substituted by at least one halo group; and it is pharmaceutically acceptable salts and dispensers thereof.

In an additional embodiment, the summer suspensors are (Ι-Α) as defined herein

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43291Α1

29

Ri is abiotyl, 3-paralyzed-abiotyl, (cyclo-loop) paralyzed or 2- (cyclopropyl) - 1-isl; R is chloro;

R³ Is hydrogen or fluoro; and

En is vinyl substituted by at least two fluoro groups;

5 The pharmaceutically acceptable salts and solvents thereof

The summer compounds (Ι-Α) are as disclosed in global patent publication RWM W02009 / 033704 and can be prepared according to the processes described here, which are incorporated accordingly as a whole reference.

10 Includes summer selections (Ι-Α)

<img file="MA43291A1_D0026.tif" />

Mk

43291Α1

<td>0 Limit The terrible Raem 21-a</td><td>The Righteousness of The terrible Raam 4a</td>

<td>αρύ OH The terrible Raem 22-A</td><td>0 "Dagd 'b' m 0 Complex number 5-A</td>

<td>\ R1 this tool 0 ορύ The terrible Raem 23-A.</td><td>0 The Righteousness of Ν Complex number 6-A</td>

<td>D-1L1A0 tearful From Shout No. 24-A</td><td>0 CI1581A Trait F Complex No. 7-A</td>

<td>Ο 1 Sam 71 A0 Thordank From Shout No. 25-A</td><td>1 h Al-Murwab No. 8-A</td>

Mk

43291Α1

<td>Ει b g; Mayda Ο</td><td>7.2 Kh 0</td>

<td>; B b 20 a For no Ο</td><td>6--21 Ma Freezing 0 or 1 1 p. 11 0</td>

<td>E-combining 21 what 0 Csegk 0 Al Makkam 1 SAR 0</td><td>E-8 h oam &lt;Ala Hahnam 77^NÇ (, 5</td>

<td>; -01 b * 5 ^ 1 are 0 788</td><td>A-7, appeared HO 0 about 1</td>

<td>-6 'blak' Mmm Imagine him</td><td>; -9Ζ leads 21 Ma Glow</td>

τε

Wk

43291Α1

<img file="MA43291A1_D0027.tif" />

And pharmaceutically acceptable salts and cyclists.

Mk

43291Α1

In one embodiment of the invention, the awe of the summer (Ι-Α) is

or

<img file="MA43291A1_D0028.tif" />

Complex No. 25-A

<img file="MA43291A1_D0029.tif" />

Complex number 2-a

A pharmaceutically acceptable pharmacy, or a parent.

The desirability of mGluR2 PAM is also chosen from the synthesis of the invention, specifically from which it was adsorbed in the European stage of invention despite PCT / EP2O14 / O68676. The aforementioned desires listed in the European patent section No. PCT / EP2O14 / O68676 can be identified by

The next summer (Ι-Β)

<img file="MA43291A1_D0030.tif" />

(Ι-Β)

And irrigation forms from the chemical point of view, from that

R1 would be chosen from the group consisting of 6_a 0alkyl, (0.03 annular alkyl) 3 cj alkyl, and (3_a alkyl oxy) 3-9 alkyl;

Each R is independently selected from c_3, Cl, Falkyl, 3_Cj alkyloxy, mono or 15 poly-halo 3-C alkyl, and mono or poly-halo 3-1 ter alkyl oxy;

η is an integer selected from 1, 2, and 3; pharmaceutically acceptable salts and their replacements.

MA

43291Α1

MGluR2 PAMs are selected from the combination of the inventions specifically from the summer (B-!) Triggers, as defined previously, and the incomparable emerald forms of them, where! R we choose from the group consisting of? CH3CH2CH2, CHjCH, (cyclic propyl) amelic, (butyl annular) ) Muscle, amyl oxymethyl and amyl oxymethyl; the rest of the variables are as they are packaged here; pharmaceutically acceptable salts 5 and their solvents.

In another embodiment, the mGIR PAM selectors are selected from the synthesis of the invention by specifying a of the summer passed-Β pat pat pat as defined previously, and the auxiliary zygotic forms from them, where Ri is chosen from the group consisting of? CCH, (cyclic propyl) Miguel,) Cyclic bertil (MSA) and methyl oxy-10 methyl; the rest of the enzymes are as they are packaged here; and for pharmaceutically acceptable salts and their solubility.

In an additional embodiment, the mG! UR2 PAM selectors are selected from the synthesis of the invention and specifically from the summer EE pat pat as are as defined earlier, and for the spatial forms of Zubeiria, since Ri is chosen from the group consisting of? CCH, (cyclic POP) fun (Butyl cyclohexyl) amelor and acyl-oxy-methyl; the rest of the enzymes are as described herein; and for pharmaceutically acceptable salts and the 15 solubles thereof.

Thus, according to a specific embodiment of the required, the positive allergic axis (PAM) of a type 2 metabolism glutamate receptor (mGluR2) is a summer or hub as defined here.

20

In an additional embodiment, the summer nuns are (Ι-Β) as defined here,

Saluting that

Each R2 is independently selected from CHO, CH, Cl, F, and? CF; and for pharmaceutically acceptable salts and their solubility.

25

In an additional embodiment, the summer ideologies (Ι-Β) as defined herein possess the summer (Ι-Ba)

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43291Α1

<img file="MA43291A1_D0031.tif" />

(Ι-Ba)

Where the variables are as set in the summer (1-Β) here, and pharmaceutically acceptable salts and the solvents thereof.

5 In an additional embodiment, the summer mirrors (1-Β) as defined herein possess the summer (Ι-Bb)

<img file="MA43291A1_D0032.tif" />

Where the variables are as specified in the summer (Ι-Β) here, the acceptable salts are poured 0 ligna and the solvents thereof.

Summer Ghee Garment Ghee (da-Β)

10 3- (Basil of paralyzing paralysis) -7- [A- (4-polypotoxy) ethyl] -8- (trichloro-paralyzed) [4,2,1] tri-azulo- [3,4-shs];

3- (Basil of paralyzing paralysis) -7 - [(a * jj۶là-4) -l- (R Phyxoxy) Idil] -8- (trifluid paralyzed) [4,2,1] tri azulo [3,4-9 Pyridine

3- (Propyl cycloid) -7- [(1 * c) -1- (4-dia fodoxy) Ishl] -8- (trifluoro-15 paralyzed) [4,2,1] cyanobactyl azulo- [3,4-9 Pyridine

3- (propyl paralytic immobilization) -7- [(1c) -1- (4,2 phyto-phytooxy) ethyl] -8- (trifluorinated parasite) [4,2,1] tri-azulo [3,4-shs;

3- (Propyl paralytic immobilization) -7- [(1m-A- (4,2-dichloro-fethoxy) ESHL] -8- (tetrahydroform) [4,2,1] tetrazolu [3,4-9yeridine] ;

20 3- (propyl paralyzed) -7- [1- (4,2-fluorovoxi) ethyl] -8- (tri-chloro-paralyzed) [4,2,1] tri-azulo [3,4-haredin;

Wk

43291Α1

36

3- (propyl amniotic propylate) -7 - [(51) -1- (5.3 fluoroxidoxy) ethyl] _8- (trifluoro-amelase) [4,2,1] tri azulo [3,4-9] Q ;

3- (Immunomodulatory Propyl) -7- [(1c) -1- (4,3-fluorofluoxy) ethyl] -8- (triflu-methyl) [4,2,1] tetra-azulo [3,4-3] Pyridine;

5 3- (cyclamenyl amylase) -7- [(1c) -1- (3,2-Fluorodifroxic) ESL] -8- (Tri-Fluoryl Mile) [4,2,1] Tri Azulo [3,4-pearl] Pyridine;

3- (cyclopropyl alcohol) -7- [(A3) -a- (5,2-diethyl ether) ethyl] -8- (triflu-methyl) [4,2,1] tri-azolo [3,4-e] Pyridine;

3— ((propyl cyclohexylase) -7- [(Ah) -1- (6,2-t-fluorotoxin) ethyl--8- (J-Rui

10 Amla) [4,2,1] Tri Azulo [3,4-e] pyridine;

3- (Propyl Miguel cycloid) -7 - [(A8) -1- (4-fluoroc-2-methoxy-phytooxy) ethyl] -8- (trifluoro-miil) [4,2,1] tri-azulo (3,4-hargarden ;

3- (Butyl methyl cyclic) -7 - [(1h) -a- (4,2-dichloro-fethoxy) ethyl] -8- (triflu-methyl) [4,2,1] tri azulo [3,4 - H] pyridine;

15th 7 - [(1h) -a- (2-chloro-4-phytoxyethyl) ethyl -3- (propyl miguel layer) -8- (trifluoro)

Methyl) [4,2,1] tri azulo [3,4-3] pyridine;

3- (Propyl methyl cyclohexide) -7 - [(A3) -a- (4CHMO-2-Miguel fethoxy) ESL] -8- (Tri-Fludo-Muscle) [4,2,1] thalasso azulo [3,4-3 ]s;

3- (C-propyl methyl) -8- (triflu-methyl) -7- [(1c) -1- (6,4,2-trifluorocarbon)

20 Fiodoxyl] [4,2,1] thalati aru [3,4-3] PS;

7 - [- (4,2 fludo phytooxy) ethyl] -3- (ethoxy methyl) -8- (triflu-methyl) [4,2,1] tris azolo [3,4-c] belene;

3-ethyl-8- (tri-methyl methyl) -7- [a- (6,4,2 tri-phosphorous) ethyl] [4,2,1] tris-azulo [3,4-3yeridine;

25 7- [1- (4,2-Fae Shamo Faidoxy) Ishl] -3-Ethyl-8- (Triflu-methyl) [4,2,1] Tri

Azulo [3,4-9yearidine];

MA

43291Α1

37

3- (Butyl methyl cyclic) -7- [(1 * M-A- (4,2-dichloro-fethoxy) ethyl] -8- (triflu-methyl) [4,2,1] tri-azulo [3,4 -3] PS;

3- (Butyl-cyclo-amelase) -7 - [(A * 3) -a- (4,2 F Fluoroxy Fluorescence) ESL] -8- (TriFluorethyl) [4,2,1] tri-azulo [3,4 - Haredin;

5 3- (Ethoxy methyl) -8- (triflu-methyl) -7 - [(^) - 1- (6,4,2-trifluoride)

Phytooxy (ichl] [4,2,1] tri-azulo [3,4-9] pyridine;

3- (Ethoxy leisurely) -8- (triflu-methyl) -7- ((A0C) -1- (6,4,2-trifluoride)

Phytooxy (ichl] [4,2,1] tri-azulo [3,4-9] pyridine;

7 - [(1AJ) -1- (4,2 fluorohexi) ethyl] -3- (Eoxymethyl) -8- (trifluoro

10 Paralyzed) [4,2,1] trio [3,4,9] pyridine;

7 - [(1 * M-1- (4,2-dichloro-fethoxy) ethyl] -3- (ethoxy methyl) -8- (trifluoro-methyl) [4,2,1 to tetrazolu [3,4-9] Pyridine;

7 - [(1 * M-1- (4.2 Fluoro-phthaxic) ethyl] -3-Ethyl-8- (TriFluudo

Methyl) [4,2,1] triazolu [3,4-h] pyridine;

15th 7 _ [((A * 3) -a- (4,2 FF) ethyl] -3-ethyl-8- (trifluoro)

Methyl) [4,2,1] triazolu [3,4-9] pyridine;

7- [1- (4,2-fluorofluoxyxin) ethyl] -3-propyl-8- (triflu-methyl) [4,2,1] Azulos fridge [3-4-3yeridine]

3-Ethyl-8- (TriFluo 6,4,2) -l- (R * l)] - 7-Jjjj05 DtF (Ethyl)] -

20 [4,2,1] Tri azulo [3,4-e] pyridine;

3-Ethyl-8- (Triathlorofluoride) -7 - [(A * 5) -1- (6,4,2-Tri-Fluorodoxy) Ethyl] [4,2,1] Tri-Azulo [3,4-9] Pyridine;

7 - [(1 * P-1-(4.2 Fluoro-phytooxy) ichl] -3 berbel-8- (triflu-methyl) [4,2,1] tri-azulo [3,4-9] pyridine; and

25 7 - [(a * h) -1- (4,2 F fluoroxyx) Ischl] -3-propyl_8- (tetrafluoro miguel) -

[4,2,1] Tri azulo [3,4-e] pyridine.

Mk

43291Α1

38

Included within the scope of this list are stereo zipper forms, pharmaceutically acceptable salts and their solubles.

In an additional embodiment, the desirable may be chosen from a 3-hydrochloride salt (cyclopropyl methyl) -7-

5 [(51) -a- (4,2-Dietifluoroethoxic) Ischl] -8-) Triflu-methyl) [4,2,1] Tri

Azolo [3,4-3] pyridine.

The agonist inhalers of the stereotaxic ingredient includes d mGluR2 / 3 / mGluR2 from the synthesis of the invention, but is not available, for example, on LY-4O4O39; 2969822-ΙΥ; 2934747-ΙΥ; -ΙΥ 379268; DCGIV; 354740-ΙΥ; 314582-ΙΥ; 544344 -ΙΥ; -LY

10 2140023; 181837-ΙΥ; 389795-ίΥ; 446433-ΙΥ; 450477-ΙΥ; -LY

395756; 566332-ΙΥ; LY-54185O; 2300559-ΙΥ; 404040-ΙΥ; -7 |

281223; 2979165-ΙΥ; talaglumetad; MGS008; MGS0022; MGS0028; MGS0039; (-) - 2-oxa-4-cyclohexane [0.1.3] hexane-6,4 myrium creoxylate; (*) - 4-ametho_2-selgodil Cyclohexane [1.3 0] hexane-6,4-diacic acid

15th Cryoxile; (a) -2-amyldo-4-cycloFluorine- [1.3 00] hexane-6,2-diacryvic acid; 2 — S6, S5, R2, S1^-Amino ^—6^-Floro 4^-Cyclooxane- [0.103] hexane-

6.2-Dicrocoxylic Acid; 2 — S6, S5, S4, R2, S1-Amydo-6Fluoro-4-Hydroxy Duplex Stratum - [1.3 0] hexane-6,2-dicroxylic acid; S3, R2, Sl; S5; 2-S6 amino -3 cyclodipod-fluoride - [0.1.3] hexane-6,2 — dicrocoxylic acid; 20 2 ^ S6, S5, S3, R2, sl ^ amyldo ^ 6-fluoro ^ 3 ^ cyclohydroxy- [0.1.3] hexane-

6,2-Dicaroxylic Acid; (+) - 4-amytho-2-sulfogyl cyclohexane [[0.1.3] hexane-

6,4-aqueous acid creoxy; (0) -2-amyldo-4 cyclofluorine- [1.3 0] hexane-6,2 dicarboxylic acid; 2 — S6, S5, R2, S1— amino-6 fluoro-4-double oxo annular-

[1.3 0] Hexane — 6,2 — Dicarboxylic Acid; 2 - S6, S5, S4, R2, S1-Amylo-6Fluoro-25 4-Hydroxy-Duplex- [03 1 00] Hexane-6,2-Dic acid Creoxile;

2 ^ S6, S5, R3, R2, Sl ^ Ametho-3-cyclo-fluoride - [0.103] hexane-6,2-dic acid

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43291Α1

Cryoxyl; or 1g, 2a, 5,53 c, 6h-2-amydotho-6-fluoro-3-hydroxy dichloride 0.1.3] hexane-6,2-disoxylic acid.

We include a specific group of agonists 379268 — mGluR2 IY; DCG-IV; -IY

5 354740; 404039-ΙΥ; 2969822-1; 2934747-ΙΥ; 544344-ΙΥ -17

2140023.

A stereotaxic antagonist is also selected for its metabolic glutametase factor from Shit 2 from the sequence of the invention and specifically from those disclosed in the Global Invention patent number 10 W01997 / 18199 and W02003 / 104217, listed here in its entirety. Which specific vehicles

Exposed here are (-) - (4, RI c, 4- (S6, S5 amytho-2-cyclic double sulfonyl [0.1.3] - hexane-6,4 — dicarboxylic acid (also known as Z404039-LY)

<img file="MA43291A1_D0033.tif" />

Or salt or melt from it, and (4, RI c, 5 c, 2- (S2) l} 4 (S6 — amino-4— (methylthio) —Oxu

15th Butyl] Ametho] -2-cyclohexane [0.1.3] hexane-6,4-dicarboxylic acid 2,2-dioxide (also known as [7-55-lY-2140023 [CAS635318)

<img file="MA43291A1_D0034.tif" />

Or salt or dissolved from it, for example monohydrate from it.

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The names of the compounds of the present invention have been created according to the rules for the designation verified by the Chemical Abbreviation (CAS) using the modern chemical development greedy tower (ACD / product name version 10.01.14105, 1st December 2006). In the case of the Sunnite forms, the Sunnite depiction of the structure was generated. However it must be clear that the other colored unpainted chairs pearl form is also included on the side of the present invention.

From the group of a saturated, straight, or branched hydrocarbon root group possessing 1 to 3 or 1 to 4 or 1 to 6 zoned Creons, such as amylase, mule, abruel, 1-MSM, butyl, 1-methyl propyl, 2-MSL-A2-propyl, 11— Shayl methyl ethyl, 3-MSL-1 butyl, aptenyl, 1 hexyl and the like.

Sharaf Al Ghurair 7-C3 annular alkyl or ` 8_3 " annular alkyl as a group or ablative of the header-crane root group; a saturated cycloid, possessing 3 to 7 or 3 to 8 crystallized sions, such as cyclic propyl, cyclobionyl, cyclopentyl, cyclohexyl , Cycloheptyl, and cyclohectyl.

We refer to the hare or halogen tuber as it is later used as a group or group from group to fluoro, chloro, bromo or yodo, with preference of fluoro or chloro.

Al-Zubayr would refer to 'mono - and poly-halo3_alkyl or mono-poly poly-halo4_alkyl' to 3_kyl or 4_0kyl respectively, as defined previously, replacing 1, 2, 3, or wherever possible, sowing more of the halo as previously played.

When the term “substitute” is used in the present invention, it means, unless otherwise indicated or clear from the context, indicating that one or more units of hydrogen atoms have been replaced, preferably from 1 to 3 hydrogen peroxide, and more preferably from 1 to 2 hydrogen atoms, and more

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Prefer 1 hydrogen atom over the atom or root referred to in the convention that uses a substitution of Bakhnyar from the group referred to, provided that the natural equivalence is not exceeded, and that the substitution leads to a chemically stable desirable, that is, a compound strong enough to survive the insulation to a restricted degree of purity by a mixture Interaction, switching to a therapeutic agent.

As used later, unless otherwise indicated, the terminology will use a therapeutic agent and greening the AED interchangeably with the term anticonvulsant, and as used later, denotes a factor capable of treating, mediating or preventing seizure activity or accretion when the agent is given a condition Banking or patient.

As used later, unless otherwise indicated, the term gene will use a 2Α synaptic vesicle routine to abbreviate the SV2A gene interchangeably. Examples include however

Not limited to, the desires included in the British patent portfolio of GB1,039,113; GBl.O39.692; 61262036; 801806339; global patent publication W02001 / 062726; the US patent despite

US2OO2 / O94787; Hunchtur World Group with numbers W02004 / 087658; W02005 / 12182; W02005 / 05418; W02006 / 128692; W0206 / 128693; W02007 / 065595; W02008 / 132139 and W02008 / 132142;

W02011 / 047860; W02012 / 143116 and W02012 / 143117. We include appropriate specific examples of SV2A, but we are not limited to levetiracetam, pregasetam and selesteretam.

For this, in the embodiment of the invention, the SV2A gene is selected from Legitz esetam, pregacetam

In a specific embodiment, the SV2A gene is ligetricetam.

In a specific embodiment, the SV2A gene is pregacetam.

MA

43291Α1

Processes for preparing previous SV2A genes are known from printed materials and are described as exemplified in European patent 1 1 806 339 EP; in EP 0 0 162 0 036 and in the British patent 2 225 225 322 (Levinacetam); in the Global Bulletin publication No. WO 01/62726 (pregasetam ); In 2005/121082 WO (Celesterecetam), 5 of these processes were included as a whole for reference.

In an additional embodiment, the combination according to the invention includes (a) the SV2A gene selected from levetreecetam or pregasetam; and (b)

<img file="MA43291A1_D0035.tif" />

10 Or a pharmaceutically acceptable salt thereof, preferably a hydrochloride salt thereof, or a soluble salt thereof.

In an additional embodiment, the pharmacokinetics according to the required comprise (a) a pharmaceutically effective amount of levetzetam or pravacetam; and (b) a pharmaceutically effective amount of

<img file="MA43291A1_D0036.tif" />

15th Or a pharmaceutically acceptable salt thereof, preferably a hydrochloride salt thereof, or a soluble salt thereof.

In an additional embodiment, the composition according to the required comprises (!) A pharmaceutically effective amount of levetzetam or pregazetam; and (b) a pharmacokinetic active amount of

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43291Α1

<img file="MA43291A1_D0037.tif" />

Fishy No. 2-a

Or a pharmaceutically acceptable salt thereof, preferably a hydrochloride salt thereof, or a soluble salt thereof.

In an additional embodiment, the pharmaceutical composition according to the invention is administered on (a) a pharmaceutically effective amount of litersetam or brigazetam; and (b) a pharmaceutically effective amount of

<img file="MA43291A1_D0038.tif" />

<img file="MA43291A1_D0039.tif" />

Fishy No. 2-a

Or a pharmaceutically acceptable salt thereof, or a melt from it.

In an additional embodiment, the synthesis according to the invention comprises (a) a pharmaceutically effective amount of liginetacetam or pregasetam; and (b) a pharmaceutically effective amount

<img file="MA43291A1_D0040.tif" />

<img file="MA43291A1_D0041.tif" />

Fishy F No. 25 — a or pharmaceutically acceptable salt thereof, or dissolved from it.

In an additional embodiment, the pharmacokinetics according to the invention comprise (a) a pharmaceutically effective amount of levinacetam or pregasetam; and (b) a pharmaceutically effective amount of

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43291Α1

<img file="MA43291A1_D0042.tif" />

Or a pharmaceutically acceptable salt thereof, or a melt from it.

In an additional embodiment, the synthesis according to the invention comprises (a) a pharmaceutically effective amount of levetiracetam

Or bregarecetam; and (b) a pharmaceutically effective amount of

<img file="MA43291A1_D0043.tif" />

Shout No. 26B

Or a pharmaceutically acceptable salt thereof, or a melt from it.

In an additional embodiment, the pharmacokinetics according to the required comprise (a) a pharmaceutically effective amount of

<img file="MA43291A1_D0044.tif" />

Or a pharmaceutically acceptable salt thereof, or dissolved from it.

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43291Α1

In an additional embodiment, the composition according to the invention comprises (a) a pharmaceutically effective amount of litersetam or brigazetam; and (b) a pharmaceutically effective amount of 404039-ΙΥ or a pharmaceutically acceptable salt thereof, in particular, a hydrochloride salt thereof, or dissolved thereof.

5 In an additional embodiment, the pharmaceutical composition according to the mixture includes (a) a pharmaceutically effective amount of levetiracetam or brigazetam; and (b) a pharmaceutically effective amount of LY-4O4O39 or a pharmaceutically acceptable salt thereof, in particular, a hydrochloride salt thereof, or a soluble salt thereof.

