Nothing Special   »   [go: up one dir, main page]

US20220143141A1 - Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use - Google Patents

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

Info

Publication number
US20220143141A1
US20220143141A1 US17/643,751 US202117643751A US2022143141A1 US 20220143141 A1 US20220143141 A1 US 20220143141A1 US 202117643751 A US202117643751 A US 202117643751A US 2022143141 A1 US2022143141 A1 US 2022143141A1
Authority
US
United States
Prior art keywords
compound
compounds
pharmaceutically acceptable
sv2a
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
US17/643,751
Inventor
Brian D. Klein
Hilde Lavreysen
Stefan Maria Christiaan Pype
Roy E. Twyman
Nancy Eulalie Sylvain Van Osselaer
H. Steven WHITE
Marc André Ceusters
José Maria Cid-Núñez
Andrés Avelino Trabanco-Suárez
Roger Francis Bone
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Pharmaceutica NV
Original Assignee
Janssen Pharmaceutica NV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US16/720,750 external-priority patent/US11369606B2/en
Application filed by Janssen Pharmaceutica NV filed Critical Janssen Pharmaceutica NV
Priority to US17/643,751 priority Critical patent/US20220143141A1/en
Publication of US20220143141A1 publication Critical patent/US20220143141A1/en
Pending legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1787—Receptors; Cell surface antigens; Cell surface determinants for neuromediators, e.g. serotonin receptor, dopamine receptor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to combinations comprising a positive allosteric modulator (“PAM”) of metabotropic glutamatergic receptor subtype 2 (“mGluR2”) or a pharmaceutically acceptable salt or a solvate thereof, or an orthosteric agonist of metabotropic glutamatergic receptor subtype 2 compound or a pharmaceutically acceptable salt or a solvate thereof, and a synaptic vesicle protein 2A (“SV2A”) ligand.
  • PAM positive allosteric modulator
  • mGluR2 metabotropic glutamatergic receptor subtype 2
  • SV2A synaptic vesicle protein 2A
  • Epilepsy describes a condition in which a person has recurrent seizures due to a chronic, underlying process.
  • Epilepsy refers to a clinical phenomenon rather than a single disease entity, since there are many forms and causes of epilepsy.
  • epilepsy is estimated at approximately 0.3 to 0.5 percent in different populations throughout the world, with the prevalence of epilepsy estimated at 5 to 10 people per 1000.
  • An essential step in the evaluation and management of a patient with a seizure is to determine the type of seizure that has occurred.
  • the main characteristic that distinguishes the different categories of seizures is whether the seizure activity is partial (synonymous with focal) or generalized.
  • Partial seizures are those in which the seizure activity is restricted to discrete areas of the cerebral cortex. If consciousness is fully preserved during the seizure, the clinical manifestations are considered relatively simple and the seizure is termed a simple-partial seizure. If consciousness is impaired, the seizure is termed a complex-partial seizure. An important additional subgroup comprises those seizures that begin as partial seizures and then spread diffusely throughout the cortex, which are known as partial seizures with secondary generalization.
  • Generalized seizures involve diffuse regions of the brain simultaneously in a bilaterally symmetric fashion. Absence or petit mal seizures are characterized by sudden, brief lapses of consciousness without loss of postural control. Atypical absence seizures typically include a longer duration in the lapse of consciousness, less abrupt onset and cessation, and more obvious motor signs that may include focal or lateralizing features.
  • Generalized tonic-clonic or grand mal seizures the main type of generalized seizures, are characterized by abrupt onset, without warning. The initial phase of the seizure is usually tonic contraction of muscles, impaired respiration, a marked enhancement of sympathetic tone leading to increased heart rate, blood pressure, and pupillary size.
  • the tonic phase of the seizure typically evolves into the clonic phase, produced by the superimposition of periods of muscle relaxation on the tonic muscle contraction.
  • the periods of relaxation progressively increase until the end of the ictal phase, which usually lasts no more than 1 min.
  • the postictal phase is characterized by unresponsiveness, muscular flaccidity, and excessive salivation that can cause stridorous breathing and partial airway obstruction.