In an additional embodiment, the synthesis according to the invention comprises (a) a pharmaceutically effective amount of levetiracetam 10 or pregasetam; and (b) a pharmaceutically effective amount of LY-214OO23 or a pharmaceutically acceptable salt thereof, in particular monosaccharides thereof, or dissolved from it.

In an additional embodiment, the pharmacokinetic composition according to the invention comprises (a) a pharmaceutically effective amount of levetiracetam or pravacetam; and (b) a pharmaceutically effective amount of LY-214OO23 or an acceptable salt 15 pharmacists or soluble thereof, specifically monohydrate.

The combination product of the present invention, in particular, the chemical composition according to the invention, is particularly suitable for treating epilepsy and for related disorders. Sikin is appreciated for containing mGluR2 relaxants, specifically astringent compounds / 8,171 m mGluR2 from p, and additional pharmaceutically acceptable 20 additional salts, solvents from them and one or more centers of irrigated asymmetry and present as VAGs.

The term is intended to include the compounds of the invention as used later, PAM mG! UR2 sprays, specifically summer sprays (Ι) / (Ι-Α) / (Ι-Β) and mGluR2 agonists as disclosed 25 later, and for salts and solubles thereof.

MA

43291Α1

46

As used herein, i.e. a chemical summer with the strings shown only as continuous lines and not as strings of interchangeable interchangeable or interchangeable interchangeable, or otherwise indicated by having a specific body (e.g., R, S) around one or more of the agglomerates, the retention of each vertebra, or A mixture of two hypogenic or hypersensine zebra

5

Later on and later, the terms are intended to include the mGluR2 terrain and the synthesis of the riser / PAM mGluR2 space-zyberant denotes, both of them and of the synthetic ones. Above and later terms Zero-Zero Zero, Zero Zero Zero or Zipper Zipper forms are used interchangeably in chemical terms. The invention includes all the azoospermic aperitifs of the inventions of the invention either as a pure 10-temporal zubir or as a mixture of two or more vacuum zipers. Irrigated irrigators are the stereoisomership that is

Irrigated images not overlapping to each other. A 1: 1 mixture of a pair of irrigated sulfur is a rosemate or a mixture of Zsyme. Dredges (or hiccups) are streptococcus 'irreversible' that are not irrigated; that is, they are not attached as irrigated images. If the terrain contains double armpits, the alternatives may be in an E or Z fitting. Alternatives to the monovalent (spherical) annular valentine roots can have either a coupled fitting 15 (-cis) or a groove (-trans); for example if the aperture contains On the double-cycloalkyl group, substitutions may be coupled or submerged. Consequently, Al-Akharana includes irrigated rirates, separated rirates, alkalis, ZB-asphalt, see-zamirat2, coupled sulfur, prosper spree Zuber, applications,, and U, and mixtures thereof, when possible chemical. The meanings of all of these terms, i.e. irrigated buffers, differential reirs, helios, ezubirat E, Rbizat 2, sulfur of 20 coupled, liqueur reir, and false errors are known to the skillful person. Ultimate styling is set according to a system

Cahn-lngold-Prelog. Airing at a non-specific atomizing atom, either D R or S. Dissolved buffers can be labeled with an unknown current (+) or (-) depending on the direction in which a plane polarized light is rotating. For example, dissolved irrigated sulfur with an ultimate irritation that is not known can be denoted d (+) or (-) depending on the direction in which the polarized light is diverted.

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When a specific hysterosclerosis is known, this means that the auxiliary zeri zyr is essentially free, that is, it is associated with less than 50%, preferably less than 20%, more preferably less than 10%, and even more selectively less than 5%, specifically less than 2% , And the maximum preference is less than 1%, of the other zeir. Thus, when a compound identifies mG0uR2 as n (R), this means that the preceptor is essentially (Z) 5 zer (S); when the mG! UR2 compound identifies as E, this means that the preceptor is essentially) of

Zaira; when the mGluR2 compound identifies an example as a podcast, this means that the filter is chelating) intrinsically from the zuhr zuhr.

We may also have some mGluR2 additives in their sunny form. These shapes we are in, 10 although not explicitly indicated in the previous summer, are intended to be included in

Aspect of the present invention. What proves that a flashing compound can exist in both its Zair and Zionist forms.

For use in the medicine, we limit the relaxants' salts of this invention and to pharmaceutically acceptable salts other than 15 toxic (salts from the promoter of the present invention where the antagonist ion is pharmaceutically acceptable). anyway

In any case, other salts may be useful in preparing or selecting compounds according to this extract or their pharmaceutically acceptable salts, and may include acids and bases not included in the framework of the present invention.

20 It is intended to include additional salts of acid and an acceptable basis for beans, as indicated above and later, forms of supplemental salt of acid and non-toxic, therapeutically effective basis for which the relaxants of the invention are able to be transferred. The pharmaceutically acceptable salts suitable for evaporators include additional acid salts which may, for example, induce freshness of a solution from the precursor with a pharmaceutically acceptable solution of acid, for example, inorganic acids such as halogens,

25 Such as hydrochloric acid, hydrobromic acid, sulfuric acids, meteorites, gosphoric acids and the like; or organic acids, for example, acetic acids, propanoic,

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Hydrogen cystic acid, lactic, peric acid, oxalic (i.e., anaediotic), malonic, succinic (i.e., butanedoic acid), malic, guaric, malic, tartaric, citric, methane sulfonic, ethane sulfonic, benzene sulfonic, P-toluene sulfonic, Cycladic, salicylic, P-amino salicylic, pamoyk and the like. On the other hand, the forms of the mentioned salt can be reversed by treating them with a basis of 5 appropriate to the base-free form. Likewise, when deception agents have an acidic sign, the pharmaceutically acceptable salts may include appropriate organic and inorganic foundations. Appropriate forms of base salt include, for example, ammonium salts, alkaline minerals and alkaline minerals, such as salts of sodium, sodium, potassium, magnesium, calcium and similar salts with organic foundations, i.e. aliphatic amines, primary, aromatic, secondary, tertiary, methyl amine, ethyl 10 Amine, propyl amine, ino propyl ad, four pomers of butyl amine, diene-minyl amine, Eduardo-isel amine, di-ethianol amino, di-propyl amine, Faei-air propyl amine, 'di-21 for butyl amine, pyrolidine, piperidine, Morpholine, triple amine amine, triple amyl amine, trippropylamine, quinoclidine, pyridine, quinoline, ware quinoline; benzurene, a / l-methyl-e-glucad, head-acid salts, and for salts with amino acids K, for example, arginine, lysine, etc. 15 similar. Alternatively, the salt profile can be reversed by acid treatment to the acid-free form.

The term solubility includes the additional forms of the solvent as well as the salts thereof, from which the desired (I) is desired. Examples of these additional forms of solvent are, such as aids, alcohols and the like.

In general, CoA-Β summer triggers can be prepared according to the invention in a sequence of steps, each of which is known to a skilled person. Specifically, the triggers can be prepared according to the following synthesis steps: Summer Ι-G desiurants can be synthesized in the form of seismic mixtures of spinners, which can

25 Separate them from each other by following the known separations from the field. The summer diaphragms (Pat-Β) can be converted into lobule forms of salt conducive to interaction with a zero acid.

I

43291Α1

The irrigated symmetry is appropriate. Subsequently, we then separate the salubricoate forms of salt, with selective or fractional crystals, and the irrigated irrigations are released from them with an alkali metal medium. An alternative method is used to separate the irrigated irrigated forms of summer bet (Ι-Β) irrigators by asphalting liquid or liquid into the ultra-critical phase (SFX) using a fixed asymmetric irrigated phase. Also 5 can be derived from these Zubair forms from the chemical Alzaghri from the shapes Alzebir are the pure Alzogh chemical side corresponding to the appropriate starting source, with the start that the reaction occurs in a foggy fluid.

a. Prepare the summer nuns (Ι-Β)

10 The final nuns can be prepared according to the summer (Ι-Β), with a median monster from the summer (II) with a monster from the summer (III) according to the interaction scheme (1), an reactor carried out on the classic Mitsunobu terms. It is preferable that the reaction be carried out with gosphine and ester azo-dioxin or amide in tetrahydrofen, 4,1-dioxane, diethyl ether, toluene, two wells, dichloromethane or mixtures thereof, at 30 - to 150 ° C, under thermal heating or Radiate

15th Classroom waves. The often used phosphines are Triphenyl Phosphine, Tri-Butyl Phosphine and Typhilene Typically with Dimethyl Azo-Carboxylate, Dimethyl Azo-Dichroxylate, D-Iserropyl Rdoxylate, D-(4-Chlorobenzyl) Azo-Droxylathyl, D-Benzyl Azo-Croxadite !, Diph-tert-butyl-azo-dicarboxylate, azo-di-acid

- double acids- (dimethyl elamide), dipipyridide, azo-dimethoxylic acid, or 20-dimorulide, azo-dimoxylic acid, in the reaction diagram (1), all the ligands are isolated as in summer (B— A).

Interactivity Diagram (1)

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<img file="MA43291A1_D0045.tif" />

Schematic chart 1

<img file="MA43291A1_D0046.tif" />

<img file="MA43291A1_D0047.tif" />

B0 Preparation of intermediate nests

News Part 2

5 Intermediate brides can be prepared according to summer (II) by exposing a medium from guest (IV) to known conditions for those skilled in the art. This is shown in the interaction diagram (2), where all the instruments are played, as indicated above. The methods of exploding these sobs are well known to those skilled in the art. Treatment of aldehyde from summer (IV) with a metallic organic substance such as lithium miguel or methyl magnesium bromide gives a compound of summer (II). A suitable solvent for this reaction is an ether such as a tetrahedron 10-head-phonate - the reaction usually at a guilt between -78 ° C and 40 ° C.

In the Naqil chart (2), all the variables are defined as in summers (Ι-Β).

Interactivity Diagram (2)

<td></td><td></td><td>Action Diagram 2</td><td></td><td></td>

<td>.</td><td>N — N Mutter w</td><td>HgX</td><td rowspan="2">'F No 102</td><td>Ν-Ν H</td>

<td></td><td></td><td></td><td></td>

<td>H</td><td>(IV)</td><td></td><td></td><td>(II)</td>

News Part 3

15th Intermediate broths can be prepared according to summer (IV) with an intermediate reaction of summer (V) under the terms of the B-wastewater and oxidation fission and for information of those skilled in the field and can be achieved, for example, with oxon, orium oxide. The process can be divided into a newsletter within a solvent such as 4,1 oxan, water and usually at a guideline temperature between about -100 ° C and about 100 ° C. A summary of such a method can be found at

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Comprehensive Organic transformations, VCH publishers, (1998),

RClarock, ΡΡ595-596.

This is shown in the interaction diagram (3), where all the deficiencies are known as they were referred to.

Conveyor planner (3)

Interaction diagram?

<img file="MA43291A1_D0048.tif" />

<img file="MA43291A1_D0049.tif" />

<img file="MA43291A1_D0050.tif" />

Optional part 4

Intermediate regards can be prepared according to summer (V) conducting reactions, such as yours, Stille or

Suzuki is a middleman of summer (VI) with a desirable one of summer (VII) under known conditions for those skilled in the art. The process can optionally be separated into a solvent, such as a 4.1-edible Okan, water

10 Usually, at a grade of grade between about 20T and about 200 ° C, there is a base. This is shown in the interaction diagram (4), where all the variables are played, as previously mentioned, where M is the keletepin, boronic acid or boron ester, and the palladium zallaloe

It is Chloro, Promo or Yudo.

Interactivity Diagram (4)

<img file="MA43291A1_D0051.tif" />

<img file="MA43291A1_D0052.tif" />

<img file="MA43291A1_D0053.tif" />

Interaction diagram. 4B (VII)

Palladium catalyst

<img file="MA43291A1_D0054.tif" />

Test part 5

The desirable products can be prepared according to the summer (VI), by following the known parts in the field

In a syringe of a wanted medium from summer (VIII) with a halogenated agent, for example, oxy

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(P0CI3) phosphorous (V) chloride in an appropriate solvent, for example, dichloroethane, stirred under zero-wave fracture, for an appropriate period of zine that allows the reaction to be completed, e.g. 5 minutes at a groove between 140 - 200 ° C, In the interaction diagram (5), you know!! R as in summer (Ι-Β) and for Halu it is Clolo, Promo or Yudo.

Interactivity Diagram (5)

E. Interaction diagram

FF

N — N

Pupil

<img file="MA43291A1_D0055.tif" />

(VI)

52R '

<img file="MA43291A1_D0056.tif" />

Optional part 6

Intermediate nests can be prepared according to summer (VIII) with the known steps from the field by the reaction of the heidazine medium from summer (IX) with acid halides of summer (X). The reaction may be carried out using an inert solvent, n, for example DCM, with the presence of the k base, for example, triethylamine, for example rt, for an appropriate period of lead allowing the reaction to be completed, for example 20 minutes. In the reaction diagram (6), Ri is played as in summer (Ι-Β). Interactivity Diagram (6)

Interaction diagram 6

<img file="MA43291A1_D0057.tif" />

D

<img file="MA43291A1_D0058.tif" />

Test Part 7

IX can be prepared according to summer (IX) by means of an intermediate transfer of summer (XI) with head ze according to the reaction scheme (7), and the reaction carried out within a suitable inert solvent of the reaction, k, on

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Irradiate the waves

70 ° C for 16 hours. in a

For example, ethanol, THF or 4.1 dioxide under N conditions, for example, heating the reaction mixture for example at 160 ° C sub-zero for 30 minutes or conventional fractional heating at reaction pattern (7), halo is chloro, Promo or Yudo.

Plan to 1 to match (7)

Interaction chart 7

<img file="MA43291A1_D0059.tif" />

<img file="MA43291A1_D0060.tif" />

<img file="MA43291A1_D0061.tif" />

Optional part 8

The intermediate extra terrestrial preparations according to the summer (XI) can be prepared by an intermediate reaction of the summer (XII) with benzyl alcohol according to the reaction scheme (8), a reaction that takes place within a suitable inert solvent solvent, n, on

10 For example, ^ methylation of methyl foramide with a suitable basis, n, for example sodium hydrate with a degree of groove of rt, for an appropriate period of butter allowing completion of the reaction, k, for example 1 hour. In the reaction scheme (8), halo is chloro, bromo or yudo.

Interactivity Diagram (8)

Interaction chart 8

<img file="MA43291A1_D0062.tif" />

<img file="MA43291A1_D0063.tif" />

15th Test part 9

Intermediate horrors can be prepared according to summer (XII), with an intermediate reactant from summer (XIII), with a suitable trichloromethyl reaction factor, such as, for example, the ester methyl acetofluorosulfonyl (diFluor), according to the reaction scheme (9). This reaction is carried out within a suitable inert solvent of the reaction, 4, for example, Ν, Ν-dimethyl formamide in the presence of a joining agent

MA

43291Α1

Suitable n, for example, copper (I) iodide, under fractional conditions n, for example, heating the reaction product for example at 160 ° C under irradiation with zero waves for 45 minutes. In the vein diagram (9), halo is Claudo, Promo or Yudo

Interactivity Diagram (9)

Interaction chart 9

<img file="MA43291A1_D0064.tif" />

(XI) (XII)

Starting mode according to formulas (X), (VII), (II) or (XIII) are either commercially available triggers or they can be prepared according to the traditional reaction parts generally known to those skilled in the art.

As used later, the term 'teryah' may also include a product that includes ingredients that are specified in the specified quantities, in addition to any product that results directly or indirectly, from combinations of 10 ingredients specified in the specified quantities.

As used later, the term pathological condition refers to a animal, preferably a mammal, the most preferable human being to a more severe, child or infant, who is or has been the subject of treatment, the pest or test.

15

The term means a therapeutically effective amount, as it is used later, that amount of the active compound or pharmaceutical agent, in which we stimulate the biological or inferior response in a tissue system, an animal or a human being, and sought by a researcher. A veterinarian, health doctor, or other clinical laboratory, which includes alleviating one or more symptoms of the patient or disorder under treatment, and / or reducing the 20 or more severe of one or more symptoms of the disease under treatment.

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55

The combination of compounds (a) for the SV2A gene and (b) positive narcotic narcotic (PAM) syringes for type 2 mutant glutamerica (mGluR2) or pharmaceutically acceptable or dissolved salt from it, or stereotaxic agonal agonists of type 2-containing glutamate receptor or pharmaceutically acceptable salt Or dissolve the yin, only the compounds (a) and (b) were given together, separately or in charge, to be 5 useful compared to the effect of desires (a) and (b) taken alone. Specifically, there can be at least a beneficial and beneficial effect, such as a mutual improvement of the effect of ingredients A and B, more than additional effect, specifically an auxiliary effect, additional beneficial effects, including, for example, a significantly reduced effective dose for a combination (A) and (b); an additional therapeutic effect not observed for either (a) and (b) alone, constituting a more beneficial side effect, or a combination therapeutic effect in an ineffective dose of one 10 or both (a) and ( B)·

As defined (herein 'fixed dose ratio d (a) clamp vesicle protein 2Α indicates (b) desirable from summer (I) is from 1: 1, calculated on the ED values₅0 For songbirds (a) and (b) to a composition comprising a (b) and (b) desires with a fraction corresponding to 50% of the special dose of 5555 for single (a) and (b) odors, or a multiple of this constant dose ratio. The term refers to a fixed dose ratio of 15 (a) for a gene Brunin vesicle 2Α: (b) a compound of summer (I) of 1: 3, calculated on

EDso values for ocher A and B to a composition comprising (B) desirable from summer (I) at a dose corresponding to 75% of the approved ED55 dose and desirable (A) at a approval dose of 25% of the ED50 dose approved by desirable (A) ) Or a multiple of this constant dose ratio, and so on.

20 Thus, in another embodiment of the invention, (a) the SV2A gene and (b) the desirable summer (I) are present in the pharmaceutical implantation with a fixed dose ratio (A): (b) about 10: 1 for about 1:10, preferably about 5 : 1 for Hawalli 1: 5, and more favored around me 3: 1 for about 1: 3, in another embodiment of about 1: 1 for about 1: 3; in an alternate embodiment of those around me 3: 1; and also in another embodiment of 1: 1; An embodiment of 1: 3, where the fixed dose ratio is calculated on the EDso values of the stimuli (a) 25 and (b).

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Since the present invention is directed to lekin an adjunctive or combination therapy, it involves giving (a) a bronine gene to a synthetic vesicle (SV2A) 2; A); and (b) a agonist inhalers compound / mGluR2 PAM, specifically frightened from the summer (1) / (Ι-Β) / (Ι-Α) As indicated later, as the pharmaceutically or therapeutically effective amount will mean that the combination of the factors taken together so that the recombinant effect provokes the terrifying biological or pharmacological response. For example, the quantity will be

Therapeutically effective adjuvant therapy involving administration of (a) the SV2A gene as subsequently promoted, and (b) the Agonist inhalers promoter / mGluR2 PAM in particular the intruder from the summer (Ι “Β) / (Ι” Α) / (Ι) as defined later , The quantity of (a) of the SV2A gene as later comforted and the amount of (b) agonist inhalers stirrer / mG! UR2 PAM, specifically the stirrup of the summer (1) / (1-Β) / (Ι-Α) which at 10 take them together Or, therefore, they have a therapeutically effective combined effect. Also, the owner will appreciate

The skill in the field is that in the case of adjuvant therapy with a therapeutically effective amount, as in the example above, the amount of the agitator / mGluR2 PAM, in particular the intimidation of the summer (Ι-Β) / (1-Α) / (Ι), and / Or an amount of individually appropriate appropriate SV2A ligament is therapeutically effective.

15th The present invention provides methods of protection or treatment that include the need for satisfactory condition, a stimulated treatment with a therapeutically effective amount of the SV2A gene and a therapeutically effective amount of a promoted agitator / mG! UR2 PAM, specifically an adjective of the summer (Ι) / (Ι-Α) / (Ι-Β), as described here. To this end, the nests or flakes of this invention must be used in the correct therapeutically effective quantity or dose, as described below.

20

The given doses and the best appointments may be determined easily by those in the field, and will vary according to the specific skill used, method of administration, strength of preparation, method of administration, and progression of the disease. Additionally, factors associated with the specific patient being treated, which include patient's age, weight, diet and timing of administration, will lead to a need for 25 dose adjustments.

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The skilled person in the field will realize that the therapeutically effective dose for current biopsies may include repeated doses within a long-term treatment regimen which will produce clinically important results.

Quantities of agitating agonist inhalers may vary / mGluR2 PAM, determining the patient's summer (C-A) / (8 -!) / (A),

5 In the combination of invention given on a daily basis from about 0,01 to about 2000 mg. Examples of daily quantities for the summer compound are (1,0, 0,5, 0,1, 0,05, 0,01, (Ι) / (Ι-Α) / (Ι-Β, 2,5, 5,0, 10.0, 15,0, 25,0, 50,0,100, 150, 200, 250, 300, 400, 500, 750 and 1000 mg for accidental amplitude modification of the patient being treated. It is normally warm at a dose level of around 0,01

10 Mg / kg to about 150.0 mg / kg of body weight per day or any extent of that. Preferably, the range from about 0.1 to about 100.0 mg / kg of body weight each day, and more preferably, from about 0.5 mg / kg to about 50 mg / kg, more preferably From around 1.0 to around of 25.0 mg / kg of body weight every day. Broths may be given as 1, 2 '3 or 4 times each day. Quantities for the S72A gene may vary

15th Given on a daily basis from about 0.01 to about 7000 mg, it would be preferably between 250 and 5000 mg and would be more preferably between 500 and 3000 mg. Examples of the daily amount of Lignin are 5,0, 2,5 S72A, 150, 100, 50,0, 25,0, 15,0, 10,0, 200, 250, 500, 750, 1000, 1500 and 3000 grams In order to accidentally adjust the dose of the patient being treated. An effective amount of warmth is normally supplied in a level

20 A jar of about 0.01 mg / kg to about 150.0 mg / kg of body weight per day or any extent of that. More preferably, the range is from about 0.1 to about 100.0 mg / kg of body weight each day, preferably more, from around 0.5 mg / kg to about 50 mg / kg, preferably More, from about 1.0 to about 25.0 mg / kg of body weight each day. Broths may be given as 1, 2, 3 or 4 adsorbed every day. All quantities are indicated

25 Referred to in this clause and to the following clauses in free form (that is, unsalted form). The above values represent free-form equivalents, i.e. as if free-form amounts will be given. As for if it is given.

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Salts, the quantities will need to be calculated in the function of the average molecular weight between the salt and the free form.

The above daily doses were calculated as an average body weight of about 70 kg and should

Recalculate it in the event of medical applications on children, or when used with two physically skewed patients 5

Doses may be represented in units of one, two, three or more secondary doses or more, which will be given as appropriate indentations during the day. The dose used preferably corresponds to the daily intake of Merck—, agonist inhalers / mGluR2 PAM, the determination of the summer compound (Ι) / (Ι — Α) / (Ι-Β), or from lignin

10 SV2A, referred to above, or a secondary dose of it, such as 1/2, 1/3, 1/4 of it. The dosage form may contain a compound, astringent / mGluR2 PAM, compound dilution (Ι) / (Ι-Α) / (Ι-Β), or the SV2A gene, or both together, in an equal amount to the range or amounts in the preceding items, for example a form may contain Inventory 10 Tg, 25 Tg, 50 Tg, 100 Tg, 150 Tg, or 200 Tg of a stalking vehicle / mGluR2 PAM, select from vehicle (C -!) / (8-A) / (A), 10 tg, 25 Tg , 50 TG,

15th 100 Tg, or 250 Tg, from the SV2A Ligine, either as separate formulas or embedded labels. In one

The embodiments, the cryogenic aphid are given / mGluR2 PAM, specifying the summer hypogene-Ι) / (1-Α) / (Ι

(B) Daily pass (.qd), determined as a unit dose per day, and the SV2A gene is given once or twice a day (.qd or .bid), specifically as a unit dose or two doses per day. In the example where both relaxers are given once a day, this is achieved by giving two separate doses, a unit with 20 agonists / mGluR2 PAM, determining the summer compound (Ι) / (ΙΑ) / (Ι-Β), and a unit with two ligines

SV2A, or by administering a combined dose containing a riser compound / mGluR2 PAM, specifically the summer compound (Ι) / (Ι-Α) / (Ι-Β), and the SV2A committee.

The combinations of the invention may be given one, two, three, four times, or if required, multiple times 25 per day. In one embodiment, the combination is given once a day. In another embodiment, it is given

The mixture is twice daily, or three times a day. Dosage may be given in forms

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A separate dose, that is, the dosage forms contain only a agonist inhalers agonist inhalers / mGluR2 PAM, the specification of the summer agonist inhalers (Ι) / (Ι-Α) / (Ι -, A), or the SV2A gene only; or by combined dose forms under the agonist inhalers compound ingredients / mG! uR2 PAM is active, specifically the summer compound -1) / (1) / (Ι-Α (B), and the SV2A gene. Likewise, a mixture of using the combined dose form and 5 separate dose forms may be used. Following, oral dosage forms, preferably tablet or capsules.

The active ingredients in pharmaceutical fluffs may be formulated either separately or as a combined pharmaceutical composition. In the last example, a pharmaceutical inducement was provided that paralyzes a therapeutically effective amount of 10 agonist inhalers desires / mGluR2 PAM, a selection from the desirable summer (Ι) / (1-Α) / (Ι-Β), or a pharmaceutically acceptable salt thereof, and the SV2A gene The above shall be allocated here, and a pharmaceutically acceptable pregnant woman.

On the other hand, this invention relates to a pharmaceutical induction preparation process, as specified herein, which involves performing aliquotous images by mixing a pharmaceutically acceptable holder with a therapeutically effective amount of 15 aspirants / mGluR2 PAM, determined from the desirable summer (1) / (Ι - Α) / (Ι-Β), or a pharmaceutically acceptable soluble or dissolved salt thereof, and a therapeutically effective amount of at least one SV2A gene.

The combinations provided herein may also be formulated in a combined preparation for simultaneous, separate or consecutive use in the prevention or treatment of epilepsy and related disorders; neuropathic pain 20; migraine or resistant headache; bipolar disorder and related disorders; in protecting nerves; Or in the prevention of epilepsy. In the case of this case, a precarious modulator / mG! UR2 PAM, specifically the desirable summer (Ι) / (Ι-Α) / (Ι-Β), is formulated in a pharmaceutical composition containing other pharmaceutically acceptable excipients, and the SV2A gene is formulated separately in A pharmaceutical composition that contains other pharmaceutically acceptable Diabetes. Conveniently, these 25 separate pharmaceutical microvilliations can enable traction from multiple use simultaneously, separately, or successively.

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Individual components of the present invention may be given simultaneously or separately at different times during the course of the treatment or in singular or segmented form simultaneously.

Accordingly, the agitators of the agonist inhalers are formulated / mGluR2 PAM, specifically the summer triggers -1) / (1).

5 (Α) / (Ι-Β), and the SV2A ligne, in loquat or combined form, in a variety of convenient pharmaceutical fluffs

For purposes of administration. In this, a therapeutically effective amount of the intended benefactor, or of both desires, is combined with a pharmaceutically acceptable holder, which may thicken forms of broadened variety depending on the form of preparation required for administration. Pharmaceutical ingredients may be prepared as drugs to be administered orally, by injection (including subcutaneous (.SC), intramuscular (.im), in 10 intravenous (.iv)), orally, transcutaneously, buccally. From through the nose. Pharmaceutical villi may be prepared to be given directly into the nervous system by pathways that include, but are not limited to, inside the brain, inside the two sides, ventricle, inside my brain, inside my heart, inside of the hernia, inside the medulla and / or spinal berry pathway by delivering PO Needle cough, intracranial, or vertebrae and / or tubes with or without infusion. The appropriate 15 desirabilities for oral administration include powder, granules, pellets, pods, coated or pressed pills, sugar coated pills, perfumed sachets, hard or gel capsules, drinking and suspensions. Appropriate triggers for parenteral administration include aqueous or aqueous solutions or emulsions, while appropriate promotions for oral administration include suppositories with a water-soluble or hydrophilic solution. Suitable transdermal delivery systems may be used for local administration and 20 perineal delivery systems suitable for nasal delivery.

For example, in preparing the intended carcasses for administration by the cloud, any of the usual pharmaceutical means may be employed such as, for example, water, glycol, oils, alcohol and the like in the case of liquid oral carcasses not suspensions, drinking, elixirs, orthoses and Solutions; or solid carriers such as starch, sugars, caustic, lubricants, casings, dissociation agents and the like in case of solid 25 coma. As far As the injection fluff is concerned, the carrier usually includes sterile water, with at least a large section, but it is possible to add other ingredients to it, such as solvents, emulsions or aids.

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Additional. Injectable solutions can be prepared in which the carrier contains brine, glucose solution or a mixture of both. Injectable suspensions can also be prepared in which suitable liquid holders, suspensions and the like can be employed. It also includes solid form preparations that are to be converted, shortly before use, into liquid form preparations such as powder for 5 remodeling. In intimidation appropriate for intradermal administration, the carrier optionally includes a fold-enabling enzyme and / or a benzyl agent, combined with an optional human-compatible supplement in secondary proportions. A mesophilic aphid / mGIR P AM, in particular, the summer hub (Ι) / (1-Α) / (1-Β), or SV2A gene, or combinations thereof, may also be given by inhalation or oral blowing by formulas appropriate to this pattern From administration such as solution, suspension or dry powder. The pharmaceutical intimidation 10 is appropriate for administering in the form of a fog or I airbrush, for example, terrible suspensions

6jj ^ tU / mGluR2 PAM, specifying the summer terrain (Ι) / (Ι-Α) / (Ι-Β), or 11 resonant 2A / 9-T or both, in a pharmaceutically acceptable liquid carrier, such as ethanol or water, or a mixture thereof . If necessary, the summer can also additionally contain other pharmaceutical aids such as surfactants, emulsifiers, methylates along with a propellant. Such preparation usually contains the active monk 15 in agitation from approximately 0.1 to 50%, limiting from about 0.3 to 3% by weight.

Pharmaceutical intake may contain the active ingredient the extra terrestrial ^^ mGluR2 PAM, specifically the summer fright (Ι) / (1-Α) / (1-Β), or the SV2A gene, or both merge into a preparation from about 0.1% to about 50% , Or about 1% to around 30 huh, or about 3% to around 20%, or about 20% 5 to around 20%; all percentages are formed by the two balloons, where the sum of all

Ingredients 00% in said pharmaceutical intimidation. In combinations that contain both terriers, freaks are ^^^^ mG! UR2 PAM, specifically the formula terrors (G-a) / (8-a) / (a), and the SV2A gene, a riser aperture / mG! UR2 PAM, specifically terrors of the Formula (H-A) / (8 -!) / (A), is present in a concentration of around 0.1% to about 50 AH / H, or about 1% to around 30%; or about 3% 25 to around 20. %, Or about 5% to about 20%; wikin for the SV2A gene, is present in concentration

From about 3% to about 50 AH / H, or around 5% to around 50 AH / H, or about 0% to

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About 50%, or around 100% to about 040 / h, or about 10% to about 30%, as the total of all components 00% does not trade in the said pharmaceuticals.

Pharmaceutical irregularities may be conveniently present in the form of a single dose for ease of administration 5 and uniformity of dose. Examples include tablets (including edited or coated tablets), capsules, pills,

Suppositories, powder packs, wafers, injectable solutions or suspensions and the like, and multiple insulators. Solid dosage forms for most important oral administration such as tablets or capsules.

Solid dosage forms of a single dose form may be packaged in any known rice, 10-bubble packages are preferred, specifically, for the tablet and capsuldaf. Where a washed garage is constructed / 8,171 m mGluR2,

Specifically, the summer garage (Ι) / (Ι-Α) / (Ι-Β), and the SV2A gene separately, can be resinued into separate bubbles, but also a single bubble may include unit dose forms of the ^^^ mGluR2 PAM garage, specify The summer garage (Ι) / (Ι-Α) / (Ι-Β), and the SV2A panel, for example with a single row the row with units of the garage ^ = ^ \ mGluR2 ΡΑΙ, specifically the garage of 15 summer (Ι) / (Ι “Α - ” Α ) / (Ι-Β), and it is another row with the S72A Lujain. You may also have other possibilities.

Nullivates of this invention can be used to treat or prevent epilepsy and related disorders; neuropathic pain; migraine or resistant headache; bipolar disorder and related disorders; or it can be used as a neuroprotective or as a prophylaxis. Who is epilepsy?

20

As it has been used here, the term treatment increases to refer to all operations, where it may be slowing, intercepting, restraining or stopping the presentation of the litter or alleviating symptoms, but not necessarily indicating complete disposal of all symptoms.

25 As it is used here, unless it is observed differently, the term epilepsy and related disorders or epilepsy or a disorder related to it means any disorder where the pathological condition is (on

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Towards the preference of an adult person, child or infant) in which one or more seizures and / or tremors are reported. Suitable examples include, but are not limited to, epilepsy (including, but not limited to, postural epilepsy, generalized epilepsy, generalized and localized epilepsy, and the like), running start seizures with or without generalization, muscle tonic seizures, seizures Initial generalized quadruple tensonism specifically in 5 patients of generalized idiopathic epilepsy, nuclei accompanied by Linux gastro syndrome, nuclei as complications of a disease or condition (such as fits associated with cerebral encephalopathy, phenylketonuria, Juvenil Goucher's disease, Lundberg epilepsy, advanced muscle tension, vascular injury, Head injury, carbonation changed, Use and discontinuation of the drug, use and discontinuance of alcohol, lack of sleep, fever, inflammation, and the like), epilepsy (convulsive or non-convulsive) idiopathic or parasympathetic tremors 10 fidgeting of blink, and the like preferably, the disorder of epilepsy is chosen (exchangeably) Regardless of the pattern, the priority of the cause or origin) complete tremor or stuttering fidgeting the blink. More preferably, the disorder is epilepsy (regardless of pattern, priority to cause or origin) or idiopathic tremor. A specific example of refractory epilepsy is also referred to as treatment or treatment of resistant epilepsy. This term is often used when patients fail with three anti-epilepsy drugs 15 (or AEDs) (jd). Also, refractory epilepsy, refractory running epilepsy, and generalized refractory epilepsy

(Includes idiopathic or episodic).

As used herein, the term neuropathic pain includes pain that results from chronic or debilitating conditions or disorders. It includes conditions or chronic or debilitating disturbances that can lead to neuropathy, but not limited to d, severe peripheral diabetic neuropathy, neuralgia neuralgia, trigeminal neuralgia, post-thrombotic pain, pain associated with multiple sclerosis, pain Associated with neuropathy such as idiopathic neuropathy after trauma and mono-neuritis, pain associated with HIV neuropathy, concomitant neuropathic pain, pain with neuropathy of the tunnel, pain associated with spinal cord injury 25, concomitant complicated local pain, accompanying neuralgia Fibromyalgia, lumbar and cervical pain, dystrophy

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Reflex homogeneity, placebo flare-up and pain sequences associated with the flexible and other weak conditions.

As used here, the term sister should mean flexible, frail, and frail clinical conditions

5 That is diagnosed with a median of mean presence to act on palpitations pain from the side and a term ending between 4 and 72 h, which includes sister without EN and sister with the AR. As used herein, a sister without a prognosis should mean at least five attacks that meet the following criterion: (a) A head pain attack lasts 4_72 hours with a head pain characterized by at least two of the following features: unilateral positioning, how to pulsate, moderate intensity or Severe, with a direct impact on daily activities, stacks of 10 streptococcus episodes and similar approaches are observed: (b) It occurs during the headache and at least one of the following: nausea and / or vomiting, light rap and sound of the rap. As has been used here, a sister with at least two attacks accompanied by D3 of at least 4 should have the following symptoms: (a) a fully reversible ALA the symptom or one or more: (b) at least one ALA symptom that gradually develops more than Show four or two minutes or more that occur sequentially; (c) No shame of the 15th that lasts more than 60 minutes; (d) The pain of the previous head occurs, at a time unified with or the following next to, with a free separation between the first pain and pain less than around me 60 minutes.

As used here, the term bipolar and related disorder must include bipolar disorder I (e.g., manger mania kin, almost new light mania keel, almost 20 new mania keel, reported new keel keel, reporter dismal new keel and new unspecified is listed at the keel Approx.), Bipolar Disorder 11, Fun Circulatory Disorder and Bipolar Disorder Not Specified in Other As These Terms are Defined by the Diagnostic Standard, in Diagnostic and Statistical Manual of Mentak Disorders 4^th Edition, Text Revision, American Psychiatric Association, 200 (DSM-IV25 (TR or at, 5^th Edition, Text Revision, American Psychiatric Association

(TM 5-2013 (DSM).) Preferably, bipolar disorder is characterized by a phase

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Depressive and manic (or slight mania), where the phases successive. Preferably, bipolar disorder is 1 dipole I disorder or 11 dipole disorder. As used here it must include ` mania mania or develop a manic state, regardless of the cause. Implicit. As used herein, the term manic bipolar associated with mania means 5 special or occasional bipolar disorder. Hence, the manic dipole treatment methods of the present invention are direct to the methods that manic mania and / or the manic phase of bipolar disorder. As used herein, the term bipolar depression means its associated depression, special or occasional bipolar disorder. Consequently, the methods for treating bipolar depression of the present invention are direct to the second method treating depression and / or a dismal parasite for the 10 bipolar disorder. As used here, unless observed in other respects the terms rotating or bipolar rotation should refer to the switching of turf between the bleak and obsessive phases of bipolar disorder. Consequently, the empty invention includes methods for fixing the said recycling, including, but not limited to, d, reducing recycling and / or reducing the risk of manic and / or depressing phases.

Thus, in the embodiment, the pharmacokinetic depression of the present invention can be used to treat the condition, in particular 15 to stabilize the case of manic depression.

As used here, the term 'epilepsy formation' refers to the progressive process in which epilepsy develops. This process can occur after brain damage or a number of conditions, including neurotrophic diseases, traumatic brain injury, thrombosis, brain tumor, cerebral nervous system infection, 20 and epileptic status; or it can occur after genetic mutations.

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

As used herein, the term "about" has its traditional meaning. In embodiments, especially, at 25 denoting the numerical value, it can be enlarged to mean the numerical value ± 0%, or ± 5%, or ±

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% 2,% 1, or 0.1%. In other embodiments, the intent is the exact value, which is the mean of omitting the word around me.

D and / or means that each, two, or all components or almaria are a varied list of possible 5 varieties, especially two or more of them in an alternative or combined manner.

Also - it was used here, the term “disguise and definition” and similar terms used in the context of the present invention (especially in the context of the protection elements) must be interpreted as covering both the monkey and the plural unless it is referred to here in other ways or is clearly evident in the context.

10

Examples

The following examples are provided to assist in the invention of the invention, it is not increased and must not be formed to limit any of the methods of the invention presented in the claims that followed thereafter.

A) Summer compounds (Ι-Β) - chemistry and laboratory test

15th Various ways to prepare summer passed. e nuts for this invention are illustrated in the following examples. Unless noticed in other respects, all the initial modules are acquired from commercial equipment and used without additional purification.

Below, means aqueous .aq; a means 2 DCE, dichloroethane, means DCM dichloromethane; DIPE means diisoyeroyl ether; a means N, N-DIPEA-disopropyl ethyl 20 amine; a means N-, N-DMF dimethyl dimethyl furamide; ES means electric response; means' EtN

Triethylamine; means Et₂0 Diethyl ether; a means EtOAc ethyl acetate; a means hourly; HPLC means high performance liquid spindle; HRMS means mass spectrometry / spectrophotometry; means I or I liters; IRMS means mass spectrometry with low dissolution / spectra; meaning MeOH methanol; a means d minutes (minutes); a means (mp) the melting point; 25 means 4 (PPh₃Hypothetical (Pd) (Triphenyl Phosgene) palladium (0); RP means reverse phase;

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.t.2 degrees of emptying groove; tha seconds seconds; sat saturated; SFC means supercritical fluid chromatography; a means .sol solution; THF means tetrahydro-weight.

The Zero-wave auxiliary interactions are performed in a single-mode reactor: Biotage AB (Initiator ™ Sixty EXP), or in a multi-mode reactor: MicraSYNTH 5. (Milestone, Inc.-) labstation

Co-Layer Chromatography (TIC) was performed on MERCK (Silica Gel Sheets 60 F254)

60 Unstrom (Â), mesh - 230-400 (Merck) using standard techniques. Electron flashing column chromatography was performed using a Merck contact loudspeaker cartridge, on gel

10 Irregular silica Sol, particle size 15-40 ومترm (flashing columns available for normal phase) on the SPOT or IAFIAFH system from Armen Instrument.

The absolute monochemical chemotherapy of some germs was determined using VCD. It was measured on a Bruker Equinox 55 equipped with the 37 دD, in a KBr fluid cell using 2 CD CD as a solvent (1350: PEM cm-a, IIA: amol voltage,: precision: 4 cm 1). may be

15th There is a characterization of the use of VCD to clarify an absolute body in Dyatkin Α.Β. et. al. (2002) 14: 215-219, Chirality

Whenever an RS encoding is indicated here, it indicates that the suspicious is a zeemic mixture, unless otherwise indicated. A colloidal chemotherapy body was identified for some of the R or S buffers when the mixture was separated; for some sorbents, a colloidal chemotherapy body 4 R e was identified¹¹ 20 or S *, while the absolute stereochemistry is not specified on the rim, the fish itself is isolated as a single spatial zygron and is pending. A symmetric position surplus of the rose botanicals was determined here by the non-smoking rooms mixture analysis medium by a superfluid chromatography (SFC) followed by a separate irrigated SFC amplifier.

25 Preparation of feedstock

Description 1. The Intermediate Article 1

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<img file="MA43291A1_D0065.tif" />

The cyclo-propyl acetate acid ([7-82-5239 50, [CAS G, 500 mmol]) has been dissolved in

300) CHCIj ml) Then 100 (SOC ml) was added. The reaction mixture was stirred at 60 ° C for 2 h and then the solvent was evaporated to produce intermediate 1 (53 g, ο90 / 5), which was used 5 without further purification.

Description 2 - Intermediate material 2

<img file="MA43291A1_D0066.tif" />

Methyl 2; 2-fluoro-2- (fluoro salgodyl) acetate ([9-15-680 403], the CAS has been added

10 G, 2098 mmol) and 403 (Cul g, 2,13 mol) to a solution of 2,4 dichloro-3 iodo pyridine ((2-36-343781 290 (CAS g, 1058 mmol) at 1.7) DMF l ), Then the tank was heated at 100 ° C for 5 h.

The reaction was cooled and quenched. Filtrate was diluted with 0, removed with EW and rinsed with NHg solution. The organic layer (NA2SO4) was dried, grounded and softened to produce the material

15th Intermediate 2 (160 g), which was used without additional purification.

<img file="MA43291A1_D0067.tif" />

Benzyl alcohol (35 g, 325 mmol) was added to a 60% NaH solution in oil, 24 g,

20 600 mmol (at 2 DMF L) at 0 ° C, then the reaction was stirred for 2 d

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Add intermediate material 2 (160 mg, 741 mmol) in one section, and stir at 0 ° C for 1 h. The reaction was reduced by adding HO and calculating it with 0 ET. The organic layer (NSO4) was dried, filtered and deflated in a vacuum. The residue was purified by column chromatography over silica gel (Rinse: Ether / EtOAc E 1/20). Pure fractions were collected and the oscillator 5 was evaporated to produce intermediate 3 (100 g, 5/38).

Description 4 - Intermediate Article 4

<img file="MA43291A1_D0068.tif" />

Headset ΝΗΝΗ (85% solution in water, 300 g, 9,11 mol) was added to the feedstock solution of 3 (100 g, 277 mmol) in 4, dioxane (1.5 L), then 10 reactions were heated in Locked tube at 160 ° C for 2 h. The mixture was concentrated in the vacuum, thawed

At DCM, rinse it with ^ NaHCO. The organic layer (NSO4) was dried, sliced and loosened in a blanket to produce feedstock 4 (90 g, 90%), which was used without additional purification.

<img file="MA43291A1_D0069.tif" />

15

Triethylamine (64,3 g, 636 mmol) was added to the solution solution. Intermediate 4 (90 g, 318 mmol) at 1,5 (CHC-L), the mixture was cooled at 0 ° C, and then the solution was added Intermediate material 1 (53 g, 449 mmol) in CHC. The solution was moved at the Gaza ID point for 1 h. The reaction mixture was rinsed with a saturated aqueous solution of

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^ NaHCO, stripped with organic layer (NO) dried, drained and concentrated

In the vacuum, the intermediate material 5 (4 (104 g, 5/90)) is obtained.

The following intermediates that follow were synthesized with a similar synthetic sequence as described in Description 5 (D5).

<td>Circumstances</td><td>Acid chloride</td><td>Material material</td>

<td>Additional play at RT</td><td>Clulad Prionel CAS 79-03-]) ([8</td><td>Intermediate Article 6</td>

<td>Conditions as in D5.</td><td>Yonban acetyl cyclic chloride ([CAS 59543-38-3])</td><td>Change it Intermediate Article 7</td>

<td>Conditions as in D5.</td><td>Chloride 2-Eoxylacyl ([CAS 14077-58-8])</td><td>Kit 0 Intermediate Article 8</td>

<td>Conditions as in D5.</td><td>As the master of Butterrill CAS 141-]) ([75-3</td><td>His love Intermediate Article 25</td>

Description 6

(A) Intermediate Article 9

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<img file="MA43291A1_D0070.tif" />

Phosphorous (V) oxy-clopid (84,7 g, 553 mmol) and ^ isopropyl ethyl amino (71,3 g, 553 mmol) were added to intermediate solution 5 (101 g, 277 mmol) in 1, 2) CHCN l). The reaction mixture was stirred at 90 ° C for 38 h. Then 5 the reaction was diluted with DCM and rinsed with AO solution. The organic layer was dried

(ASO4), and its displacement and displacement in the vacuum. The residue was purified by column chromatography over silica gel (eluent: ether petrol / 1/4 = EtOAc). Pure fractions were collected and the solvent was evaporated to produce intermediate habit 9 (31,39 g, 41 h / e).