  • Atonic seizures are characterized by sudden loss of postural muscle tone lasting 1-2 s. Consciousness is briefly impaired, but there is usually no postictal confusion.
  • Myoclonic seizures are characterized by a sudden and brief muscle contraction that may involve one part of the body or the entire body.
  • SV2A synaptic vesicle protein 2A
  • SV2A synaptic vesicle protein 2A
  • SV2A ligands include levetiracetam (Lynch et al. “The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam” Proc. Natl. Acad. Sci. USA 2004, Vol. 101, pp. 9861-9866), brivaracetam and seletracetam (Kaminski R M, et al. “Targeting SV2A for Discovery of Antiepileptic Drugs”. In: Noebels J L, Avoli M, Rogawski M A, et al., editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition.
  • Keppra® is an antiepileptic drug. It showed no activity in traditional acute models (maximal electroshock and pentylenetetrazol seizure tests) but was found potent in chronic epilepsy models and in genetic models of generalized epilepsy. It has shown a high safety margin compared to other antiepileptic drugs (Klitgaard “Levetiracetam: the preclinical profile of a new class of antiepileptic drugs” Epilepsia 2001, 42 (Supplement 4), pp. 13-18). It is commercialized under the trademark Keppra®, available as tablets, as an oral solution, and as a concentrate made up into a solution for infusion.
  • Keppra® has been approved in Europe as a monotherapy in patients from 16 years of age with newly diagnosed epilepsy, in the treatment of partial-onset seizures (fits) with or without secondary generalization and as an add-on therapy for use with other anti-epileptic drugs in the treatment of partial-onset seizures with or without generalization in patients from 1 month of age; myoclonic seizures in patients from 12 years of age with juvenile myoclonic epilepsy; and primary generalized tonic-clonic seizures in patients from 12 years of age with idiopathic generalized epilepsy (www.ema.europa.eu).
  • Keppra® has also been approved in the USA as an add-on therapy for the treatment of partial onset seizures in patients from 1 month of age; myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy; and primary generalized tonic-clonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy.
  • Keppra XR® available as extended-release tablets, has been approved in the USA for the add-on treatment of partial onset seizures in patients 16 years of age and older with epilepsy (http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm).
  • Processes for the preparation of the three compounds are known in the literature. For instance, processes for making Levetiracetam are disclosed for instance, in EP 0 162 036 and in GB 2 225 322. A process for the preparation of Brivaracetam is disclosed for instance in WO 01/62726. A process for the preparation of Seletracetam is known for instance from WO2005/121082. Alternative processes for making the three compounds are disclosed in EP1806339.
  • Antiepileptic drugs have found usefulness in neurological and psychiatric disorders, including neuropathic pain, migraine, essential tremor and in anxiety, schizophrenia and bipolar disorder (Landmarck “Antiepileptic drugs in non-epilepsy disorders. Relations between mechanisms of action and clinical efficacy” CNS Drugs 2008, Vol. 22(1), pp. 27-47; Calabresi et al. “Antiepileptic drugs in migraine: from clinical aspects to cellular mechanisms” Trends in Pharmacological Sciences 2007, Vol. 28(4), pp. 188-195; Rogawski and Loscher “The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions” Nat Med 2004, Vol. 10, pp. 685-692).
  • Levetiracetam has been found effective or potentially effective in a wide-spectrum of neuropsychiatric disorders including mood disorders (Muralidharan and Bhagwagar “Potential of levetiracetam in mood disorders: a preliminary review” CNS Drugs 2006, Vol. 20, pp. 969-979; Mula et al. “The role of anticonvulsant drugs in anxiety disorders: a critical review of the evidence” J Clin Pshycopharmacol 2007, Vol. 27, pp. 263-272), anxiety disorders (Kinrys et al. “Levetiracetam as adjunctive therapy for refractory anxiety disorders” J Clin Psychiatry 2007, Vol. 68, pp. 1010-1013; Zhang et al.
  • levetiracetam may have potential for restraining post-traumatic epilepsy, such as those caused by status epilepticus, traumatic brain injury and ischemic stroke, and it appears to have neuroprotective effects.