(B) Intermediate Article 10

<img file="MA43291A1_D0071.tif" />

The reaction was performed in 4 batches and then combined for diagnosis and purification. Ν, Ν-isopropyl ethylamite (3,96 mL, 22,69 mmol) and then phosphorous oxide (2,12 mL, 22,69 mmol) were added to intermediate solution 6 (7 g, 20.6 mmol) Mol) in DCE (50 mL), the reaction mixture was heated in a microwave at 150 ° C for 5 d. Then 15 DCMs were added and the organic layer was rinsed with a saturated solution of NaHCOg d, dehydrated (^ taSO) and slowed in order to give the desired hustle, which was purified by a column chromatography medium (gradient elution: 100% DCM to (% 2 MeOH.NHg in DCM) For the intermediate material 10 (2.5 g, 49%).

The following intermediate modulus synthesized that followed a similar synthesis sequence mentioned in description 6 (a) or 20 (b).

<td>Circumstances</td><td>The primary material</td><td>Intermediate material</td>

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<td>A reaction was performed as in (a) but in CHCN. After the reaction was completed, the reaction mixture was purified in ice water and then rinsed with a saturated NaHO solution and removed with DCM, dried (NSO4), filtered and changed. Purification was performed in a spot (Si cartridge, DCM / EtOAc chamfer until 5-10/520).</td><td>Intermediate Article 7</td><td>Terrified Subject Middleware 11</td>

<td>A reaction was performed as in (b). Purification by means of consulting column and bite (Sdldca; EtOAc at 100/0 DCM to 60/40).</td><td>Intermediate Article 8</td><td>A — 0 FN Razela Intermediate Article 12</td>

<td>A reaction was performed as in (a). Suitable for medium and column consultation (Silica; MeOH in 2A-2A, from 100/0 to 96/4).</td><td>Intermediate material 25</td><td>r Intermediate Article 26</td>

<img file="MA43291A1_D0072.tif" />

2,096) (PhgP ^ Pd g, 1,81 mmol) has been added to the motive solution of the intermediate habit 9 (10 g, 36,28 mmol) and 5,5,4,4-hypothesis paralytic-2-fethel-2, 3.1 Asi-oxo-Born [0-49-75927 7,77, ([CAS ml, 43,53 mmol) in dioxide deoxygenated (30 ml) and NaHO saturated solution (30 ml) under nitrogen.

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73

The mixture is stirred at 100 ° C for 18 h. The mixture is diluted with EOAc water and filtered through a pillow of mycobacterial loaf. The rest was treated with brine and removed with EtOAc. The organic layer was separated, dried (NSO4), dissolved and evaporation of the solvents in the powders ۶. The crude product was purified by column and field chromatography (Silica; EtOAc at 100/0 CHC 5 to 95/5). The desired fraction was added to the vacuum to produce the feedstock 13 (is 6,08).

63%) as a smaller solid body.

The following intermediates are synthesized following a similar synthesis sequence mentioned in Description 7.

<td>Circumstances</td><td>The primary material</td><td>Abusive substance</td>

<td>The reaction was performed at 150 ° C. It is purified by column and chimney chromatography (silica; amine m in methanol at 100/0 DCM to 9/1).</td><td>Intermediate Article 10</td><td>/ Ν-emergency Calm down Intermediate Article 14</td>

<td>Disarm with DCM. Adhered to the column and melange (Silica; MeOH in DCM 96/4).</td><td>Intermediate Article 11</td><td>Clear Intermediate Article 15</td>

<td>Smoke stabilization and column stabilization (silica; EtOAc at DCM 100/0 to 10/90).</td><td>Intermediate Article 12</td><td>7 years old Intermediate Article 16</td>

<td>A mixture reaction was performed at 150 ° C in a microwave. It is filtered by the column stabilizer and smoker (Celica; EtOAc at DCM 100/0 to 10/90).</td><td>Intermediate Article 26</td><td>r Intermediate Habit 27</td>

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Description 8

(A) Intermediate Article 17

Osmium tetroxide was added (2.5% at 10,103 mL-t0-Bu0, 0,781 mmol)

5 Then, sodium periodide 12.53 g, 58.58 mmol) in water (48.5 ml) to intermediate suspension of 13 (is 6,08 g, 20.02 mmol) in dioxane (192 ml). The mixture was whipped at vacuum temperature for 2 h.

The mixture was treated with EtOAc, water and dissolved through a split soil pad. Jerk off with EtOAc. The organic layer is separated, dried (Na Ο4), dissolved and evaporated

10 Solvent in the foam. The raw product was washed with Et O and filtered and dried to produce the feedstock

17 (4,25 g, 79%) as a solid brown body.

(B) Intermediate Article 18

<img file="MA43291A1_D0073.tif" />

A sodium rhodate suspension (5,04 g, 23,54 mmol) in distilled water (19 mL) was added to a 15 solution released aurium tetroxide (2.5% at 4,06, t-BuOH ml, 0,31 mm

Mol) and the intermediate material 14 (2,08 g, 7.85 mmol) in dioxane (75 ml). The mixture was stirred at vacuum temperature for 150 min, and then the mixture was treated with solution

NaHCOg and brine, and remove it with DCM. The organic layer was separated, dried (NSO4), comforted and concentrated in vacuum. The product was crushed with 0 Et and its metal was emptied. The last was placed in 20 desiccants at 50 ° C for 18 h, the intermediate material 18 (1.6 g, 5/80) is produced as a solid is a solid object.

The following intermediate modulus synthesized is followed by a similar synthesis sequence mentioned in Description 8.

<td>Circumstances</td><td>The primary material</td><td>Intermediate Article</td>

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<td>Part as in (a).</td><td>Intermediate Article 15</td><td>And wim Intermediate Article 19</td>

<td>The part as in (a).</td><td>Intermediate Article 16</td><td>Intermediate Article 20</td>

<td>The part as in (a), addition tribute: a tetra oxide was added to the intermediate solution shake of 27 in 4 for dioxide, then a sodium pyridite suspension was added in water and the reaction mixture was whisk for 2 h at a free degree of gass without filtering through Brace incision pillow.</td><td>Intermediate Article 27</td><td>Load —FN 0 Article 28</td>

Description 9

(A) Intermediate material 21a, i.e. and 21c

<img file="MA43291A1_D0074.tif" />

<img file="MA43291A1_D0075.tif" />

<img file="MA43291A1_D0076.tif" />

5 Intermediate Article 21 A Intermediate Article 21 B Intermediate Article 21 C

Methyl Magnesium Bromide (1.4 M at 12,40 mL, THF mL, 17.37 mmol) diameter after another was added to the release suspension of the feedstock 17 (4.25 g, 15.79 mmol) in

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76

281,07 (THF mL) at -20 ° C under 00 ° C₂ The mixture was stirred at -20 ° C for 45 minutes. The ore was treated with saturated solution of NHCI and removed with EtOAc. The organic layer was separated, dried (Na₂SO₄), Nhiziba, nominated in the vacuum. The residue was purified by flashing chromatography (Silica; MeOH at 100/0 DCM to 96/4). 5 The desired refractory materials were collected and prepared to produce the intermediate material 21a (Zsemmic mixture) (2,96 g,

66%. The intermediate material was filtered 21A (1,82 g) with an asymmetric irrigated medium of the SFC: (fixed code: 5) CHIRALPAK ad-η micrometer 250 20χ mm), moving phase: 80% 0₂And, 20% EtOH] produces 21 b (R-irrigated irrigation) (0,453 g, 10%) as a pale radioactive solid and the intermediate material 21 c (c-irrigated irrigation) (0,439 g, )10 / 5).

10 (B) The Intermediate Article 22

<img file="MA43291A1_D0077.tif" />

Methyl Magnesium Bromide (1,4 M at 3,97, THF ml, 5,56 mmol) diameter after another was added to the feed suspension of feedstock 18 (1,23 g, 5,06 mmol) in THF (90 Ml) at -20 ° C under Ν₂. The mixture was stirred at 20 ° C for 15 to 45 min. The ore was treated with saturated solution of NHCI and removed with EtOAc. Layer separated

Organic, dried (Na₂SO₄), Filter it, and move it in the wrong way. The residue was purified by flashing chromatography (Silica; MeOH at 100/0 DCM to 96/4). The desired fraction was collected and concentrated in vacuum. The residue acquired with Eto was then crushed to produce feedstock 22 (620 mg, 35%) as a smaller solid body in Het.

20

The following feedstocks that followed a similar synthetic sequence were described in Description 09

<td>Circumstances</td><td>The material is preliminary</td><td>Intermediate Article</td>

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<td>Alaa (b).</td><td>Intermediate Article 19</td><td>F N-r6M OH Intermediate Habit 23</td>

<td>Procedure B.</td><td>Intermediate Article 20</td><td>/ 150 No. OH Article 24!</td>

<td>Procedure B.</td><td>Intermediate Article 28</td><td>Extended OH Intermediate Article 29</td>

The intermediate material 24A was also separated from the intermediate material 24b and the intermediate material 24c:

<td>r OH The usual habit 24 c</td><td>F OH Intermediate Habit 24b</td>

<td colspan="2">Mirrored asymmetric SFC conditions: Stable phase 5 CHiRALPAK AD-Ηm 250 * 30mm; Mobile phase: 80h / h 0, 15% EtOH</td>

Preparing the final foaming dye (Ι-Β)

Example 1

5 (A) Synthesis of triggers 4-b, 6-b and 5b

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43291Α1

<img file="MA43291A1_D0078.tif" />

<img file="MA43291A1_D0079.tif" />

Trick 5-B Trick 6-B Trick 4-b

2,07 (DIAD mL, 10.52 mmol) (diameter after another) was added to the feedstock solution 21a (2g, 701 mmol), 2.4 psi fluorine (1,00 mL, 10.52 mmol). Triphenylphosphine (2.76 g, 10,52 mmol) at 74,18 THF (ml) was at 0 ° C and under nitrogen atmosphere. The mixture was adhered to 100 ° C for 10 minutes under scratch radiation. The organic layer was separated, dried (NSO4), rested and agitated 'in the air. The residual was selected by a flash-chromatography medium (Silica; MeOH at 100/0 DCM to 3/97). The desired concentration of the broken particles was collected and concentrated. The residue was crushed with DIPE to give the 4-b aphid (1,46 g, 52%) as a white body habit, which was purified by a specular asymmetric SFC (fixed phase: 5) Chiralpak AD micrometer 250 * 30 mm, transfer phase: 85% 0, 5/1515 iPrOH)], a compound yield of 6b (0,659 g, ο24 / 5) and a 5-b compound (0,693 g, ο25 / 5).

<img file="MA43291A1_D0080.tif" />

Shout 6-b

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79

31,06 (DIAD Micrones, 016 mmol) (diameter after another) were added to the yolk solution of intermediate material 21B (30 g, 0.11 mmol), 2,4 diphenyl vinyl (15,07 ولl).

0.16 mmol) and triphenylphosphine (41,38 mg, 0.16 mmol) in 1,11 (THF ml) at 0 ° C and under nitrogen atmosphere. The mixture was stirred at 100 ° C for 10

5 Minutes under zero wave radiation. The mixture was diluted with EtOAc and washed with saturated NaHO solution. The organic layer was separated, dried (0,4 c 2 ^), relaxed and concentrated in the alkhoa. Done

Purification of the residue by flashing chromatography (Celica; MeOH at 100/0 DCM to 3/97). The desired concentration of the broken particles was collected and concentrated. The residue was crushed with DIPE to give jam 6-b (40 mg, ο96 / 5) as a white object.

10 (C) Synthesis of compound 6-b hydrochloride (HCI) salt.

207,06) DIAD microlens, 1.05 mmol (diameter after another) were added to the yolk solution of feedstock 21B (200 mg, 0.70 mmol), 2.4 dsFF (100,45 تزl, 1,05 mmol). Mol) and triphenylphosphine (275.84 mg, 1,0516 mmol) in

4) THF mL) at 0 ° C and under nitrogen atmosphere. The mixture was stirred at 100 °

15th Celsius for 15 minutes under zero-wave radiation. The mixture was diluted with EtOAc and washed with saturated NaHO solution. The organic layer was separated, dried (NS04), filtered and vacuumed. The residue was purified by RP HPIC medium (fixed phase: C18 XBride 30 X

100 5 .m, mobile phase: slope of 0.1% 0.1% NH4CO3H / NH4OH solution.

9 pH in water, 5/540 CHgCN to 5/543/5/50.1 solution 9 ΝΗ₄ΟΟ₃Η / ΝΗ₄H pH in 20 water, 57% CHCN, produces a residue of a white solid that has been dissolved in H 2; p (8 ml) and

1.4 Diet oxan (0,5 ml). Hence Μ4) HCI was added in dioxane, 200 )m) acquired to the solution of diameter one by one. The dusty white solid body was irritated, washed with 2θ; Ε, dried (^ NSC) and evaporated under alkali. So the white residue acquired with Et₂0 To give the compound 6-B110) .HCI tug, 36%) as a white solid.

25 The following mirrors were created following a similar sequence of sequences that were mentioned in Example A (b), starting with intermediate material 21b.

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<img file="MA43291A1_D0081.tif" />

<td>(RkCr</td><td>Compound number</td>

<td>C</td><td>9-b</td>

<td>C</td><td>10 b</td>

<td>Γ</td><td>11 b</td>

<td> ٠-</td><td>Compound number</td>

<td>See</td><td>12-b</td>

<td>See</td><td>3a b</td>

<td>G.</td><td>4b</td>

Bladder 2

<img file="MA43291A1_D0082.tif" />

Procedure (a): 31,06 (DIAD Microlens, 0,158 mmol) diameter after another was added to the burned solution (for the intermediate material 21b (30 mg, 0.105 mmol), 3,5-- diphenyl vinyl (20,52 mg, 0.158 mmol) and triphenylphosphine (41.38 mg, 0.158 mmol) in

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1,113) THF mL) at 0 ° C and under nitrogen atmosphere. The mixture was stirred at 100 ° C for 10 minutes under zero-wave radiation. The mixture was diluted with EtOAc and washed with saturated solution of NaHO. The organic layer was separated, dried (NSO4), sliced and concentrated in bulk. The residue was purified by flashing chromatography (Silica; MeOH at 5 100/0 DCM to 4/96). The desired fractions were collected and concentrated. The residue was crushed with

DIFE to give 7-B dread (21 mg, 50%) as a white solid.

Part (b): Instead of this, the talent 7, which follows a similar synthetic sequence, was mentioned in Example A (b), starting with intermediate material 21b.

Example 3

10 Terrifying synthesis of 8 — b

<img file="MA43291A1_D0083.tif" />

Complex No. 8-b

Procedure (a): 31,06 DIl 0l, 0,158 mmol) diameter by one added to

The release solution for the feedstock is 21B (30 mg, 0.105 mmol), 3,4 — diphenylphenyl (20.52 mg, 0.158 mmol) and triphenphosphine (41.38 mg, 0.158 mmol) at 15 1,11) THF mL) at 0 ° C and under nitrogen atmosphere. The mixture was stirred at 100 °

Celsius for 10 minutes under zero-wave radiation. The mixture was diluted with EtOAc and rinsed with a saturated solution of NaHO. The organic layer was separated, dried (NSO4), filtered and removed in a vacuum. The residue was purified by flashing column chromatography (Silica; MeOH at DCM 100/0 to 4/96). Wanzhez desired fractions were collected in Khakh. The residue was crushed with DIFE 20 to give the aphid 8 - b (10.6 mg, 25%) as a white solid.

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Part (b): Instead, the 8-b trainer, which follows a similar synthetic infiltration, was mentioned in Example 1 (b), starting with intermediate material 21b.

Example 4

Synthesis of terrifying 15-b

Complex No. 5A-B

Part A: 155,3) DIAD Microns, 0,789 mmol) were added after another diameter of an engine solution, from intermediate material 21b (150 mg, 0.526 mmol), 6,4,2 - Tefluorol (116,8). Mg, 0,789 mol) and triphenylphosphine (206,88 mg, 0,789 mmol) in 5,56 (THF ml) at 0 ° C and under nitrogen atmosphere. The mixture was stirred at 100 °

Celsius for 10 minutes under a zero wave. Dilute the mixture with DCM and wash with saturated solution of

NaHCOg. The organic layer was separated, dried (*, NSO), filtered and concentrated in the vacuum, then purified with flashing column columns (Celica; N 7 MeOH / NHg at 100/0 DCM to 10/90). The terrified fractures were collected 9 concentrated in the lead. Then purify it with RP HPIC medium (fixed phase: 100 x 30 018 XBridge mm 5 ومترm, purity phase: regression ratio of 54% ο0,1 / 5 NHCOgH / NHOH pH 9 solution in water, 46% ΟΗ3ΟΝ to 5/6464/50, 1 NHCOgH / NHOH pH 9 solution in water, 36% CHgCN) Colorless oil extracted and crystallized upon discontinuation (two days). The solid material was crushed with hitane to give the compound 15–b (129.8 mg, 59%) as a white solid. Part B: Instead, the trainer 15-b was also created after a homogeneous chain of synthesis for that mentioned in Example A (b), starting with the intermediate material i.e.

Example 5

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Creator of relaxants 1 — b, 2b and 3 —b

<img file="MA43291A1_D0084.tif" />

<img file="MA43291A1_D0085.tif" />

Gutter, gutter, 2b, compound 3b

The celibates 1-b, 2-b and 3b were synthesized after the portion described in Example 1 (1). Thus, 5 reactions 500,05 (DIAD Microls, 2.54 mmol), intermediate material 121 (483 mg,

1.69 mmol), 4-fluoro-phenol (227.77 mg, 2.03 mmol) and triglyphosphine (666.14 mg, 2.54 mmol) in 17.91 (THF ml) as described in Example 1 (1) Which residue yields were purified by flash column emulsion (Celica; EtOAc at DCM 100/0 to 10/90). The desired fractions were collected and centered on / off. The resulting residue 10 was crushed with DIPE to obtain a 1-b compound (320tg, 50%) as a solid white substance, which was purified by an SFC-like quenching medium [constant phase: 5] Chiralpak AD 250 30m 30m 30, motion phase: 5/577 0, ο23 / 5 MeOH)], compound yield 2-b (131teg, 20%) and 3-b) (129teg, 20g) as a white solid.

Example 6

15th Synthesis of compounds 24b, 26b and 27b

<img file="MA43291A1_D0086.tif" />

<img file="MA43291A1_D0087.tif" />

<img file="MA43291A1_D0088.tif" />

Gutter 24 B Gut 26 B Gut 27 B

The features were created 24–b; 26–b and 27b after the portion described in Example 1 (1). Thus, the interaction of 364,57 (DIAD 1,l, 1.85 mmol), intermediate material 22 (320 tg, 1,23 20 mmol), 4.2 dichloro-phenol (176,86 ترl, 1.85 mmol) and tertiary Vinyl

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Phosphine (485,67 mg, 1.85 mmol) in 1HF; 13,06 ml) as described in Example A (A) that obtained residue was purified by flash chromatography (Silica; MeOH at 100/0 DCM to 4 / 96). The desired fractions were collected and concentrated in obtaining

Colorless oil that crystallizes with DIPE to give fishy

24 As a white tincture, which has been made

Purified by RP HPLC medium (constant phase: 100 x 30 C18 XBridge mm 5 micrometre; motion phase: slope ratio of ΝΟΗ / ΝΟΗ 0% 1 ο / ο54 pH 9 solution in water, /46 / 5 CHgCN to 5/564 ο 0.1 / 5 ΝΟΗ / ΝΗ life pH 9 solution in water, 36% CON (colorless oil extractor crystallized upon crushing with heptane to give 240 mg (52%) of fishy 24b as a solid white habit, purified by SFC quenched coherence (constant phase): 5 CHIRAIPAK ad-η Microx 20x250

Mm; kinetic phase: 5/585 0, 515/15/5/50.3 (iPOH iPH)), compound strength 26-B (103 mg, 22%) and Lamib 27-B (107 mg, 23%). The following contraceptives were obtained

Which we recite with synthetic paralysis similar to that mentioned in Example A '(a).

<td>a Complex 29b</td><td></td><td>a Fishy 28 b</td><td>Horror Marble Fishy 25 b</td>

<td colspan="2">20,250 mm); united phase: 5/5 1/22)</td><td colspan="2">Primary Article: Intermediate Article 22 SFC conditions Parallel symmetry: Constant phase: 5 Chiralpak AD “H m 85% 5/1515, CO2 mixture ν / ν 50/50 EtOH / iPrOH (B3, &lt;</td>

<td>s: I ride_, 18 —b</td><td>R</td><td>r Fishy August 7</td><td>tuck Honor 6 to 2 12</td>

<td colspan="2"></td><td colspan="2"></td>

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Primary Article: Intermediate Article 23

SFC conditions Irrigative symmetry: stationary phase: 5) Chiralpak AD-and 250m 250 * 30 mm); liberated phase: 80% 02, 20 e / h 50/50 MeOH / iPrOH mix 7/7 (+0) 3 iPN)

The following compounds were synthesized after a synthetic sequence as mentioned in Example A (b), starting with the intermediate mod. Referred to. a

<img file="MA43291A1_D0089.tif" />

<img file="MA43291A1_D0090.tif" />

The monk 20 20b; obtained from intermediate material 24c

The terrible 221b; obtained from intermediate material ^ 2b

<img file="MA43291A1_D0091.tif" />

<img file="MA43291A1_D0092.tif" />

The terrible 19b; obtained from intermediate material 24a

The monk 2A2B; obtained from the intermediate substance 24c

<img file="MA43291A1_D0093.tif" />

<img file="MA43291A1_D0094.tif" />

Monk 23b; obtained from intermediate material 24b

<img file="MA43291A1_D0095.tif" />

Obtained from intermediate material 29

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<img file="MA43291A1_D0096.tif" />

<img file="MA43291A1_D0097.tif" />

:? F

0

The terrible 31 — b;

The monk 2a 3;

Primary Article: Intermediate Article 30

SFC conditions Irrigation symmetry: stationary phase: 5 Chralpak AD-Η ومM (20 Χ250 mm); motion phase: ο85 / 5 iPrOH% 15, 0.

Table A lists additional compounds of summer (IB) aggregates prepared by homogeneity to the above examples (example number).