  • the potential of levetiracetam in easing epileptogenesis or cognitive dysfunction remains to be ascertained by conclusive animal and clinical studies (for reviews: Loscher and Brandt “Prevention or modification of epileptogenesis after brain insults: experimental approaches and translational research” Pharmacol Rev 2010, Vol.
  • Seletracetam and Brivaracetam have been found to reduce the severity of dystonia in the dt sz mutant hamster model and may be helpful in some patients suffering from dyskinetic and dystonic movement disorders (Hamann et al. “Brivaracetam and seletracetam, two new SV2A ligands, improve paroxysmal dystonia in the dt sz mutant hamster” European Journal of Pharmacology 2008, Vol. 601, pp. 99-102).
  • glutamate levels Prior to seizure activity, increases in extracellular glutamate are measured in human hippocampus and the increase is sustained during epileptogenic activity (During and Spencer “Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain” Lancet 1993, Vol. 341(8861), pp. 1607-10), thus lending support to the idea that a reduction in glutamate levels may be of benefit in the treatment of epilepsy.
  • glutamate levels increase to potentially neurotoxic levels. Seizure activity results in progressive structural damage in human brain inducing further abnormalities in glutamate metabolism (Petroff et al. “Glutamate-glutamine cycling in the epileptic human hippocampus” Epilepsia 2002, Vol. 43(7), pp. 703-10).
  • an mGluR2 positive allosteric modulator or an mGluR2 orthosteric agonist may be expected to protect against seizure-induced neuronal damage.
  • WO2009/033704 and WO2010/130424 disclose mGluR2 positive allosteric modulators, uses thereof and processes for synthesizing the compounds.
  • WO1997/18199 and WO2003/104217 disclose excitatory amino acid receptor modulator compounds that later were shown to have mGlu2/3 orthosteric agonist activity (see for example Rorick-Kehn et al. (2007) The Journal of Pharmacology and Experimental therapeutics Vol. 321, No. 1, pp. 308-317), further scientific and patent literature disclose additional examples of compounds having mGlu2/3 orthosteric agonist activity, and WO2008/150233 discloses compounds with mGluR2 allosteric activator activity.
  • a significant limiting factor in the use of SV2A ligands is tolerability and side-effect profile.
  • the effective dose of levetiracetam for partial onset seizures is dosed at 1000 mg, 2000 mg, and 3000 mg, given as twice-daily.
  • levetiracetam The side effects reported for levetiracetam include aggressive or angry behavior, anxiety, change in personality, chills, cough or hoarseness, crying, depersonalization, diarrhea, dry mouth, euphoria, fever, general feeling of discomfort or illness, headache, hyperventilation, irregular heartbeats, irritability, joint pain, loss of appetite, lower back or side pain, mental depression, muscle aches and pains, nausea, painful or difficult urination, paranoia, quick to react or overreact emotionally, rapidly changing moods, restlessness, shaking, shivering, shortness of breath, sleepiness or unusual drowsiness, sore throat, stuffy or runny nose, sweating, trouble sleeping, unusual tiredness or weakness and vomiting.
  • levetiracetam the side effects reported for levetiracetam include aggressive or angry behavior, anxiety, change in personality, chills, cough or hoarseness, crying, depersonalization, diarrhea, dry mouth, euphoria, fever, general feeling of discomfort or illness, headache, hyper
  • FIG. 1 Dose response for the 6 Hz 44 mA ED 50 determination for the Co. No. 2 and LEV alone and in combination.
  • FIG. 2 Isobolographic analysis for the combination of Co. No. 1 with levetiracetam (LEV) in the 6 Hz (44 mA) assay.
  • Initial ED 50 values (shown below) were determined for both Co. No. 1 and LEV (data points on x- and y-axes; filled diamonds).
  • the theoretical line of additivity connects the calculated ED 50 values for the two compounds (solid black line).
  • Theoretical ED 50 (+SEM) for three fixed dose ratio combinations (LEV:Co. No. 1) are plotted: 1:3—filled squares/solid black line, 1:1—filled upward triangles/solid black line, and 3:1—filled downward triangles/solid black line.
  • Experimental treatment doses were initially derived from theoretical values and adjusted according to observed effects.
  • FIG. 3 Combination Studies for Co. No. 25-a with levetiracetam (LEV) in the 6 Hz Assay (44 mA). At a dose of 10 mg/kg s.c., Co. No. 25-a increases the potency of LEV, leading to an approximate 70-fold shift in the ED 50 . This suggests a positive pharmacodynamic relationship.
  • LEV levetiracetam
  • FIG. 4 Combination Studies for Co. No. 2-a with levetiracetam (LEV) in the 6 Hz Assay (44 mA). At a dose of 10 mg/kg s.c., Co. No. 2-a increases the potency of LEV, leading to an approximate 35-fold shift in the ED 50 . This suggests a positive pharmacodynamic relationship.
  • LEV levetiracetam
  • FIG. 5 Combination Studies for Co. No. 6-b with levetiracetam (LEV) in the 6 Hz Assay (44 mA). At a dose of 10 mg/kg p.o., Co. No. 6-b increases the potency of LEV, leading to an approximate 100-fold shift in the ED 50 . This suggests a positive pharmacodynamic relationship.
  • LEV levetiracetam
  • FIG. 6 Combination Studies for LY-404039 with levetiracetam (LEV) in the 6 Hz Assay (44 mA). At a dose of 5 mg/kg s.c., LY-404039 increases the potency of LEV, leading to an approximate 27-fold shift in the ED 50 . This suggests a positive pharmacodynamic relationship.
  • LEV levetiracetam
  • the present invention relates to a combination comprising
  • the invention as described herein relates to a pharmaceutical combination, in particular a pharmaceutical combination product, comprising
  • the invention relates to the combination described herein for use as a medicament.
  • a further embodiment of this invention relates to the use of the combination described herein for the manufacture of a medicament or a pharmaceutical product for the treatment or prevention of epilepsy and related disorders; neuropathic pain; migraine or resistant headache and bipolar and related disorders.
  • a further embodiment of this invention relates to the use of the combination described herein for the manufacture of a medicament or a pharmaceutical product for neuroprotection.
  • a further embodiment of this invention relates to the use of the combination described herein for the manufacture of a medicament or a pharmaceutical product for the prevention of epileptogenesis.
  • a further embodiment relates to the treatment or prevention of epilepsy and related disorders; neuropathic pain; migraine or resistant headache; and bipolar and related disorders of a subject comprising administering concurrently or sequentially to the subject in need thereof a synaptic vesicle protein 2A (“SV2A”) ligand; and a positive allosteric modulator (“PAM”) of metabotropic glutamatergic receptor subtype 2 (“mGluR2”) compound or a pharmaceutically acceptable salt or a solvate thereof, or an orthosteric agonist of metabotropic glutamatergic receptor subtype 2 compound or a pharmaceutically acceptable salt or a solvate thereof, in amounts that would be therapeutically effective when the SV2A ligand and mGluR2 compound are administered together.
  • SV2A synaptic vesicle protein 2A
  • PAM positive allosteric modulator
  • mGluR2 metabotropic glutamatergic receptor subtype 2
  • a further embodiment relates to a combination as described herein for neuroprotection; or to a combination as described herein for use in neuroprotection.
  • a further embodiment relates to a combination as described herein for the prevention of epileptogenesis; or to a combination as described herein for use in the prevention of epileptogenesis.
  • the invention relates to a method of treating or preventing epilepsy and related disorders; neuropathic pain; migraine or resistant headache; bipolar and related disorders in patients comprising administering a fixed dose combination of
  • the invention relates to a method of neuroprotection with a combination as defined herein.
  • the invention relates to a method of anti-epileptogenesis with a combination as defined herein.