5 Schedule A: Representative Nuns according to Summer (1-Β).

# Indicates that the experimental procedure is described in the examples

<td colspan="6">N — N The Righteousness? Theres</td>

<td>Chemist hermetic</td><td colspan="2">En!</td><td>R1</td><td>Example number</td><td>Compound number</td>

<td>RS</td><td colspan="2"> '٥,</td><td>No 000</td><td>Example 5 #</td><td>1_b</td>

<td>"R</td><td>M</td><td></td><td> ١•</td><td>Inclined 5 #</td><td>2-b</td>

<td>* S</td><td>M</td><td></td><td> ٦٧</td><td>Example 5 #</td><td>3-b</td>

<td>RS</td><td>M</td><td></td><td> ٠٠١</td><td>Example 1 #</td><td>4b</td>

<td colspan="2"></td><td colspan="4"></td>

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<td>RS</td><td>,'M.,</td><td>No/</td><td>Inclined 1 #</td><td>5-b</td>

<td rowspan="2">s</td><td rowspan="2">P</td><td rowspan="2">V</td><td>Example 1 (a) and (b)</td><td>6-b</td>

<td>Example 1 (c) #</td><td>6b. HCI</td>

<td>s</td><td>Çiï</td><td>V</td><td>Example 2 #</td><td>6-b</td>

<td>s</td><td>No</td><td> /١١١٢</td><td>Example 3 #</td><td>8-b</td>

<td>s</td><td>F No</td><td>No/'</td><td>Example 1 (b)</td><td>9 — b</td>

<td>s</td><td>No</td><td>No'</td><td>Example 1 (b)</td><td>10 b</td>

<td>s</td><td>à.</td><td>No-</td><td>Example 1 (b)</td><td></td>

<td>s</td><td>As 0 for 0 g2</td><td>V</td><td>Example 1 (b)</td><td>12 b</td>

<td>s</td><td>0 no</td><td>7 no</td><td>Example 1 (b)</td><td>13b</td>

<td>s</td><td>,No</td><td> ^'٠١</td><td>Example 1 (b)</td><td>14b</td>

<td>s</td><td>Be , Z</td><td>No</td><td>Example 4 #</td><td>5 to 2b</td>

<td>RS</td><td>-No</td><td>O</td><td>Example 1a</td><td>16 b</td>

<td>* R</td><td>,No</td><td>O</td><td>Example 1a</td><td>The verse</td>

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<td>* S</td><td>P</td><td>Ό</td><td>Example 1a</td><td>18 b</td>

<td>RS</td><td>A</td><td>1 K10-A.</td><td>Example 1 (b)</td><td>Wap</td>

<td>* R</td><td>M</td><td>\ A10 r.</td><td>Example 1 (b)</td><td>20 b</td>

<td>* S</td><td>A</td><td>\ A10 t-</td><td>Example 1 (b)</td><td>21b</td>

<td>* R</td><td>F , Z</td><td> ١٥'</td><td>Example 1 (b)</td><td>22 b</td>

<td>* S</td><td>A</td><td>1</td><td>Example 1 (b)</td><td>23 b</td>

<td>RS</td><td>A,</td><td> ٠٠١.</td><td>Example 6 *</td><td>24b</td>

<td>RS</td><td>, Z</td><td> ٠٠٠١.</td><td>Example 1a</td><td></td>

<td>* R</td><td>A</td><td>.00ι \</td><td>Example 6 #</td><td>26b</td>

<td>* S</td><td>A</td><td> ٠٠١.</td><td>Example 6 #</td><td>216 b</td>

<td>* R</td><td>, 'Z</td><td> ٠٠٠١.</td><td>Example 1a</td><td>28 b</td>

<td>* S</td><td>Ladd</td><td> \'٠٠.</td><td>Example 1a</td><td>29b</td>

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<td>RS</td><td>;Count</td><td>V</td><td>Example 1 (b)</td><td>30-b</td>

<td>* R</td><td>,M,</td><td> ٧•</td><td>Example 1 (b)</td><td>31-b</td>

<td>* S</td><td>,Count</td><td>V</td><td>Example 1 (b)</td><td>32 b</td>

Analytical section

Optical rotation

Optical rotation was measured on the 341 Perkin-Elmer polarization tool with a sodium lamp and determined 5 as the automatic 5 (λ) (ag / 00mL, solvent, Celsius).

Ad [Ixc) / (alOO) = (a a): where 1 is the path length in dm and is the is the concentration in g / 100 mL for a sample at a grade of 1 (degree C) and a wavelength λ (in nanometers). If the wavelength of the light used is 589 nm (sodium D line), then baking D can be used instead. The indication of rotation must always be given (0 or-). When using this equation, the alnizez 10 and the solvent are always provided in parentheses after the circulation. The rotation is decided using degrees and no concentration units are given (it is assumed to be g / 00mL).

LCMS

For the MS-LC features of the compounds of the present invention, the automated methods have been used.

Affliction

15th A high-performance liquid chromatography (HPLC) measurement was performed using an LC pump, a dual-valve array (DAD) or a UV detector and a column as specified in proportional methods. If necessary, include additional detectors (see table of methods below).

A flow was brought from the column to the plaster spectrometer (MS) that was prepared with a atmospheric ion source. It is within the knowledge of the person with the oryx to control coefficients of harmony (eg, wiping it range, group of 20 silence ...) in order to obtain ions allowing for the definition of single isotope molecular color.

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The nominal horror (MW). Data acquisition has been performed by appropriate software. The terrariums are described with optional retention bands (; R) and their ions. If not specified differently in the spreadsheet, the prescribed molecular ion is proportional to [Μ + Η] (a proton-added molecule) and / or [Μ-Η] (a proton-denominated molecule). In the event that the terrifying vehicle is not directly demolished, the type of the addition output 5 (ie; [MtHCOO], [Μ + ΝΗ4], etc.) is specified. For molecules with an isotopic patterns (Cl, Br ...) the stated value is that obtained for the lowest isotropic mass. All results were obtained with experimental uncertainties jointly associated with the method used. Later, SQD means single quadruple detector, RT, degree emptying degree, BEH ethyl silocan silica Sol silica Sol bridle, high-strength silica HSS, DAD detector 10 home diode array.

Table B: LCMS method (stream expressed in minutes; column column grade (°) in ° C; decorate in minutes).

<td rowspan="2">method ICMS</td><td rowspan="2">Operating time</td><td>flow</td><td rowspan="2">Downward stroke</td><td rowspan="2">Develop a movement</td><td rowspan="2">Column</td><td rowspan="2">the tool</td>

<td>Degree heat Column</td>

<td rowspan="2"> 1</td><td rowspan="2"> 5</td><td> 1</td><td rowspan="2">5/95 a to 5% a in 4,6 minutes d 0,4 minutes</td><td rowspan="2">A: 95% CCOON 6,5 miles Molly * 5% CHCN, b: CHC</td><td rowspan="2">Agilent: Eclipse Plus C18 RRHD (1.5 ومترm, 50χ2,1 mm)</td><td rowspan="2">Waters: Acquity I IPI DAD and SQD</td>

<td> 50</td>

<td rowspan="2"> 2</td><td rowspan="2"> 5</td><td> 1</td><td rowspan="2">From 095 / H to 5% A in 4.6 minutes, carry Dr. 0,4 minutes</td><td rowspan="2">A: 95% CHCOON 6,5 drained Molly + 5% CH3CN, b:</td><td rowspan="2">Waters: CSH C18 (1.7 ومترm, 50χ2,1 mm)</td><td rowspan="2">Waters: Acquity UPLC- DAD and SQD</td>

<td> 50</td>

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<td></td><td></td><td></td><td></td><td>CCN</td><td></td><td></td>

<td rowspan="2"> 3</td><td rowspan="2"> 6,2</td><td> 0,343</td><td rowspan="2">84,2% for a period 0.49 minutes, to 10.5% A at 2,18 1 minute, pregnancy for 1.94 minutes, returned to 84,2% in 0.73 minutes, pregnancy for 1 minute 0.73</td><td rowspan="2">A: 95% CHCOONH 6 wages Molly / 5 huh CHCI, b: CHCN</td><td rowspan="2">Waters: BEH 1.7) C18 Micrometers, 2,1 x 100 mm</td><td rowspan="2">Waters: Acquity UPCDAD and Qusttro Micro;</td>

<td> 40</td>

<td rowspan="2"> 4</td><td rowspan="2"> 9</td><td> 1</td><td rowspan="2">From 95% A to 5% in 7.8 minutes, carry for 1.2 minutes</td><td rowspan="2">A: 5/95 CHCOOH 6,5 miles Molar; 5% CHCN, b :. CH3CN</td><td rowspan="2">Waters: CSH “C18 (1.7 ومترm, 50 x 2.1 mm)</td><td rowspan="2">Waters: Acquity UPLC- DAD and SQD</td>

<td> 50</td>

Al-Thawyan score

Values are peak values, and are obtained by empirical uncertainty generally associated with this analytical method.

Prepare the Mettler FP81HTZFP90

For a number of relaxants, melting points were identified in the tubes. The Open lattice on the Mettler-Toledo (FP8T / FP90). The melting points were measured by a slope rating of 1, 3, 5 or 10 ° C / min. The maximum gauge score was 300 ° C

Read the melting point from the digital display.

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Table C: Physico-chemical data for some compounds; retention time (., R) per minute, peak + M + HJ] (proton-added molecule), LCMS method and melting point (melting point in ° C). (nd = not specified).

<td>Optical rotation</td><td>method LCMS</td><td>[16</td><td>9 (Accurate)</td><td>Μρ (temperature)</td><td>Desired number</td>

<td></td><td> 1</td><td> 380</td><td> 2,32</td><td> 156,3</td><td>1-b</td>

<td>-5 A 58 ° C (589 nm, C 53 (0 ow / v / 5, 20, DMF ° C)</td><td> 3</td><td> 380</td><td> 2,93</td><td> 176,9</td><td>2b</td>

<td>-4 (59 ° C) 589 nm, C 52 (0/5/5/7/7, DMF Celsius)</td><td> 3</td><td> 380</td><td> 2,93</td><td> 177,3</td><td>3b</td>

<td></td><td> 1</td><td> 398</td><td> 2,41</td><td> 121,7</td><td>4b</td>

<td>- * 7 (95 ° C (589 nm, C 69 (0 20, DMF,% w / v m Doha))</td><td> 3</td><td> 398,3</td><td> 2,99</td><td> 142</td><td>5b</td>

<td>-4 (95 ° C) 589 nm, C. 7 (0 7 / k 18%, 20, DMF ° C)</td><td> 3</td><td> 398,2</td><td> 2,99</td><td> 142,4</td><td>6b</td>

<td>-7 (55 ° C (589 nm, C 96 (0 20, DMF,% w / v℃)</td><td> 2</td><td> 398</td><td> 2,37</td><td> 170,08</td><td>6b</td>

<td>L6.2a</td><td> 2</td><td> 398</td><td> 2,32</td><td>nd</td><td>8 — b</td>

<td></td><td> 2</td><td> 398</td><td> 2,32</td><td>nd</td><td>9b</td>

<td>Li 1a</td><td> 2</td><td> 398</td><td> 2,25</td><td>nd</td><td>10-b</td>

<td>No. 1</td><td> 2</td><td> 398</td><td> 2,28</td><td>nd</td><td>11 b</td>

<td>E. 1a</td><td> 2</td><td> 410</td><td> 2,16</td><td>No. 1</td><td>12 b</td>

<td>nd</td><td> 2</td><td> 410</td><td> 2,68</td><td> 144,1</td><td>3a b</td>

<td>nd</td><td> 2</td><td> 394</td><td> 2,51</td><td> 161,7</td><td>14b</td>

<td>-0 (167 ° C) 589 nm, C.</td><td> 2</td><td> 416</td><td> 2.3</td><td>nd</td><td>15-b</td>

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<td>0,55 20, DMF,% w / v degrees allowed</td><td></td><td></td><td></td><td></td><td></td>

<td>nd</td><td> 2</td><td> 412</td><td> 2,50</td><td>E 21</td><td>16 b</td>

<td>nd</td><td> 3</td><td> 412</td><td> 3,12</td><td>nd</td><td> 17</td>

<td>nd</td><td> 3</td><td> 412</td><td> 3,12</td><td>nd</td><td>18 — b</td>

<td>nd</td><td> 2</td><td> 402</td><td> 2,39</td><td>nd</td><td>9a b</td>

<td>nd</td><td> 2</td><td> 402</td><td> 2,3</td><td>nd</td><td>20 b</td>

<td>2..ά</td><td></td><td> 402</td><td> 3,36</td><td>nd</td><td>21-b</td>

<td>No. 1.1</td><td> 2</td><td> 420</td><td> 2,35</td><td>E. 1a</td><td>A-b</td>

<td>H. 21</td><td> 2</td><td> 420</td><td> 2,35</td><td>nd</td><td>23-b</td>

<td>nd</td><td> 2</td><td> 372</td><td> 2,05</td><td> 135,7</td><td>24b</td>

<td>nd</td><td> 2</td><td> 390</td><td> 2,13</td><td> 138,3</td><td>65-b</td>

<td>-83.9 ° C (589 nm, c 0.52, 25, DMF,% w / v degree °)</td><td> 3</td><td> 372</td><td> 2,80</td><td>nd</td><td>26b</td>

<td>-1 for 92 ° C (589 nm, 0,55 c-25, DMF, o / ow / v ° C)</td><td> 3</td><td> 372</td><td> 2,80</td><td>nd</td><td>27-b</td>

<td>-129.2 ° C (589 nm, C. 0.5 25, DMF,% w / v℃)</td><td> 3</td><td> 390</td><td> 2,85</td><td>For 1.2 a</td><td>28-b</td>

<td>137.3 ° C (589 nm, C 0.51 oW / v / 5,25 DMF ° C)</td><td> 3</td><td> 390</td><td> 2,85</td><td>nd</td><td>29b</td>

<td>nd</td><td> 2</td><td> 386</td><td> 2,29</td><td> 130,6</td><td> (30</td>

<td>-67,5 ° C (589 nm, C 0,83 ow / v / 5,25, DMF ° C)</td><td> 2</td><td> 386</td><td> 2,29</td><td> 127,85</td><td>31-b</td>

<td>89,5 ° C (589 nm, C. 0.80 7/20, DMF,% w ° C)</td><td> 2</td><td> 386</td><td> 2,29</td><td> 127,69</td><td>32 b</td>

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SFC-MS

Public performance

'The SFC measurement was performed using a Berger tool analytic system that includes a control pump 5 with a dual pump fluid 1200-FCM for carbon dioxide delivery (C02) and a rate, CTC analyzes, a 20000-TCM thermal control trip for a groove heating column Vacuum to 80 ° C. The 1100 Agilent UV array reagent used a high pressure flow cell that stands at 400 bar. The stream was separated from the column to the MB spectrometer. The MB detector was prepared with a pressure denominator. The following result coefficients from the Waters ZQ mass spectrometer 10 scale are: corona: 9 وةm, source temperature: 140 ° C,

Cone: 30V, PRB 450 ° C, 3V Extract, Analysis Gas

400 For a terrace, a cone gas of 70 liters. The nitrogen was used as a mardan glove. A data equation was segmented using the Waters-Micromass Masslynx-Openlynx data controller.

/ Rarka A: In addition to the general segment: Analytical-quenched analog separation was performed at-SEC 15 MS on column 10 (CHIRALPAK AD DAICEL micrometers, 250 χ4,6 mm) at 35

° C with a flow rate of 3.0 min. The phasing phase is 85%? IPrOH to 15%, co (+ 0,3 iP%₂) Holds a 7-minutes in airchat mode

Al-Ark 2: In addition to the general part: The analytical, Meroitic analog separation was performed in-SEC

MS on column 10 (CHIRAIPAK AD DAICEI micrometers, 250 χ 4,6,6 mm) from 35 to 20 ° C with a flow rate of 3.0 min. The phasing phase is 75% iPrOH to 15%, co₂

(+ 0,3% iPrN) Holds 7 minutes in ISOCrT mode.

Alakah 3: In addition to the general procedure: analytical irrigated separation was performed in-SEC Ms On column 10 (CHIRALPAK AD DAICEL micrometers, 250 χ4,6 mm) at 35 ° C with a flow rate of 3.0 minutes. The phasing phase is 80% of 10%, co₂ Methyl + 25% 10 iP2NH₂ 0.3% + - (iPrOH) holds 7 minutes in the Air Karate mode.

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Table D: Analytical SFC data - means; R retention time (minutes), MH means the mass to which a proton has added to the compound, the method indicates the method used to elongate the SFC / MS

Of symmetric pure salary. Measured against mixture.

<td>0 rinse off Colleague</td><td>method</td><td>Mqays 7 No 0 / e</td><td>[Μ + Η] 0</td><td>R '</td><td>Compound number</td>

<td>A</td><td> 1</td><td> 100</td><td> 398</td><td> 4,28</td><td>6 — b</td>

<td>B</td><td> 1</td><td> 100</td><td> 398</td><td> 5,98</td><td>5-b</td>

<td>A</td><td> 2</td><td> 100</td><td> 380</td><td> 2,13</td><td>2 — b</td>

<td>B</td><td> 2</td><td> 100</td><td> 380</td><td> 2,97</td><td>3-b</td>

<td>A</td><td> 3</td><td> 100</td><td> 412</td><td> 2,46</td><td>17-b</td>

<td>B</td><td> 3</td><td> 100</td><td> 412</td><td> 3,12</td><td>18-b</td>

<td>A</td><td> 1</td><td> 100</td><td> 386</td><td> 2,93</td><td>31-b</td>

<td>B</td><td> 1</td><td> 100</td><td> 386</td><td> 3,81</td><td>32-b</td>

* A means the first zipper to eliminate. B means the second Zair remover.

Nuclear Magnetic Zin (NMR)

For a number of educators, the H NMR spectrometer was registered either on the Bruker 400-DPX spectrometer or on the 500-Bruker AV in standard pulse sequences, operating at 400 MB and 500 MHz, respectively. Chemical transformations (δ) have been reported in 10 million parts (ppm) below tetramethyl silane (TMS), which have been used as an internal standard.

Complex No. 6-B: 400) ¹H NMR MHz, C (CDCI3 part ppm 0,30-0,38 d) 1.72, (Hl, m) 1.12-1,22, Η2, m (0.68-part 0,59,) Η2, m), L = 6.5 Hz, 5,84, (Η2, m), 3.14-3,02, (Η3) 9, L = 6.3 Hz, (Hl, m) 6,73 -6.67, (HI 6,89-6,80 (d) 7,30, (Η2, m, L = 7.4 Hz, Η1) 4 d) 8,11, L = 7.4 Hz, Hl ),

15th Complex No. 7-B: H NMR; (400MHz, C) CDCI3 ppm 0.30-0.39 (d) 1.70, (Hl, m), 1.23-1.11, (Η2, m (02,68,68 m2, m, L = 6.5 Hz,

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5,83, (Η2, m), 3,14-3,01, (Η3 (9, L = 6,2 Hz, Η3, m), 6,45-6,35, (Hl),

7,13 (d, L = 7.2 Hz, d), 8,08, (Hl, L = 7.4 Hz, Hl)

Compound No. 8B: 400 (H NMR megahertz, CDC13 δ ppm 0.33-0.38 million)

(d) 1,69, (Hl, m) 1,22-1,11, (Η2, m), 0.68-0.58, (Η2, m, L = 6,2 Hz,

5 5,79, (Η2, m) 3,13-3,01, (Η3) 9, L = 6,2 Hz, dtd (6,67), HI, L = 9.2,

3,1,1,1'7 Hero, 6,72 (ddd, L = 11,6,6,5,3 Hz, 7,04-6,95)

(d) 7,15, (Hl, m, L = 7.4 Hz, d), 8,07, (Hl, L = 7.4 Hz, Hl)

Complex No. 15B: 500 (H NMRMHz, C) CDCI3 part Upper part 0,30-0,41

d) 1.70, (Hl, m) 1,25-1,16, (Η2, m), 0.71-0.59, (Η2, m), to = 6.4 Hz,

10 5,80, (Η2, m) is improved to 3.16-3,05, (Η3) 9, L = 6.4 Hz, (Η2, m) 6,70-6,62, (Hl

7,45 (d, L = 7.5 Hz, d) 8,16, (Hl, L = 7.2 Hz, HI)

Compound No. 13B: 500 (H NMR MHz, C) CDCI3 Palm Millions of 0.27-0.39

(d) 1.73, (Hl, m) 1,21-1,12, (Η2, m), 0.67-0.58, (Η2, m, L = 6.4 hr,

qd (3,06, Η3, s), 2.22, Η3, l = 15,4, 6,6 h, 5,92, (Η2) 9, l = 6,4 h, 15 d) 6, 71 (Hl, L = 8.4 hr, dd) 6,89, Hl, L = 8.4, 1.4 Hr, d (7,18), HI,

L = 7, aharo, d (7,32), (Hl, L = 7,2 haro, d), 8,07, (Hl, L = 7.2 haro, Hl)

Complex number 4 AP: H NMR; (500 megahert, CD (CDCI3 ppm 0.28-0,39 d) 1,70, (Hl, m) 1,21-1,12, (Η2, m) 0, 69-0,57, (Η2, m), l = 6.6 hr,

5,79, (Η2, m) 3,12-3,01, (Η3, s), 2,31, (Η3) 9, L = 6.6 H, 6,55 (HI)

20 6,4,3,4 dd Hero, TD (6,69), Hl, 8,5,0,0 Hero, 6,87 dd (HI),

L = 9,0,2.9 H, d (7,17), (Hl, L = 7.5 H, d) 8,06, (HI, L = 7,2 H, Hl) Complex No. 20-B CDCI3: 500 (H NMR) Haifa Hero, t L L, l22 million

Hr 7,1 d (H2,1.7), L = 6,4 H, 3,58, (Η3) 9, L = 7,1 hr, 5,03, (Η2-

5,10 (5,84), (Η2, m) 9, L = 6.5 hr, 6,88-6,81, (Hl, m) is 6.74-6,67, Hl 25 (d) 7 34, (Η2, m, L = 7.2 hr, d), 8,40, (Hl, L = 7.5 hr, Hl)

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Complex No. 22-B: 500) ¹H NMR megahertz, C CDCI3 1, 1,23 (t), L = 6.9 Hz, d (1.70), Η3, L = 6.4 Hz, 3.58, (Η3) 9, L = 7.0 Hz, Η2), 5,12-5.05 (5,81), (Η2, m) 9, L = 6.6 Hz, 7,48, (Η2, m) 6,70-6,62 , (HI d) 'l = 7.5 Hz 4 d) 8.45' (Hl 'l = 7.2 hersch' Hl)

5 Complex No. 31-b: H NMR; (400MHz, 7 (CDCI3), with a threshold of 1.07 (, t to = 7,40 Hz, d) 1,72, (Η3, L = 6,24 Hz, sxt) 1.92, (Η3, L = 7.63 Hz, 5.84, (Η2, m), 3.14-2.98, (Η2 (9, L = 6.47 Hz, HI, m) is 6.74 -6,65, (HI), 6,89-6,78 (d), 7,29 (Η2, m, L = 7,40 Hz, d), 8,02, (HI, L = 7,40 Hz, HI) .

10 Test for summer desires (Ι-Β) in the laboratory

The summer triggers (IB) supplied in the present invention are mGluR2J positive GIs. These promoters appear to stimulate glutamate conjugations by binding to a continental site other than the location of the glutamate binding. GluR2 increases the response to glutamate glutamate in the presence of quality adhesives

I — B)). Summer stimuli (B— a) are expected to have a significant effect at mG! UR2, preferring their ability to improve the function of the receiver. The positive GG axis were invented at mGluR2

Using the method of checking the 1 SJGTPyS rib described below which is appropriate to define these desirables, specifically the desirables according to summer (B— A), is encapsulated in Table E.

35TP [Check] GTPyS]

The SJGTPyS ligation assay is a membranous baseline functional assay that is used to study a function that will accept 20 gprin metabolites (GPCR) where the incorporation of a non-degradable form of GTP is measured,

SJGTPyS (Guinosine 5 'Triphosphate, tagged gamma emission ³⁵S). The secondary unit G a catalyzes of the guanosine exchange protein 5 'diphosphate (GDP) by gua-nosin triphosphate (GTP) and upon activation of a GPCR agonist inhalers medium, SJGTPyS], becomes combined and otherwise cannot be split into a continuation of countries. (Harper (1998) Current Protocols) in 25 Pharmacology 2,6,1-10, John Wiley &amp; Sons, Inc.). The amount of radiation incorporation

SJGTPyS] is a direct measure of G-protein activity and thus the agonist inhalers activity can be determined. Turns out

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The mGlu2 receptor is preferentially coupled to the Gai-protein, a preferential conjugation of this method, and it is used extensively to study the activation of a receptor mGlu2 from both the recombinant cell lines and into the tissue. We describe here using link checking³⁵SJGTPyS] using diaphragm cell membranes with a human-adapted mGlu2 receptor from Schaffhauser et al. (Molecular 5 (4: 798-810, 2003, Ptiarmacology) to reveal positive HVAT properties (PAM)

To patrol this invention.