  • a further embodiment relates to a method for the treatment or prevention of epilepsy and related disorders; neuropathic pain; migraine or resistant headache; bipolar and related disorders said method comprising administering a therapeutically effective amount of a combination or a combination product comprising
  • a further embodiment relates to a method of neuroprotection, said method comprising administering a therapeutically effective amount of a combination or a combination product comprising
  • a further embodiment relates to a method of anti-epileptogenesis, said method comprising administering a therapeutically effective amount of a combination or a combination product comprising
  • the present invention relates to a pharmaceutical product or a commercial package comprising a combination according to the invention as described herein, in particular together with instructions, for simultaneous, separate or sequential use thereof in the treatment or prevention of epilepsy and related disorders; neuropathic pain; migraine or resistant headache bipolar; and related disorders.
  • the present invention relates to a pharmaceutical product or a commercial package comprising a combination according to the invention as described herein, in particular together with instructions, for simultaneous, separate or sequential use thereof in neuroprotection.
  • the present invention relates to a pharmaceutical product or a commercial package comprising a combination according to the invention as described herein, in particular together with instructions, for simultaneous, separate or sequential use thereof in anti-epileptogenesis.
  • the invention relates to a combination comprising a quantity which is jointly therapeutically effective against epilepsy and related disorders; neuropathic pain; migraine or resistant headache; bipolar and related disorders; of
  • the invention relates to a combination comprising a quantity which is jointly therapeutically effective as neuroprotectant, of
  • the invention relates to a combination comprising a quantity which is jointly therapeutically effective in the prevention of epileptogenesis, of
  • the invention relates to the use of
  • mGluR2 compounds or “mGluR2 PAM/agonist compounds”, or “positive allosteric modulator of mGluR2/mGluR2 orthosteric agonist compound” meaning that the compounds have mainly activity at the metabotropic glutamatergic receptor subtype 2, and are in particular selected from positive allosteric modulators (PAMs) of metabotropic glutamatergic receptor subtype 2, and orthosteric agonists of metabotropic glutamatergic receptor subtype 2.
  • PAMs positive allosteric modulators
  • a skilled person will be familiar with the large homology of mGluR2 and mGluR3, due to which some mGluR2 orthosteric agonists also display activity as mGluR3 orthosteric agonists.
  • mGluR2 compounds or “mGluR2 PAM/agonist compounds”, or “positive allosteric modulator of mGluR2/mGluR2 orthosteric agonist compound” does therefore not exclude compounds displaying some other additional minor activity in vitro or in vivo.
  • mGluR2 PAM compounds of the combination of the invention are in particular selected from those disclosed in WO2010/130424.
  • a particular subgroup of said compounds disclosed in WO2010/130424 can be defined by the following Formula (I)
  • R 1 is selected from the group consisting of (C 3-7 cycloalkyl)C 1-3 alkyl-, mono- or polyhaloC 1-4 alkyl, and (C 1-4 alkyl)-O—(C 1-4 alkyl);
  • R 2 is halo or polyhaloC 1-4 alkyl;
  • A is a covalent bond or a —CH 2 —;
  • L is selected from the radicals (a), (b) and (c):
  • R 3a is selected from unsubstituted phenyl or phenyl substituted with 1 or 2 halo substituents;
  • R 4a is selected from the group of hydrogen, C 1-3 alkyl and halo; or
  • R 3a —C—R 4a together represent a radical of formula (a-1)
  • R 5a is hydrogen or halo
  • R 3b is selected from the group of phenyl substituted with 1 or 2 halo substituents, pyridinyl substituted with 1 or 2 halo substituents, unsubstituted pyrimidinyl and pyrimidinyl substituted with 1 or 2 C 1-3 alkyloxy substituents; or a pharmaceutically acceptable salt or a solvate thereof.
  • the positive allosteric modulator (“PAM”) of metabotropic glutamatergic receptor subtype 2 (“mGluR2”) compound is a compound of Formula (I) as defined herein.
  • R 1 is selected from the group consisting of cyclopropylmethyl-, 2,2,2-trifluoroethyl, and CH 3 —O—CH 2 —;
  • R 2 is chloro or CF 3 ;
  • A is a covalent bond or a —CH 2 —;
  • L is selected from the radicals (a), (b) and (c):
  • R 3a is selected from unsubstituted phenyl or phenyl substituted with 1 or 2 fluoro substituents;
  • R 4a is selected from the group of hydrogen, methyl and fluoro; or
  • R 3a —C—R 4a together represent a radical of formula (a-1)
  • R 5a is hydrogen or fluoro
  • R 3b is selected from the group of phenyl substituted with 1 or 2 fluoro substituents, pyridinyl substituted with 1 or 2 fluoro substituents, unsubstituted pyrimidinyl and pyrimidinyl substituted with 1 or 2 methoxy substituents;
  • the compound of Formula (I) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • mGluR2 PAM compounds of the combination of the invention are also in particular selected from those disclosed in WO2009/033704.
  • Said compounds disclosed in WO2009/033704 can be defined by the following Formula (I-A)
  • R 1 is C 1-6 alkyl; or C 1-3 alkyl substituted with C 3-7 cycloalkyl, phenyl, or phenyl substituted with halo, trifluoromethyl or trifluoromethoxy
  • R 2 is halo, trifluoromethyl, C 1-3 alkyl or cyclopropyl
  • R 3 is hydrogen, fluoro, hydroxyl, hydroxyC 1-3 alkyl, hydroxyC 1-3 alkyloxy, fluoroC 1-3 alkyl, fluoroC 1-3 alkyloxy or cyano
  • Ar is unsubstituted phenyl; or phenyl substituted with n radicals R 4 , wherein n is 1, 2 or 3
  • R 4 is selected from the group consisting of hydrogen, halo, C 1-3 alkyl, hydroxyC 1-3 alkyl, polyhaloC 1-3 alkyl, cyano, hydroxyl, amino, carboxyl, C
  • R 1 is C 1-6 alkyl; or C 1-3 alkyl substituted with C 3-7 cycloalkyl, phenyl, or phenyl substituted with halo, trifluoromethyl or trifluoromethoxy;
  • R 2 is halo, trifluoromethyl, C 1-3 alkyl or cyclopropyl;
  • R 3 is hydrogen, fluoro, hydroxyl, hydroxyC 1-3 alkyl, hydroxyC 1-3 alkyloxy, fluoroC 1-3 alkyl, fluoroC 1-3 alkyloxy or cyano; and
  • Ar is unsubstituted phenyl, or phenyl substituted with n radicals R 4 , wherein n is 1, 2 or 3;
  • R 4 is selected from the group consisting of hydrogen, halo, C 1-3 alkyl, hydroxyC 1-3 alkyl, polyhaloC 1-3 alkyl, cyano, hydroxyl, amino, carboxyl, C 1-3 alkyl
  • R 1 is C 1-6 alkyl; or C 1-3 alkyl substituted with C 3-7 cycloalkyl, phenyl or phenyl substituted with halo, trifluoromethyl or trifluoromethoxy;
  • R 2 is halo, trifluoromethyl, C 1-3 alkyl or cyclopropyl;
  • R 3 is hydrogen, fluoro, hydroxyl, hydroxyC 1-3 alkyl, hydroxyC 1-3 alkyloxy, fluoroC 1-3 alkyl, fluoroC 1-3 alkyloxy or cyano; and
  • Ar is unsubstituted phenyl; and the pharmaceutically acceptable salts and solvates thereof.
  • R 1 is 1-butyl, 2-methyl-1-propyl, 3-methyl-1-butyl, (cyclopropyl)methyl or 2-(cyclopropyl)-3-ethyl;
  • R 3 is hydrogen, fluoro or cyano; and
  • Ar is unsubstituted phenyl; and the pharmaceutically acceptable salts and solvates thereof.
  • R 1 is 1-butyl, 3-methyl-1-butyl, (cyclopropyl)methyl or 2-(cyclopropyl)-1-ethyl;
  • R 2 is chloro;
  • R 3 is hydrogen or fluoro; and
  • Ar is unsubstituted phenyl; and the pharmaceutically acceptable salts and the solvates thereof.