Prepare the membrane

CHO cells were provoked to pre-aggregate and induced at 5 mM mol to potter for 24 h. 10 cells were collected by PBS scraping and the cell suspension was expelled (10 minutes at 4000 rpm)

The minute in a supermodel centrifuge). The supernatant was removed and the pellet suspension gently in 50 mM Iris — HGI, pH 7,4 by mixing with a bloody or pipette above and below. The suspension was centrifuged at 16,000 rpm (Sorvall RC-5C puls rotor 34 — SS) for 10 minutes and the supernatant was removed. The pellet was homogenized in 5 mSi-Iris 15 HGI, pH 7,4 using the Ultra-turrax homogen and maryem phase again (18,000).

Turn per minute, 20 minutes, 4 ° C). The last nacelle was resuspended at 50 mM Iris-HCl, pH 7,4 and stored at 80 ° C in appropriate aliquots before use. Bio-Rad, USA (Bradford) medium protein metabolism was identified with bovine serum albumin as a standard.

20

SJGTPyS hyperlink check]

A measure of the mGluR2 positive differential axis activity of the newsgroups was as follows. Examination buffers and glutamate were diluted in a co-assay containing 10 mM. HEPES acid, 10 mM HEPES salt, pH 7,4, 100 mM 3, NaCI mM

25 ^ MgCI and 0A Micromolecular GDP. Membranes containing a human mGlu2 receptor were thawed on ice and diluted in the auxiliary examination supplement D4a وغg / mL saponin. Pre-incubation

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For membranes with a compound alone or pre-defined (EC20-) glutamate concentration (PAM assay) for 30 minutes at 30 ° C. After adding 0.1 fc) [SJGTPyS nano-molly], the test mixtures were briefly shaken and further incubated to allow SGTPyS to incorporate on activation (30 min, 30 ° C). The last assay mixtures contained 7 رمg of protein membrane in 10

5 10 mM acid, HEPES mM HEPES salt, pH 7,4, 100 mM 3, NaCI mM 10, MgC micromolecule GDP and 2 ميكرg / mL saponin. The total reaction volume is 200 microns. Interactions were destroyed by the rapid clearance via -Unifilter 96 GF / Β Panels (Perkin Elmer, Massachusettes, USA) using 96 global harvesting well filtermate. The 6 filters were washed with 10 mM NaH Ο4 cold ice / 10 10 mM NHP, and 4, pH 7,4. The filters are dried with air, and 40

ولl of a flash fluorescent mixture (Microscint-O) was added to each well. The radioactivity of the membranous membrane was calculated in Microplate Scintillation and luminescence Counter from Perkin Elmer.

15th data analysis

Concentration response curves were provided for representative compounds of the current required obtained with the presence of EC20 of mGluR2 glutamate agonist inhalers to identify positive asynchronous modulation (PAM) using the lexis software interference (optimized at J&amp;J). The% of Bad data was calculated for the control glutamate response, defined as the maximum response generated when adding glutamate alone. Response curves of 20 sigmund concentrations were analyzed by planning these percentages versus the concentration of rule for a news compound using non-linear regression analyzes. The effect concentration is then calculated to half the maximum product as X; EC. The PEC5Q values below were calculated as the EC5Q record, when the EC50 is expressed in M. Efnax is defined as the ictal maximum effect (i.e., the relative maximum% effect of the control glutamate response).

Table E below shows pharmaceutical data obtained for summer (IB) donations and data

25 A current pharmaceutical obtained for the Summer Assistants (IA) J (I).

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Grandfather;, has e: Pharmaceutical data for compounds according to the invention.

<td>GTPyS-hmGIR PAM ECmax</td><td>GTPyS-hmGIR PAM pECso</td><td>Compound number</td>

<td> 296</td><td> 6,59</td><td>1-b</td>

<td> 228</td><td> 6,84</td><td>2-b</td>

<td> 187</td><td> 5,79</td><td>3-b</td>

<td> 256</td><td> 7,39</td><td>6 — b</td>

<td> 141</td><td> 6,06</td><td>5-b</td>

<td> 329</td><td> 7,04</td><td>4 — b</td>

<td> 292</td><td> 7,31</td><td>6 j</td>

<td> 244</td><td> 7,04</td><td>8 — b</td>

<td> 260</td><td> ٦١٦</td><td>9-b</td>

<td> 218</td><td> 7,47</td><td>0 a b</td>

<td> 239</td><td> 8,25</td><td>11 b</td>

<td> 178</td><td> 6,99</td><td>12 b</td>

<td> 284</td><td> 7,54</td><td>16 b</td>

<td> 280</td><td> ٦١٦5</td><td>13b</td>

<td> 281</td><td> 7,53</td><td>14b</td>

<td> 293</td><td> 8,16</td><td>5a b</td>

<td> 297</td><td> 6,71</td><td>9a b</td>

<td> 233</td><td> 6,9</td><td>65-b</td>

<td> 193</td><td> 6,42</td><td>24_b</td>

<td> 317</td><td> ٦١٦٦</td><td>217b</td>

<td> 213</td><td> 6,24</td><td>18 b</td>

<td> 325</td><td> 7,61</td><td>22-b</td>

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<td> 167</td><td> 5,94</td><td>223 b</td>

<td> 102</td><td> 6,32</td><td>21-b</td>

<td> 332</td><td> 7,07</td><td>20 b</td>

<td> 214</td><td> 6,78</td><td>1) 26a</td>

<td> 51</td><td>nc</td><td>27b</td>

<td>τη</td><td> 6,9</td><td>30 b</td>

<td> 234</td><td> 7,19</td><td>28 b</td>

<td> 11</td><td> 5,85</td><td>29b</td>

<td> 251</td><td> 7,05</td><td>31b</td>

<td> 116</td><td> 5,71</td><td>32 b</td>

<td> 258</td><td> 7,11</td><td> 1'</td>

<td> 286</td><td> 6,95</td><td>1a</td>

<td> 290</td><td> 7,82</td><td> 2</td>

<td> 484</td><td> 7,61</td><td>2a</td>

<td> 212</td><td>5555</td><td> 3</td>

<td> 260</td><td> 6,88</td><td> 4</td>

<td> 231</td><td> 6,26</td><td> 5</td>

<td> 263</td><td>Ί, Ί9</td><td> 6</td>

<td> 261</td><td> 7,68</td><td>6 a</td>

<td> 263</td><td> 8,45</td><td> 7</td>

<td> 360</td><td>611Ί3</td><td> 8</td>

<td> 462</td><td> 6,9</td><td> 9</td>

<td>615Ί</td><td> 7,21</td><td> 10</td>

<td> 310</td><td> 6,94</td><td> 11</td>

<td> 261</td><td> 8,36</td><td> 12</td>

43291Α1

<td>E 3</td><td>Mm</td><td> ?</td><td>a</td><td> ۴</td><td> ۴</td><td>G \</td><td> 00</td><td> ٠١</td><td>H</td><td>B E3</td><td>Yum 7</td><td>for them</td><td>What</td><td>when</td><td>Hh</td><td>G H</td><td>0Ο</td><td>01 Ή</td><td> ٠ 7</td><td>B</td><td>22-a</td><td>29 Mm</td><td>24 — a</td>

<td> 6,78</td><td> 6,84</td><td> 88'9</td><td> 6,6</td><td>E</td><td>Never mind Ό</td><td> 6,64</td><td> 6,04</td><td> 6,59</td><td> 6,88</td><td>1-1 pm</td><td> 7,03</td><td> 6,67</td><td> 6,92</td><td>G</td><td> 7,12</td><td>What 121 15</td><td>Y</td><td> 6,71</td><td> 6,91</td><td> 6,25</td><td> 6,05</td><td> 6,58</td><td> 6-91</td>

<td>What H 29</td><td> 340</td><td>39 29 yum</td><td> 269</td><td></td><td> 255</td><td>Y 01 yum</td><td>1 m M' E 3</td><td> 222</td><td> 290</td><td> 249</td><td> 242</td><td> 212</td><td> 259</td><td>29 76 yen</td><td> 223</td><td>E 3 Is Yum</td><td></td><td> 240</td><td> 243</td><td> 207</td><td> 259</td><td> 203</td><td> 258</td>

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<td> 261</td><td> 7,07</td><td>25 — a</td>

<td> 248</td><td> 6,5</td><td>26-a</td>

<td> 284</td><td> 6,48</td><td>27-a</td>

<td> 297</td><td> 6,96</td><td>28 — a</td>

<td> 317</td><td> 6,97</td><td>29-a</td>

<td></td><td>nt</td><td>30-a</td>

<td></td><td>nt</td><td>31-a</td>

<td> 347</td><td> 6,66</td><td>32 — a</td>

<td> 362</td><td> 6,58</td><td>33-a</td>

Nc means that pECso cannot be calculated

You never miss

PECso values were not calculated in cases where the focus response curve did not reach an elevated level. All triggers were selected with the presence of mGluR2 agonist inhalers glutamate at EC concentration₂₀A Predetermined,

5 To determine a positive differential modulation. The pECso values were calculated from a focus response test of at least 8 concentrations.

B) Counter studies with mGluR2 agonists (stereotaxic agonist inhalers and summer compounds (Ι-Β) / (! - Α) /. (Ι) the General Preparation of test caravans and solutions. Test caravans were given using an optimum fluid volume ratio to body fluid. White Hs, et al. General) Test for silage in a volume of 0.01 mL / g of body weight Principles: Experimental selection, quantification, and evaluation of antiepileptic drugs, in Antiepileptic Drugs, Fourth Edition, RH Levy, RH Mattson, and Bs Meldrum, Editors. 1995, Raven Press, ltd .: 15 test compounds were given inside, (SC) for subcutaneous administration (New York, pp. 99-110. (Ρ.ο) free fold of skin along the background of the fauna except for garage 6b , Which was given orally

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For each of the tests carried out on the test triggers (except compound, 6b), a final teraphenase treasury was given as an aqueous solution in 20% Hp - CD-CD. For the terrible 6b, a 40% Ηρ-β -CD brine solution was prepared and used to form a terrible 6b when the desired intimidations were tested via the oral route; the last terrier is given as suspensions in 20 and 5% Ηρ— β -CD. 20% Ηρ-β -CD solution was used for demobilized groups.

For 404039-ΙΥ, the last monk concentrations were given as subcutaneous saline length.

For 0--10-1092453 CAS, the last-terrain preparation was given in a 0% tNaCI (Ηρ-β -CD) removed following a buffered solution.

The last ligetiracetam tehizate was given in 0.5% methylcellulose (MC) aqueous solution given 10 intraperitoneal injection medium (1.Ρ)

Biological detectors

A) solutions of carrier (dissolve drugs)

0,5 H / H of methylcellulose (MC)

40% hydroxypradyl— β— cyclohexane (Ηρ— β -CD) storage solution

15th As long As she is born, for his / her vision is prepared

Four cyan (ο0,5 / 5 w / v solution) drop by point of plastic train has been added to the eyes of the animals that will later receive an alert via village electrodes.

Animals and stringed animals

1 adult male albinism mouse 1 (35-26) CF No g) was obtained from Cries River 20 Portage, Michigan. Lives were obtained on a sufficient diet (Prolab RMH

3000) It allowed easy access to water and food, except for the short time when they went out of their cages to be tested. The newly received animals were allowed in the laboratory time to correct water restrictions and for possible food incurred during transport before they were used in the test. All furnaces were housed in plastic cages in rooms created specifically for the controlled ventilation, the exchange of lighting and lighting for 25 controlled (12 working hours -12 hours extinguishing). The animals were inhabited, fed, and taken in a manner

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Ripped with. Directions in the World Council publication, Guide for the care and Use of “Laboratory Animals.”

Minimal heart failure (MMI

Acute MMI was evaluated by synthesizing direct animal observations for symptoms of overestimation of the animal's 5 or neuromuscular function. In the healer, a rotating penis segment was used to detect neurological impairment

Or muscular inferior. When a mouse is placed on a rotating rod at a speed of 6 cycles per minute, the beast can maintain its torque for long readings of adornment. The beast is considered toxic if it falls from the rotating bar of the three adsorbed within a minute.

Determination of effective and toxic bold '1 (ED50 which is T0)

10 In determining ED50 or (TD) for each of the test compounds, the first dose given is usually the same dose as that used in determining a successful TPE.

If the initial dose used is effective or toxic with more than 50% of the lives, the next dose will be half the initial dose; if the initial dose is effective or toxic with less than 50% of the lives, the next dose will have twice the initial dose. 15 third and fourth doses were chosen to produce an evenly spaced dose response line. There must be a limit

Less than 4 points either include or are between 0 and 100%.

Select TPE

Groups were given a general population of four test vehicle lives and each group tested one of five vernier points: 0.25, 0.5, 1, 2, or 4 hours after treatment (W. et al. 20 1995). TPE was determined using a 6 hr (32 mA) assay. Zain was considered (0.25,

0,5, 1, 2, or 4 hours after treatment) at which the greatest protection was observed as TPE.

At the TPE specified for this study, or preset, the garages were tested in a 6 Hz (32 and / or 44 mA) assay, between multiple doses, and including doses that did not cause or cause less than 25 protection to complete protection.

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ΕΡ50 and 95% of gene separation (CI) was calculated using Probit Analysis on a computer-supplied laboratory software (Finney Probit Analysis ”34d Ed 1971, London: Cambridge University Press).

Jem serum to lengthen ρΡ / ρΚ

5 In several tests, animals were sacrificed after the test, and the blood of the stem and / or brain tissue (all brains) was collected to determine the amount of drug levels. After the test, the heads of the animals were decapitated and the blood of the trunk was collected into a tube. BP Vacutainer contains ΕΡΤΑ2ΕΡΤΑ and contained ice until the expulsion. After the marshal expulsion (13000-18000 turns per minute, 5-7 minutes), the plasma was passed down and transferred to a delicate marshmallow centrifuge tube labeled and exuded at -80 ° C. To collect 10 brain tissue, the brains were emptied immediately after the beheading and were frozen and proceeded. The wrinkled sample was placed in a two-tube marker ejection tube and excreted at -80 ° C.

Mice psychomotor nucleation test 6 Hards in mice

The 6 HARDS fit test is used as a pharmacy-resistant limbal attacks pattern. A 6 Hz seizure exhibits a resistance of 15 to guinetine, carbamazepine, lamotrigine, and tuberate (Barton et al. Pharmacological characterization of the 6 Hz psychomotor seizure model of partial 217-222. (Epilepsy ”Epilepsy Research, 2001, Vol. 47, pp.

Method for testing a 6 Hz psychotropic fit

Focal episodes were induced in the fusion by a village precipitate (6 Hz, 0.2 mS of rectangular pulse, 3 20 fps; 2001 Barton et al.). The winners were tested either at 32 mAh or 44

MAh. Before the alarm, a drop of 0.5% tetrahydropase was applied to each eye. The disturbances that arose from village stimulation in this lengthening are characterized by a minimal grazing phase followed by typical spontaneous behaviors and we include awesomeness, spasticity of the front leg, tremors of the nasal hairs, and strobe tail. The animals that have not exhibited these behaviors are protected.

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Shawl 1 - Dzat with singles 1 and 2

1.1. Combination lesson with spindle rum 1, spindle despite 2 estetite and acetam

Otherwise, each gouge was tested in an individualized dose at a dose showing the haemolytic activity in a 6 Hz 44 mA test at each gasket TPE. When the advantages of mGluR2 PAM 5 and litigetetam are given in combination (the inventory and the zinnia point itself as a fractional option), almost complete protection is monitored in the choice of 6 hr 44 mA (Table 2). In addition to recording the efficacy and toxicity data for these singles separately or in combination, as both the plasma and brain samples were collected from all groups for inferiority, prolonged pharmacokinetics. The inferior hairlogene reactor was not teared depending on the level of features in the plasma and brain samples of 10 (data not shown). In the general description, I showed that celibacy 1 and 2 denote inferiority

Positivity with ligner-acetam in the ED 6 HERZ model that did not appear due to the interaction of inferior haemorrhagic, and subconsciously heliopathy (Tables 2'2a, 2b). Likewise, the effect of 1 dose of dilator 2 on the dose response of LEV was not tested. As shown in Table 3, there is a change of -200 fold in the EDO of the LEV by volume when testing the LEV separately. Whereas, LEV seemed to increase the potency of 15 gutter No. 2 molecularly (Table 3).

2.1. Analysis of exponential radial recording of the interactions between compound No. 1 and the litecetam in a 6 Hz ED model.

Isotropic radial thresholds were administered in order to give built-in hoseband number 1 with LEV in an analysis of (44 mA) ED 6H. The studies were also managed according to the previously described methods 20 (2011, Madsen et al.). Initial ED50 values were identified for both spill No. 1

LEVj and use them to calculate ED values₅₀ Theory (SEM, standard error, SEM) for three combinations of fixed dose rate (LEV: hustle No. 1): 3: 1; 1: 1; and 3: a. The doses used are proportional to calculating the values of Ed 05555. For example, the dose rate used for a sample if based on 0.5 ED5Û X for LEV and 0.5 ED5Q X for 25 dilator number 1. Similarly, Sample 3: 1 use 0.25 ED50 X for LEV and 0.75

50550 X for Dosage No. 1. Also, the dose ratio of 3: 1 use 0.75 ED5Q lev X and

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25; 0 ED50 X for desired No. 1. Experimental treatment doses (see Table 4) are dependent on theoretical values and adjusted according to the observed parameters. Experimental defined (0) values (± SEM; ED) were compared for a combination with a fixed dose rate with theoretical values (tested) for statistical purposes. The dose rate was determined to be above, added (synergistic) while the value of ED50 specified was experimentally 5 less than ED Theoretically significant ED50 is then experimental combined doses are determined for the same models in a 6 Hz ED nucleus test (Table 4 below). In the ED6 model, the isotropic pharmacodynamics were shown to be very important at all granular dose rates and we adhered tightly to the PLA levels of the desirable 1. On the other hand, the literal morbidity at any of the calculated dose rates of 10 was not suggested. That the synergistic inferior dynamics interact does not produce a unique literal toxicity.

3.1. Agglomerative mouse murine tumor model with compound 1

The booster was electrically stimulated with 3 sec, 3 mA, 60 Hz alarm, daily run using a village electrodes unit up to a standard of 5 interconnected stage D 5 shifts as defined here by Racine (Racine) modification of the activity of the nucleus through an electrical caution 11. Literal seizure 15 281-294 Electroneceph Clin Neurophysiol 1972, 32, pp) -. After the mice arrive

To a stable irritation state, a wanted or selector carrier is given and, in a predetermined TPE, each animal is given the electrical stimuli referred to above. Next alert, the animals were monitored for the presence or inactivity of a seizure activity recorded on the AD 5-0 scale (Racine) with a review of the high or low patch high or low. One of the LEV doses and two dose of Describer No. 1 were tested individually 20 and in a combination of opinions of corneal irritation attacks. A combination of desirable 1 with ligetracetam in this model is proposed with a positive pharmacodynamics transporter (Table 5 below).

A summary of the data for the tested descendants is shown separately in Table 1 and additional results for the achieved breaks according to Example 1 are listed in Tables 2-5 below.

Acute!!: Acute anticonvulsant drug data for ED 6Hz ED model 32 mAh 25 and 44 mA for 2, 11, 2, 1 mG! UR2 PAM— A, 25 — A, 6 — B

The 404039 — LY subordinate to subcutaneous administration (with the exception of the desired 6-b, which was tested in mines).

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TPE crosses the peak-effect, a CI crosses the reliability interval, SC subcutaneous, meaning Ρ.Ο by cloud, and means untested nt. TPE was determined in a 6 Hz 32 mAh test. Effects are generally monitored at doses that do not result in morbidity in the Rotarod test. For the extra terrestrial 11 and 2-A, the alpha-values are provided for repeated trials. For compound 25a, each of the 0.25 lpa period points was used for studies (44 mA) ed 6 Hz.

<td>Nucleus score (dose)</td><td colspan="2">Ha Ha (95% Cl) mg / kg, subcutaneously</td><td rowspan="2">TPE (Sa)</td><td rowspan="2">Compound number</td>

<td>Corneal irritation</td><td>44 mAh</td><td>32 mAh</td>

<td>2.8 (100 mg / kg)</td><td> (47,3-15,1) 31,5</td><td>14096 LAL-66 JLM</td><td> 0,5</td><td> 11</td>

<td>3,4 (40 kg / kg)</td><td> (8,45-3,89) 5,89</td><td> (6,71-1,62) 3,83</td><td> 0,25</td><td> 2</td>

<td>E 2 tgm know</td><td> (12,4-3.1) 10,2</td><td> (4,3-1,3) 2,8</td><td> 0,5</td><td> 1</td>

<td>nt</td><td>ASA 15,5) 25,9: TPE- 33,7) 0,25 SA TPE: 29,1 (39,6-21,6)</td><td> (18,4-2,3) 7,7</td><td> 1</td><td> 1—25</td>

<td>4.4 (100tg / kg)</td><td>50% protection at 100 mg / kg 21 (17.9-27.4)</td><td> (80,5-23,4) 44,7 (31,7-10,0) 20,8 (17,4-8,4) 12,2</td><td> 0,5</td><td>2-a</td>

<td>nt</td><td> (20,1-13,0) 16,1</td><td> (11,8-4,2) 7,2</td><td> 0,5</td><td>6 — b</td>

<td>3.1 (100 tg / kg)</td><td>nt</td><td> (12,4-3,62) 10,2</td><td> 0,5</td><td>7a 404039</td>

Table 11: Summary of TPE Identification Ed 6 Hrsh 32 mA for Compound No. 1

<td>Motor impairment</td><td>6 Hz 32 mAh</td><td>Period (sa)</td><td>Dosage (mgacg, subcutaneously)</td>

<td>0.0</td><td> 410</td><td> 4</td><td rowspan="5"> 10</td>

<td> 0/0</td><td> 410</td><td> 2</td>

<td> 0/0</td><td> 4/3</td><td> 1</td>

<td> 0/0</td><td> 4/4</td><td> 0,5</td>

<td> 0/0</td><td> 4/4</td><td> 0,25</td>

<td> 010</td><td> 12/8</td><td> 0,5</td><td rowspan="2"> 5</td>

<td> 0/0</td><td> 12/8</td><td> 0,25</td>

<td> 0/0</td><td> 8/5</td><td> 0,5</td><td rowspan="2"> 2,5</td>

<td> 0/0</td><td> 8/1</td><td> 0,25</td>

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(Number of winners shielded at 6 Hz or capacitive on a rotary drive laboratory number)

The grandfather. Game: Studies of the stump response for the monk Rom. TPE Ed for Tier 1 has been previously stretched to 0.5 h (results are shown above in Table A). A few 5 doses of aphid No. 1 were given at this TPE and tested in the 6 Hz ED analysis, using both Nubia intensity 32 and 44 mA.

<td>Physiognomy (DETOD # / Anesthetist</td><td>Laboratory heater</td><td>Dosage (mg / kg, skin opacity)</td><td>Exam</td>

<td> 8/1</td><td> 8/8</td><td> 20</td><td>6 Hz 32 mAh</td>

<td> 8/0</td><td>6</td><td> 10</td><td></td>

<td> 12/0</td><td> 12/8</td><td> 5</td><td></td>

<td> 16/0</td><td> 16/7</td><td> 2(5</td><td></td>

<td> 8/0</td><td> 8/1</td><td> 0،5</td><td></td>

<td colspan="4">2,8: (Cl% 95) EDjo / kg (1,3 to 4,3)</td>

<td> .8/1</td><td> 8/8</td><td> 20</td><td>6 Hz 44 mAh</td>

<td> 8/0</td><td> 8/7</td><td> 15</td><td></td>

<td> 8/0</td><td> 8/4</td><td> 10</td><td></td>

<td> 8/0</td><td> 8/0</td><td> 2،5</td><td></td>

<td colspan="4">10,2: (Cl% 95) ED_SO Kg / kg (3,1 to 12,4)</td>

- Summary of the interaction of terrible number 1 and compound Duqm 2 with ligetizetam (LEV) in the mouse

6 Hz, sample core 44 mAh. The results were recorded in a table as a number of two furnaces were shown

10 Total protection / total number of mice of choice in each dose group (at the test compound

Specified or combination dose levels).

<td># Motortox / #</td><td>* He is chubby</td><td>Time (sa)</td><td>dose</td><td></td>

<td>Anesthetist</td><td></td><td></td><td></td><td></td>

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<td> 6/0</td><td> 6/1</td><td> 1</td><td>10 mg / kg intraperitoneal</td><td>LEV</td>

<td>Ha 6</td><td>5 aa</td><td> 0,25</td><td>3 mgacg retains skin</td><td>Complex number 2 * LEV</td>

<td> 6/0</td><td> 6/1</td><td> 0,25</td><td>3 kg / kg subcutaneously</td><td>Al-Moarkak) No. 2</td>

<td> 8/0</td><td> 8/1</td><td> 1</td><td>10 mg / kg intraperitoneal</td><td>Okay</td>

<td> 8/0</td><td> 8/6</td><td> 0,5</td><td>2.5 mg / kg subcutaneously</td><td>Complex No. 1A LEV</td>

<td> 8/0</td><td> 8/0</td><td> 0,5</td><td>2.5 mg / kg subcutaneously</td><td>Al-Marri R. Qum 1</td>

Limit; L2A: Plasma and brain levels of Meryem Raem 1 in a combination with Legiterium (LEV). BQI means below the measurable limit.

<td>Protection 6 Hz</td><td>Plasma (Nalo gr / ml)</td><td>Complex number 1</td><td>Plasma (Nadu ghzm / ml)</td><td>LEV</td><td>Complex number 1</td>

<td>Yes</td><td>BQL</td><td>5, 2 mg / kg</td><td> 9350</td><td>10 mg / kg</td><td>6 Hz 44 Mil Hotel is situated</td>

<td>No</td><td> 244</td><td></td><td> 8580</td><td></td><td></td>

<td>Yes</td><td> 314</td><td></td><td> 10900</td><td></td><td></td>

<td>Yes</td><td> 382</td><td></td><td> 10300</td><td></td><td></td>

<td>Yes</td><td> 416</td><td></td><td> 9780</td><td></td><td></td>

<td>Yes</td><td> ٦٦٦</td><td></td><td> 9780</td><td></td><td></td>

<td>No</td><td> *2260</td><td></td><td> 13700</td><td></td><td></td>

<td>Yes</td><td> 607</td><td></td><td> 10100</td><td></td><td></td>

<td> 8/6</td><td> 657،1 (390)</td><td></td><td> 10311</td><td></td><td>Average level Plasma</td>

<td colspan="6"></td>

<td></td><td> 438</td><td> 8/0</td><td> 8254</td><td> 8/1</td><td>Average levels Plaza (not</td>

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<td></td><td></td><td></td><td></td><td></td><td>blend)</td>

The average plasma level indicated in an intercepted sentence () is calculated with a statistical chart 0 removed

Eccentricity of Plasma and Brain Levels of Compound No. 2 in Combination Study with Legiterium

5 Kiev Zhuliany airport (IEV). AQ1 means below the measurable limit.

<td>protection 6 Hz</td><td>Brain (natu ghzm / ml)</td><td>Plasma (tattoo bag / ml)</td><td>Terrifying Number 2</td><td>Brain (natu ghzm / ml)</td><td>Plasma (natu gsm / ml)</td><td>IEV</td><td>Al-Marri, No. 2</td>

<td>Yes</td><td> 1540</td><td> 1830</td><td>3 mg / kg</td><td> 6290</td><td> 6450</td><td>10 Pigment '</td><td>6 Hz 44 mAh</td>

<td>Yes</td><td> 1020</td><td> 386</td><td></td><td> 7990</td><td> 8200</td><td></td><td></td>

<td>Yes</td><td> 1310</td><td> 4700</td><td></td><td> 4760</td><td> 3540</td><td></td><td></td>

<td>No</td><td>I</td><td> 467-</td><td></td><td>NA</td><td> 3850</td><td></td><td></td>

<td>Yes</td><td> 1120</td><td>AQL (500 &lt;)</td><td></td><td> 6380</td><td> 7150</td><td></td><td></td>

<td>Yes</td><td> 1140</td><td> 2080</td><td></td><td> 3960</td><td> 3890</td><td></td><td></td>

<td colspan="8"></td>

<td>6</td><td> 1226</td><td> 1893</td><td></td><td> 5876</td><td> 5513</td><td></td><td>Average playa / brain levels</td>

<td colspan="8"></td>

<td></td><td> 1113</td><td> 1295</td><td>AA 6</td><td> 5113,</td><td> 8750</td><td> 6/1</td><td>Average plasma levels of the brain (not synthesis)</td>

Sample - NA is not available for analysis

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- ED selections_SO For a 6 Hz (44 mAh) nucleus model for compound No. 2 and a LEV separately or in a combination. Ed IEV response at a dose of 10 mg / kg of MDG No. 2 (fold change-~ 5 in EDso). The response of the desired DGM 2 at a dose of 3 mg / kg has both effect (to 100% protection) and the effectiveness of IEV (fold change ~ ~ 200 in EDso).

Figure 1 shows the dose response for the 44 Hz EDso selections of 44 mA for desired despite the individual I and D combinations.

<td>Maximum impact (% protection)</td><td>95) EDjo E / H 1 mg / kg</td><td>Processing</td>

<td>100 e / h</td><td> (8,30-5,44) 6,97</td><td>Complex number 2 separately</td>

<td>100 e / h</td><td> (1,9-0,8) 1,35</td><td>Shout 2 + LEV</td>

<td></td><td></td><td>(0 Og / kg)</td>

<td> %75</td><td> -200</td><td>LEV separately</td>

<td> ٥/٠100</td><td> (2,24-0,23) 1,0</td><td>LEV + Shelf No. 2</td>

<td></td><td></td><td>(3 kg / kg)</td>

- Results of compound RM1 and litigetacetam in the isoform radiography study.

<td>6 Hz (44 mAh) H 0 0 Akkad</td><td>Rotarodemortortux ester</td><td>Dosage: Built in 1 dose</td><td>f</td><td>Complex number A (TG / Kg skin sculpting)</td><td>f</td><td>LEV (Kg / kg intraperitoneal)</td><td>the group</td>

<td> 8/8</td><td> 8/0</td><td> 93,1</td><td rowspan="4"> 0,5</td><td> 5,1</td><td rowspan="4"> 0,5</td><td> 181</td><td rowspan="4">Model 1: 1</td>

<td> 8/6</td><td> 8/0</td><td> 46,6</td><td> 2,6</td><td> 90,5</td>

<td> 8/3</td><td> 8/0</td><td> 23,3</td><td> 1,3</td><td> 45,3</td>

<td> 8/3</td><td> 8/0</td><td> 11,6</td><td> 0,6</td><td> 22,6</td>

<td colspan="8">5/55) EDso Cl; kg / kg): 22.2 (8.4-35.7)</td>

<td> 8/8</td><td> 8/0</td><td> 14,2</td><td rowspan="2"> 75,</td><td> 3,8</td><td rowspan="2"> 25,</td><td> 45,3</td><td rowspan="2">Model 3: 1</td>

<td> 8/4</td><td> 8/0</td><td> 7,1</td><td> 1,9</td><td> 22,6</td>

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<td> 8/2</td><td> 8/0</td><td> 3,6</td><td></td><td colspan="2"> 1,0</td><td colspan="2"> 11,3</td>

<td colspan="8">Cl% 95 (EDso; kg / kg): 22,2 (3,5-8,7)</td>

<td> 8/8</td><td> 8/0</td><td> 204,3</td><td rowspan="4"> 25,</td><td> 2,6</td><td rowspan="4"> 75,</td><td> 271,5</td><td rowspan="4">Model 1: 3</td>

<td> 8/3</td><td> 8/0</td><td> 102,2</td><td> 1,3</td><td> 135,8</td>

<td>When?</td><td> 8/0</td><td> 51,1</td><td> 0,6</td><td> 67,9</td>

<td> 8/0</td><td> 8/0</td><td> 25,5</td><td> 0,3</td><td> 33,9</td>

<td colspan="8">5/55) EDso Cl; kg / kg): 86.3 (56.8-131.4)</td>

Isoform radiographic recording analysis (Figure 2) pumped the blend mixture of RNM1 and lefetidecetam

It ends with an extremely important synergistic effect.

Table 5: A Synthesis Study of Compound Results 1 and Legitizetam in a Village Irritability Model

Mice.

<td>Average seizure score</td><td>% Protected</td><td>* Protected *</td><td>The Garage</td>

<td> 4,7</td><td> %0</td><td> 10/0</td><td>Holder (0.020-30 @ HPBCD, subcutaneous; 5.5 / 0'MC @ 6O, peritoneal)</td>

<td> 3,3</td><td>38 AH / H</td><td> 13/5</td><td>3 LEV mg / kg</td>

<td> 4,0</td><td>025 / H</td><td> 12/3</td><td>The compound for M1 is 30 mg / kg</td>

<td> 0,6</td><td>100 e / h</td><td> 10/10</td><td>3 LEV / kg / kg &amp; 1 rum a 30 mg / kg</td>

<td> 3,7</td><td>5/31</td><td>E |</td><td>The blowing time for a mother is 1 to 20 kg / kg</td>

<td> 1,9</td><td> %70</td><td>6 people</td><td>3 LEV mg / kg &amp; compound 1</td>

<td colspan="4">0 Racine score to 5 0 = not seizure activity 5 = Maximum shift activity</td>

Example 2 - Dats with 25-A and 2-A blowers

1.2. A combination lesson with a blown RM 25-A and litigetetam

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The independent dose response studies were performed in the ED 6 HERZ 44 mA test for each of the monitors to determine the ED50 values in the TPE ed of 1 SA intraperitoneal for subcutaneous litigeretam and LA SA for compound No. 25-A. The value of EDq for jam 25 - A is for 25.9 mg / kg and for the libecetacetam the value was estimated to be approximately 345 mg / kg.

5 The dose response for levetiracetam was repeated with a 10-mg / kg buyer giving jam 25-a (dose 25-a-jam that was not protected in the ED 6 of HER 44 mA unit separately). Intensive administration of 10 mg / kg of 255-A ED5Q-activated tumor in response to a levetiretetam dose of 4,9 mg / kg (fold-70 ~ less measured with ligendre acetam separately) was fully protected and significantly yielded in the ED 6 hr 44 ml model hotel is situated. These results are indicative of

10 A positive pharmacodynamic reaction in the ED 6 hub model between Educator No. 25A and litigetetam.

Table 6: Determination of the effect of the peak-ES-peak for compound No. 25-A in the analysis of AD 6 Hz

(32 mAh). Two doses were used in this study, 10 and 20 mg / kg, via

15th A few zenia points (0.25-4 h) 0 The educator showed the greatest degree of protection in the lengthening of AD 6 hr between 0.25 l and h, which is more pronounced at 20 mg / kg. The plasma levels of the educator generally matched with the protection of a behavioral fit. TPE of 0,25 h was used for 6 Herpes (32 mAh) lessons, where 0,25 and 1 h of oil points were used for 6 Hz (44 mAh) throws.

20 SC means subcutaneously

<td>Complex No. 25-Centre for average benana levels (natu gsm / ml)</td><td># Rotarod motility /#laboratory</td><td>My lick was blackmailed</td><td>The period (sa)</td><td>dose 1 cook 0, subcutaneous)</td>

<td> (2(477) 10‘983</td><td> 4/0</td><td> 4/2</td><td> 0,25</td><td rowspan="4"> '10</td>

<td> 3(330</td><td> 4/0</td><td> 4/1</td><td> 0,5</td>

<td> 700</td><td> 4/1</td><td> 4/1</td><td> 1</td>

<td> 256</td><td></td><td> 4/0</td><td> 2</td>

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<td> 40</td><td> 4/0</td><td> 4/0</td><td> 4</td><td></td>

<td colspan="5"></td>

<td> 4،095</td><td> 4/0</td><td> 4/4</td><td> 0,25</td><td rowspan="5"> 20</td>

<td> 2،800</td><td> 4/1</td><td> 4/3</td><td> 0,5</td>

<td> 1،765</td><td> 4/1</td><td> 4/4</td><td> 1</td>

<td> 618</td><td> 4/0</td><td> 4/1</td><td> 2</td>

<td> 28</td><td> 4/1</td><td> 4/1</td><td> 4</td>

The mean level of plasma was calculated in an You () with a statistical chart removed.

Dosage response studies for compound No. 25-A in the analysis of AD 6 herpes (32 mAh and 44 mA)

5 CI relieves spacer to reliable comma

<td>Compound No. 25-Î for inactive spatula lines (natu gsm / ml)</td><td>* Rotard kinetics * laboratory</td><td># Lab # is protected</td><td>Dosage (kg / kg, under scratch)</td><td>Exam</td>

<td> 5,570</td><td> 8/0</td><td> 8/8</td><td> 20</td><td rowspan="5">6 harrier 32 mAh</td>

<td> 1,201</td><td> 8/0</td><td> 8/3</td><td> 15</td>

<td> 6,113</td><td> 8/0</td><td> 8/4</td><td> 10</td>

<td> 2,558</td><td> 16/0</td><td> 8/4</td><td> 5</td>

<td> 466</td><td> 8/0</td><td> 8/1</td><td> 1</td>

<td colspan="5">5/595) EDso 7.7: Cl mg / kg (2.3 to 18.4)</td>

<td> 6,263</td><td> 8/0</td><td>6</td><td> 40</td><td rowspan="5">6 Hz 44 mAh</td>

<td> 7,220</td><td> 8/0</td><td></td><td> 30</td>

<td> 3،368</td><td> 8/0</td><td> 8/2</td><td> 20</td>

<td> (1(526) 4،345</td><td> 8/0</td><td> 8/0</td><td> 10</td>

<td> 1 ،428</td><td> 8/1</td><td> 8/0</td><td> 5</td>

<td colspan="5">29,1: (Cl% 95) EDjo mg / kg (21,6 to 39,6)</td>

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The effect of the period-to-excretion effect was determined in the length of 32MAH AD 6 HER for compound No.

25-a lekin 0.25 h (see Table 1).

The effect of the peak-to-peak period in ED 6 Hz analysis is 44 mA for Monitor 25-A similar for 0.25 SOL; results confirmed for 1 SAD 95 ED (EDso / 5 25.9) CI 5 (33). , 7-15.5) (see Table 1 and 6).

The mean plasma level is calculated in a cross beam () with a statistical chart removed.

- Combination studies for compound No. 25 — a with litigeritam (1Ε7) in ED 6 Hz (44 mA) length.

<td># Rotarod Kinetics / # Lab</td><td>C * baker</td><td colspan="2">Dosage (mg / kg, subcutaneously)</td><td>Medicine</td>

<td> 8/0</td><td> 8/2</td><td colspan="2"> 200</td><td>Okay</td>

<td>E | 9</td><td> 9/4</td><td colspan="2"> 400</td><td></td>

<td> 12/0</td><td> 12/10</td><td colspan="2"> 800</td><td></td>

<td colspan="5">5/595) EDso 345.4: Cl / kg (211.0 to 485.3)</td>

<td>Physiology and Attitude / Lab #</td><td>C * churn</td><td>Dosage (kg / kg, subcutaneously)</td><td colspan="2">Warmth</td>

<td> 8/1</td><td> 8/8</td><td> 200</td><td colspan="2">LEV + Marri number 25-a 10 tg / mg</td>

<td> 9/2</td><td> 8/7</td><td> 100</td><td colspan="2"></td>

<td> 8/1</td><td> 8/5</td><td> 50</td><td colspan="2"></td>

<td> 8/0</td><td> 8/4</td><td> 10</td><td colspan="2"></td>

<td> 8/1</td><td> 8/4</td><td> 1</td><td colspan="2"></td>

<td colspan="5">4,9: (Cl% 95) EDjo, kg / kg (0.0 to 14.2)</td>

10 Monitor No. 25-a (subcutaneously) 10 mg / kg tested in combination with LEV (intraperitoneal) Monitor No. 25-a 10 mg / kg, is not active when administered separately.

2.2. Dozen of the combination, with compound No. 2-A and leceteretam

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Dosage response studies were performed in ED6Herez 32 mA and 44 mA tests (Table 9 below) and in a combination trial with lignisecetam (effect of selector No. 2 — A on dose response from LEV in Table 1A and the effect of LEV on the dose response of compound No. 2 A) in Table 10b below) in the same manner as described for studies with Terrorist No. 25-A5 and Levenspecetam above.

Table 9: Dosage response studies for fishy No. 2-a in a 6 Hz ED analysis (32 mA to 44 mA; 0.5 SA TPE). The effect of ghtr-to-peak from 0.5 hr was determined in a 32 mAh ED test (6 sub-skin) and used for 10 6 Hz (32 mA and 44 mAh) tests.

<td># Rotarod Kinetics / # Lab</td><td>Hahay; * Bakery</td><td>Dosage (mg / kg, skin opacity)</td><td>the test</td>

<td> 8/2</td><td> 8/8</td><td> 40</td><td rowspan="5">6 Hz 32 mAh</td>

<td> 8/3</td><td> 8/6</td><td> 20</td>

<td> 8/0</td><td> 8/4</td><td> 10</td>

<td> 8/0</td><td> 8/0</td><td> 5</td>

<td> 8/1</td><td> 8/0</td><td> 2,5</td>

<td colspan="4">12,2: (Cl% 95) EDso mg / kg (8,4 to 17,4)</td>

<td># Rotaroud nephropathy / # laboratory</td><td>AM * Anesthetist</td><td>Dosage (mg / kg, Under the skin)</td><td>the test</td>

<td> 8/4</td><td> 8/8</td><td> 40</td><td rowspan="4">6 Hz 44 mAh</td>

<td> 8/0</td><td> 8/3 8/3</td><td> 20</td>

<td> 8/0</td><td> 8/2</td><td> 15</td>

<td> 8/1 8/0</td><td> 8/0 8/0</td><td> 10</td>

<td colspan="4">5/55) EDjo 21.0: (Cl mg / kg (17.9 to 27.4)</td>

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&lt;40: TDjo mg / kg

40 Mg / kg-6 by total 16 (32 mA and 44 mA combined) with morbidity.

Doses chosen for combination studies with LEV at 6 hr (44 mAh): Desired No. 2-a, 10 mg / kg.

Table 0a: Synthesis indexes for compound No. 2a with levercetam (LEV) in a 6 Hz (44 mA) analysis. A combination of 10 mg / kg of desired No. 2-a with a diversified dose of ligetisetam.

<td>Traumatic motor impairment / # laboratory</td><td># Protected / # Lab</td><td>Dosage (kg / kg)</td><td>Aldo</td>

<td> 8/0</td><td> 8/2</td><td> 200</td><td rowspan="3">For later</td>

<td> 9/0</td><td> 9/4</td><td> 400</td>

<td> 12/0</td><td> 12/10</td><td> 800</td>

<td colspan="4">5/595 (EDjo 345.4: Cl (mg / kg) 211.0 to 485.3)</td>

<td> 8/1</td><td> 8/6</td><td> 200</td><td rowspan="8">Desired t LEV No. 2-a, 10 mg / kg</td>

<td> 8/0</td><td> 8/6</td><td> 100</td>

<td> 8/0</td><td>6 &lt;?</td><td> 50</td>

<td> 8/0</td><td> 8/8</td><td> 25</td>

<td> 8/0</td><td> 8/5</td><td> 12,5</td>

<td></td><td> 8/4</td><td> 6,25</td>

<td> 8/1</td><td> 8/3</td><td> 3,125</td>

<td> 8/0</td><td> 8/0</td><td> 1,5625</td>

<td colspan="4">5/595) LEV EDjo 9,6: (Cl mg / kg (1.7 - 21.9)</td>

Complex No. 2-A (subcutaneously) 10 mg / kg is tested in combination with LEV (intraperitoneal) -

10 Describer No. 2-a, 10 mg / kg, inactive when given separately.

The additional LEV iPad control groups (low dose) were tested at 25 and 6,25 mg / kg (1/8 and 6/0 protected, respectively).

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We did not show the treated women with a pregnant woman (0,5% amelase cellulose inside the the peritoneum (1 h) 20 a)

Subcutaneous HIPBCD (0,5 h)) Protection (8/0 protected).

Table 0Ab: Combination studies for subscriber 2-a with litigetetam (LEV) in the analysis

5 ED 6 Hz (44 mAh). A combination of 350 mg / kg ligiracetam with a variety of dose-promoter No. 2-A.

<td>Dosage (kg / kg)</td><td>Warmth</td>

<td> 350</td><td>LEV (one unit)</td>

<td> 20</td><td rowspan="4">350 LEV mg / kg 0 compound 2_a</td>

<td> 10</td>

<td> 5</td>

<td> 2,5</td>

<td> 1.25</td><td></td>

<td colspan="2">Formerly EDO-2 compound (95% LEV combination of ED-2 compound_SO( Fold change -4</td>

<td># Psychopathy and anesthesia</td><td># Protected! # Lab</td>

<td> 8/0</td><td> 8/3</td>

<td> 8/2</td><td> 8/8</td>

<td> 8/1</td><td>1 a</td>

<td> 8/1</td><td> 8/7</td>

<td> 8/0</td><td> 8/5</td>

<td> 8/0</td><td> 8/4</td>

<td colspan="2">21,0: (CI غg / kg (17,9 to 27,4) 5/595 1,5: (Cl mg / kg (0.1-2.7) [~ in potency</td>

LEV ED5Q (present separately) Preset at 6 Hz (44 mAh): 345 mg / kg.

Halmerbee No. 2-A (subcutaneously) 10 mg / kg laboratory in combination with LEV (intraperitoneal);

10 Monogenic No. 2-a, 10 mg / kg, inactive after administration separately.

Control groups additional LEV d (low dose) were tested at 25 and 6,25 mg / kg (1/8 and 6/0 protected, respectively).

The treated patients did not show pregnant (0.5% methylcellulose inside the the peritoneum (1 h) or 20% HPBCD subcutaneously (0,5 h) protection (8/0 protected)).

15th At a dose of 10 mg / kg subcutaneously, the terrible number 2-A increases the potency of the LEV ed, resulting in approximately a change in the fold-35 in the ED5Q ed. This suggests a positive pharmacodynamic relationship

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(Table 10a). At a dose of 350 mg / kg intraperitoneal, LEV increases the potency of sputum No. 2A, resulting in approximately a change of fold-14 in ED50. This suggests a positive pharmacodynamic relationship (Table 0Ap).

5 Example 3 - Dizas of Bustle 6 — b

1, 03 Combination Lesson with Gutter No. 6 — B and Legiteretetam

Independent dose response studies were performed in a 446 mA ED 6 Hr test for each of the cachexers to determine DE5Q values at TP1D ed in the the peritoneum for leviteretam and 0.5 Sg in kg for ester 6-b. Where the value of ED EDQ for the spill is No. 6-b

10 It is 16.1 mg / kg, and for leviteretam, the value is estimated to be approximately 345 mg / kg.

The dose response for levlasetetam was synergized with a 10 mg / kg buyer being given to Azab No.

6-b (dose of Hz-6-b which did not protect in AD 6 Hz model 44 mAh separately). Fragmented administration of 10 mg / kg for cutting No. 6b produced the ECo in response to a litigeracetam dose of 2.4 mg / kg (-100-fold lower measured separately with lakhbenecetetam separately) 15 and fully protected extremely important in the ED 6 hub model 44 MAh. Where

These results are indicative of a positive pharmacodynamic interaction in a 6 Hz ED fit model between Hb 6 - b and ligetiracetam.

Acute 114: Determination of the effect of peak-to-peak for compound No. 6-b (in kg) in the analysis of ED 6 of 20 Hz (32 mA).

<td>Traumatic motor impairment / # laboratory</td><td>* Protected 1 * Reduced</td><td>Time (sa)</td><td>Dosage (kg / kg, kg)</td>

<td>E | e</td><td> 4/1</td><td> 0,25</td><td rowspan="4"> 10</td>

<td> 4/0</td><td> 4/3</td><td> 0,5</td>

<td> 4/0</td><td> 4/0</td><td> 1</td>

<td>21 4</td><td> 4/1</td><td> 2</td>

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<td> 4/0</td><td> 4/0</td><td> 4</td><td></td>

<td colspan="4"></td>

<td> 4/0</td><td> 4/4</td><td> 0,25</td><td rowspan="5"> 20</td>

<td> 4/0</td><td> 4/3</td><td> 0,5</td>

<td> 4/0</td><td> 4/4</td><td> 1</td>

<td> 4/0</td><td> 4/0</td><td> 2</td>

<td> 4/0</td><td> 4/1</td><td> 4</td>

TPE specified is 0,5 h

Grandfather;, for L12: Dose response response for compound number 6-b at 6 H ED ed (32 mA and 44 mA; 0.5 SA TPE).

<td># Rotarod Kinetics / # Lab</td><td>* Protected * Mudd</td><td>Dosage (kg / kg, kg)</td><td>the test</td>

<td> 8/0</td><td>6%</td><td> 20</td><td>6 Hz 32 mAh</td>

<td> 8/0</td><td> 8/6</td><td> 10</td><td></td>

<td> 8/0</td><td> 8/2</td><td> 5</td><td></td>

<td> 8/0</td><td> 8/1</td><td> 2,5</td><td></td>

<td colspan="4">7,2: (Cl% 95) ED₅₂ Smoke / kg (4,2 to 11,8)</td>

<td> 8/0</td><td> 8/8</td><td> 40</td><td>6 Hz 44 mAh</td>

<td> 8/0</td><td> 8/6</td><td> 20</td><td></td>

<td> 8/0</td><td> 8/4</td><td> 15</td><td></td>

<td> 8/0</td><td> 8/0</td><td> 10</td><td></td>

<td colspan="4">16,1: (Cl% 95) ED⁵⁰ Kg / kg (13,0 to 20,1)</td>

Limit; L13: Twife studies for a terrifying 6-b bud with LEV in the analysis of ED 6 HERZ (44 mA).

<td>Rotarrod Kinetic Disorder / #</td><td>* Protected! * Lab</td><td>Dosage (mg / kg,</td><td>Aldo</td>

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<td>Anesthetist</td><td></td><td>Bismillah)</td><td></td>

<td> 8/0</td><td> 8/2</td><td> 200</td><td>Alakka</td>

<td> 9/0</td><td>4 or</td><td> 400</td><td></td>

<td> 12/0</td><td> 12/10</td><td> 800</td><td></td>

<td colspan="4">5/55) ED₅₂ 345,4: (Cl kg / kg (211,0 to 485,3)</td>

<td> 8/0</td><td> 8/8</td><td> 200</td><td>LEV + fishy number 6-b 10 mg / kg</td>

<td> 8/0</td><td> 8/8</td><td> 100</td><td></td>

<td> 8/0</td><td> 8/5</td><td> 50</td><td></td>

<td>Rotarrod gynecology / # abbreviated</td><td>Protected</td><td>Stump (kg / kg, kg)</td><td>s</td>

<td> 8/0</td><td> 8/5</td><td> 10</td><td></td>

<td> 8/0</td><td> 8/5</td><td> 1</td><td></td>

<td colspan="4">5/595) 2.552 2,4: (CI 0 kg / kg (0.0 - 6.4)</td>

Fishy No. 6-b (in kg) 10 mg / kg tested in combination with lEV (intraperitoneal) fishy No. 6-b 10 mg / kg, inactive when given separately

5 Example 4 - LY4O4O39 Chargers

1.4 A combination of HA 404039 and lititeretam

404039 — LY was tested separately in combination with litigetetetam and according to the sections described previously. The results of the studies performed with LY-4O4O39 are recorded in Tables 15-14.

Table 14: Dosage response studies for LY4O4O39 in ED 6 hr length (32

MA and 44 mA). The effect of the peak-to-peak interval was determined from 0.5 h in the ED 6 test

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23 Hz (under the skin) and used for AD 6 hr (32 mAh and 44 mAh) chips.

<td># Rotarod motility /#laboratory</td><td>* Mahi A</td><td>Dosage (kg / kg, uncle)</td><td>the test</td>

<td> 8/1</td><td> 8/8</td><td> 40</td><td>6 Hz 32 mAh</td>

<td> 8/1</td><td> 8/6</td><td> 20</td><td></td>

<td> 8/0</td><td>So</td><td> 10</td><td></td>

<td> 16/1</td><td> 16/1</td><td> 5</td><td></td>

<td colspan="4">10.9: (Cl% 95) EDso kg / kg (7.8 to 15.9)</td>

<td> 8/2</td><td>6%</td><td> 40</td><td>6 hills 44 mAh</td>

<td> 8/1</td><td> 8/7</td><td> 20</td><td></td>

<td> 8/1</td><td> 8/3</td><td> 10</td><td></td>

<td> 16/0</td><td> 16/0</td><td> 5</td><td></td>

<td colspan="4">5/55) EDjo 14,1: Cl / kg (10.0 to 20.6) 40 TDjo Tg / Kg</td>

40 g / kg to 3 g by total 16 (32 mA and 44 mA combined) with morbidity.

5 Note: Uncooked activity follows pregnant administration at 23 mAh and 44 mA. Dosage chosen for combination lessons with LEV at 6 Hz (44 mAh): LY4O4O39⁵Ig / kg 0

Jeddah for 15: Combination chips for LY4O4O39 with litigetetam (LEV) in ED 10 to 10 Hz (44 mAh) length.

<td>Physiology and Attitude / Lab #</td><td>* Ah, bakery</td><td>Dosage (mg / kg)</td><td>Warmth</td>

<td> 8/0</td><td> 8/2</td><td> 200</td><td rowspan="3">1-EV5</td>

<td> 9/0</td><td> 9/4</td><td> 400</td>

<td> 12/0</td><td> 12/10</td><td> 800</td>

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50 345,4: (Cl% 95) E, kg / kg (211,0 to 485,3)

<td> 8/0</td><td> 8/8</td><td> 200</td><td rowspan="4">+ LEV 5LY4O4O39 Ig / kg</td>

<td> 8/1</td><td> 8/6</td><td> 50</td>

<td> 8/2</td><td> 8/6</td><td> 20</td>

<td> 8/1</td><td> 8/2</td><td> 5</td>

595) LEV EDso 12,8: Cl / kg (2.5 - 25,2)

LEV prescribed separately, fixation doses performed in combination with the compound No. 2-A (see previous table above).

Υ404039 (subcutaneously) 5 mg / kg laboratory in combination with LEV (intraperitoneal); 5 LY4O4O39 mg / kg not activated when given separately.

5 The additional LEV iPad control groups (low inventory) were tested at 25 and 6,25 mg / kg (1/8 and 0/6 protected, respectively).

The tested vitamins with pregnant (10% NaCI sterilized water; subcutaneous, 0.5 SA TPE and 0.5% MC, intraperitoneal, 1 SA TPE) did not show protection or rotarod morbidity.

At a dose of 5 mg / kg ΙΥ404039 increases the efficacy of ED LEV, resulting in approximately 10-fold turnover of 27 ED ed. This suggests a relationship with positive inferiority.

Example 5 - Studies with Nudity 0'15-1092453 CAS

1.5. Combination lesson with 2,3-tetrahydro-7-methyl-5- [3- (1-pyrerethyl methyl) 1,2,4-oxa-ashy azole-5-yl] -2 - [[4- (triflu-methoxy (Philly] methyl] - H1— 15 Izaazul-1-one [0-15-1092453 CAS] (described in the prism publication

Global Numbered Digits 2008 150-233 WO 2011084098, WO) and Ligetitisetam

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0 15 1092453 CAS was tested separately and in combination with levetiracetam according to the sections described above above. Example 5 results are also tabulated in Tables 16-17.

5 Limit 3 to 16: Indications of dose response for 0-15-1092453 CAS at 6 Hz ED (32 heli).

<td># Rotarod Kinetics / # Lab</td><td>* Protected! * Bakery</td><td>The period (sa)</td><td>Dosage (kg / kg, subcutaneously)</td>

<td> 4/0</td><td> 4/1</td><td> 0,25</td><td rowspan="5"> 20</td>

<td> 4/0</td><td> 4/0</td><td> 0,5</td>

<td> 4/0</td><td> 4/1</td><td> 1</td>

<td> 4/0</td><td> 4/0</td><td> 2</td>

<td> 4/0</td><td> 4/0</td><td> 4</td>

<td> 4/0</td><td> 4/1</td><td> 0,25</td><td rowspan="5"> 40</td>

<td> 4/0</td><td> 4/1</td><td> 0,5</td>

<td> 4/0</td><td> 4/1</td><td> 1</td>

<td> 4/0</td><td> 4/0</td><td> 2</td>

<td> 4/0</td><td> 4/0</td><td> 4</td>

<td> 4/0</td><td> 4/0</td><td> 0,25</td><td rowspan="3"> 80</td>

<td> 4/0</td><td> 4/0</td><td> 0,5</td>

<td> 4/1</td><td> 4/1</td><td> 1</td>

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Reduced activity in laboratory doses and resonance points. The largest activity is at 0.25-1 h in laboratory doses. The mixture stacks were performed using 20 mg / kg, subcutaneously, 1 s TPE at 6 Hz ED (44 mA).

5 Limit&gt; A17: Synthesization threshold for 0-15-1092453 CAS with ligithesetam (LEV) at 6 Hz ED (44 mA) prolongation.

<td># Rotarod Kinetics / # Lab</td><td>* Ed protected *</td><td>LEV dose (kg / kg)</td><td>Warmth</td>

<td> 8/0</td><td> 8/2</td><td> 200</td><td rowspan="3">LEV®</td>

<td> 9/0</td><td> 9/4</td><td> 400</td>

<td> 12/0</td><td> 12/10</td><td> 800</td>

<td colspan="4">5/595) LEV ED_SO 345,4: (Cl mg / kg (211,0 to 485,3)</td>

<td> 8/0</td><td> 8/0</td><td></td><td>20) (1O92453-15-CALA Mg / kg, unit)</td>

<td> 8/0</td><td> 8/4</td><td> 400</td><td rowspan="5">lO92453-15- [LEV + CAS 0] of 20 mg / kg</td>

<td> 8/0</td><td> 8/5</td><td> 200</td>

<td> 8/0</td><td> 8/3</td><td> 50</td>

<td> 8/0</td><td> 8/2</td><td> 20</td>

<td> 8/1</td><td> 8/1</td><td> 5</td>

<td colspan="4">5/595) LEV EDso 238,9: (Cl mg / kg (41,6 - previous Asian dose tested)</td>

The additional IEV iPad control groups (low dose) were tested at 25 and 6,25 mg / kg (1/8 and 6/0 protected, respectively).

^ [0-15-1092453 20 [CAS / mg (subcutaneous; 1 SA TPE) test in combination with

10 LEV (intraperitoneal; 1 SA TPE); display [0-15-1092453 20 [low mg / kg CAS when given separately (6 hr, 32 mA), and not tested at 6 hr (44 mAh). This is shown in the laboratory 562 = ECgo nanometers (197 = Emax Qurah)

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A pre-described GTPyS analysis and 'preoccupation' were not monitored in previous laboratory experiments in rats.

Note: Pregnant animals treated (10% HPpCD-NaCI, subcutaneously, 1 h and 0,5% MC, intraperitoneal, 1 h) did not show protection or motor impairment, = 8 N.

5

The current data set indicates that mG! U2 PAM or agonist inhalers molecules with anticonvulsant activity in the AD 6 Harz model. mGlu2 PAMs Laboratory with EC50 &lt;

1.50 nano-house (as defined in ED GTPyS analysis) 3⁵S), filtrated PK filtrated and brain penetration, activity demonstrated in both the ED 6 of HER 32 and 44 mA model. Furthermore, 10 all laboratory molecules demonstrated an effect of azri with the IEV. A continent however, the molecule CAS

1092453-15-0, which is only weekly active (562 ECq nm) in the laboratory, as no activity has been shown in each of the ED 6hr tests, as well as it displays the azar with LEV.

Melond, data show that, under conditions of the characteristics of the gamutable PK and penetration of 15 appropriate brain, mGlu2 PAMs are the most effective, depending on the ECso values in the shaker, it appeared

Metabolism more effectively in the laboratory, and suggested that efficacy can be involved in shaking and in vitro. Moreover, Azarite streams with LEV were seen coherently with mGlu2 doses

PAM is similar to ED5Q d acquired in the ED model 32 mA or at least 2-fold at least as in ED 1555 specified in the ED 44 mA model (for example, dose activity in the ED 44 test is 20 mA since the molecules are tested separately).

Also for d د404039, agonist inhalers ed mGlu2 / 3, activity was seen in both ED6 HERDs and CHS synergies at a fold-3 dose lower than ED50 ED defined in the ED 44mA model, which was invalidated when separately tested.

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Depending on the preclinical data available in the ED 6 Hz 44 mA model, it appears that the combination of an effective SV2A gene and an effective mGlu2, leads to a decrease in the mean effective dose or EDso for a SV2A ken, IEV structure, between the P-35 and the P-00A.

5 Hence, it was indicated that there was no desire to adhere to the theory, it was suggested that the positive orthogonal prognostic for mutant Glutamate receptor modules of Type 2 (mGluR2 PAM), specifically mGluR2 PAM, has an EDso potency of 150 nm (as demonstrated in SGPyS analysis), where EC50 is It is a stimulus that produces a maximum parasympathetic effect on the curvature of the response response acquired with the presence of ed E'C ^ q of glutamate, suitable PK variants and brain penetration, and terminates 10 in a synergistic combination with the SV2A gene, specifically in levetiracetam, in ineffective doses of one or both terrors (A B) To synthesize the invention-

Thus, in an additional embodiment, the positive orthogonal axis of the glutamate receptor-containing terrain of modulation 2 (mG! UR2 PAM) was chosen from the combination of the invention as defined here from the 15 mGluR2 PAM terrier with an ED5Q efficacy of 150 nm (as defined in the analysis

S] GÏP2S]), where EC50 is a stimulus that produces a maximum listening effect on the curvature of the response response acquired with the presence of EC20 glutamate.

Prophylactic signs

20 A) the Controlled the controlled relationships (DSR) in inventory in laboratory analysis

DSR analysis is divided into two models: a controlled behavioral paradigm (RDBM) for mania and a subject-oriented behavior paradigm (RSBM) for abatement. Ed RDBM, where dominant lives are addressed with the news-terrifier, and are predictive fate of the news-terrors to address mania. Ed RSBM, where subject lives are treated with the news-terrifier, and a predictive amount of 25 is given to the test-terrain for the treatment of depression.

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Dowley Male Male Spirge (140 to 160 g) From Charles Ri7er Laboratories Wilmington, MA was used in this analysis. Shipments of rats were received at periods

<img file="MA43291A1_D0099.tif" />

Consolidate and limit the selection process for one week, followed by five weeks of medication or treatment with the pregnant woman

5 For those chosen couples.

Four rats will be housed in each cage. Their access to food will be restricted to an hour after the day

Audition on Monday from Khayra Thursday. After processing on Friday, the rats will be made free to eat until they become swift again on Sunday. Where there is no. There is a time when the rats will be heated from the water. The feeding periods of food used will have little effect on weight gain, and the average weight of rats will be about 300 g at the end of the study. At the end of the trade, the rats will be slaughtered by cutting their heads, and the leg and the brain blood will be collected for laboratory experiments and measurements of the thalassemia.

The primary test apparatus consists of two chambers connected by a tunnel large enough to allow the drifting unit from the lessons in time. On the floor, at the middle of the tunnel point, there will be a bowl of 15 sweetened milk. This primary device will be folded, so the total rat fee of 4 rats can be a series video together. Camis can distinguish sealed rats in different colors. Thus, the rat rats will be colored for the purpose of the video sequence, red in one cage and the smaller in the other cage. Only a united animal can comfortably reach the feeder at the time, but both animals can read milk during the daily round for five minutes. During the 20-day daily cycle for five minutes, the time spent in the feeder area will be recorded by each medium font in the video sequence logs and saved in the text file.

The test 'will begin with a random mission of the inventory to the couples. Each member of the pair will be placed in a stone opposite to the test device. The feeding time in the feeder area will be recorded by each animal. During the first week (five days) of testing, the animals will adapt to the new environment. 25 The control will be transferred to the animal with high score during the second week of testing if the three criteria are met. First, there should be a significant difference (test-; two-tail,, 0.05) is between

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Average daily drinking score for both animals. Secondly, the controlling live score should be at least 525/5 greater than the subjected subject's score. Finally, there should be no repercussions of the week's choice of spouse as a borrower is subject to a battered inventory made outside of his isolated dominate silt. Ideally, there will be minor repercussions during the acclimatization week as well. Only 5 animal pairs that have met these criteria will be enrolled in the lesson.

Significant differences between the time consumed in the feeder will be determined by the dominant and subjected inventory of ANOVA using GraphPad software (GraphPad Prism CA, Inc. San Diego, Software) followed by a two-tail test (0,05&gt; Ρ). The continents among the treatment groups will be made using values with a regular dominant level in the animals

10 Dual. The dominant level is the value that we measure the social relationship between states

Promoter. Dominant plane (FD-FTS - DL) where FTD is the feeder interval for the dominant streams and FTS is the feeder interval for the submissive tractors. The adjustment will be calculated according to summer:

Control level (week η in%) -

Sehler level (week η,

A) Control Level (Week 2)

15th The statistical significance of the difference in the dominant level between the control group (RG of

The neighbors where the dominant animals will be treated and subject to the pregnant) and a group will be identified

Treatment (sweaty granules and dominating's pregnant granules) will be treated by ANOVA, source of a test. The activity start time value will be calculated in 50% of the (50-ΑΟΤ) response for the minor and major response to the disease based on reducing the value of the dominant level 20 using a non-linear regression analysis (CA, Inc. San Diego, GraphPad Software). Regular DL values will be used for this calculation, as the DL values will be organized for the treatment week as the presence of the second seven (previous treatment) value for the pair according to the previous summer. In these controls, the minimum response (DL) determines the positive activity of the infection. In line with the efficacy, since the values will be reduced, the response to the infection will be positive. In the event of a negative response to LAM 25 (symptoms worsening) DL values will be reduced. In the event that the disease does not have this activity, the upper limit is

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The response will not exceed 0%. Any significant DL value greater than the control value (about 100%) indicates the negative activity of the disease.

The Lecerdecetam and Desirable M 8 P mGluR2 riser (such as 2, 2-A, 25 — A, 6 — A or LY-4O4O39) will be evaluated in the RDBM Ed according to the section described in more detail below.

5 Groups of controlling rats d QD will be treated orally with levimersetam 10 mg / kg and desirable AM m / mGluR2 at different concentrations of approximately 0.05 mg / kg (A3), at 0.5 mg / kg (3 ^ η), at 2 , 5 mg / kg (3 &lt;η), at 5.0 mg / kg (3 ^ η) and at 50.0 mg / kg (21 K3). A control group with a holder of QD-dominated rats will be treated intraperitoneally with sodium valproate at 30 mg / kg (6η out of 2 dozen of each 26K3).

10 All treatments will be given approximately 1 hour before the test. All treatments will start on Saturday after the second selection week (optional week). Levitercetam and mGluR2 i ^ / map ^ cloud method (.ρ.ο) will also be given.

When treating controlling lives with levetiracetam 10 mg / kg and desired PAM / mGluR2 hemoglobin, the difference between dominant and submissive rats will be missing after the first week and for the second of 15 treatments depending on the dose. Similar depictions, when treating the dominant animals with sodium gallbrot, the difference between the controlling and submissive rats will also be missing after the first week of treatment. The possibility of dominant rats can be treated with levizisetam and desirable AM in the form of mGluR2 or sodium valproate for further increase. Consequently, the treated dominant rats will prevent their submissive substrates from increasing and feed them to the feeder.

20 For a different bite point and dose misalignment the data will be organized for the initial control week values. The initial effect of beginzecetam and the PAM / mGluR2 synthesis will be monitored where there is a significant difference in the values of the dominant level (DI) between the rats treated with the pregnant and the combination started in the second week and will be mimicking during the treatment period of 5 weeks. In comparison, the biology (30 mg) will be treated with sodium protein, with a reduced reduced level of exposure.

25 Regular after Ghana treatment week with increased effect in the following weeks.

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In order to estimate the starting activity ability (AOT), the mean daily values will be planned for the nutritional value of the sperms subject and subject, and then the important differences between these two groups will be calculated using a two-tailed test.

To simulate the start of the activity (AOT) between different treatments, the starting period of activity will be estimated from

5 Matching nonlinear reflection. The non-linear reflection model would be appropriate for each of the daily DI values of the drug, combination and dose.

The effects of LINC and PAM / mGluR2 are monitored in the RDBM ed for the dose responsible.

In this analysis, a combination of levetidacetam and a compound is monitored; PAM mGIR risers for a few 10 dominant behavior indicating that the combination is active as an anti-manic.

B) optical discs

As a specific embodiment of verbal horror, 100 mg of 171 1 ^ teratogenic mGluR2 is formulated with lactose divided sufficiently precisely to extend the total amount from 580 to 590 mg for a volume filling of 15 hard gel capsules 0.

While teaching the previous specification for the principles of the present invention, with examples provided for illustrative purposes, purposes, it will be understood that the invention of the invention will encompass all the usual variables, changes and / or modifications as described in the scope of immediate protection elements and their equivalents. Оригинальный текст: وبشكل أكثر تحديذا ، تسعى هذه الأنظمة إلى تكوين موجة ذات خصاتعى وأنكال دقيقة للغاية ، تحاكي بعض الأيا ب ي أ من ناحية ، يجب أن تكون الموجة عالية وفضل أن تكون ديناميكية ، أي أن تتحرك 15 للأمام.