  • R 1 is C 1-6 alkyl; or C 1-3 alkyl substituted with C 3-7 cycloalkyl, phenyl, or phenyl substituted with halo, trifluoromethyl or trifluoromethoxy;
  • R 2 is halo, trifluoromethyl, C 1-3 alkyl or cyclopropyl;
  • R 3 is hydrogen, fluoro, hydroxyl, hydroxyC 1-3 alkyl, hydroxyC 1-3 alkyloxy, fluoroC 1-3 alkyl, fluoroC 1-3 alkyloxy or cyano;
  • Ar is phenyl substituted with n radicals R 4 , wherein n is 1, 2, or 3;
  • R 4 is selected from the group consisting of halo, C 1-3 alkyl, hydroxyC 1-3 alkyl, C 1-3 alkyloxy, polyhaloC 1-3 alkyloxy, C 1-3 alkylcarbonyl, mono- and di(C 1-3 alkyl)amino,
  • R 1 is 1-butyl, 2-methyl-1-propyl, 3-methyl-1-butyl, (cyclopropyl)methyl or 2-(cyclopropyl)-1-ethyl;
  • R 3 is hydrogen, fluoro or cyano; and
  • Ar is phenyl substituted with halo, trifluoromethyl, morpholinyl or hydroxyC 1-3 alkyl; and the pharmaceutically acceptable salts and solvates thereof.
  • R 1 is 1-butyl, 3-methyl-1-butyl, (cyclopropyl)methyl or 2-(cyclopropyl)-1-ethyl;
  • R 2 is chloro;
  • R 3 is hydrogen or fluoro; and
  • Ar is phenyl substituted with at least one halo group; and the pharmaceutically acceptable salts and solvates thereof.
  • R 1 is 1-butyl, 3-methyl-1-butyl, (cyclopropyl)methyl or 2-(cyclopropyl)-1-ethyl;
  • R 2 is chloro;
  • R 3 is hydrogen or fluoro; and
  • Ar is phenyl substituted with at least two fluoro groups; and the pharmaceutically acceptable salts and solvates thereof.
  • the compound of Formula (I-A) is N-(2-aminoethyl)-2-aminoethyl
  • mGluR2 PAM compounds of the combination of the invention are also in particular selected from those disclosed in PCT/EP2014/068676.
  • Said compounds disclosed in PCT/EP2014/068676 can be defined by the following Formula (I-B)
  • R 1 is selected from the group consisting of C 1-6 alkyl, (C 3-8 cycloalkyl)C 1-3 alkyl, and (C 1-3 alkyloxy)C 1-3 alkyl; each R 2 is independently selected from F, Cl, C 1-3 alkyl, C 1-3 alkyloxy, mono- or polyhaloC 1-3 alkyl, and mono- or polyhaloC 1-3 alkyloxy; n is an integer selected from 1, 2, and 3; and the pharmaceutically acceptable salts and the solvates thereof.
  • the mGluR2 PAM compounds of the combination of the invention are in particular selected from compounds of Formula (I-B) as defined hereinabove, and stereoisomeric forms thereof, wherein R 1 is selected from the group consisting of CH 3 CH 2 , CH 3 CH 2 CH 2 , (cyclopropyl)methyl, (cyclobutyl)methyl, ethyloxymethyl and methyloxymethyl; and the rest of variables are as defined herein; and the pharmaceutically acceptable salts and the solvates thereof.
  • the mGluR2 PAM compounds of the combination of the invention are in particular selected from compounds of Formula (I-B) as defined hereinabove, and stereoisomeric forms thereof, wherein R 1 is selected from the group consisting of CH 3 CH 2 , (cyclopropyl)methyl, (cyclobutyl)methyl and methyloxymethyl; and the rest of variables are as defined herein; and the pharmaceutically acceptable salts and the solvates thereof.
  • the mGluR2 PAM compounds of the combination of the invention are in particular selected from compounds of Formula (I-B) as defined hereinabove, and stereoisomeric forms thereof, wherein R 1 is selected from the group consisting of CH 3 CH 2 , (cyclopropyl)methyl, (cyclobutyl)methyl and ethyloxymethyl; and the rest of variables are as defined herein; and the pharmaceutically acceptable salts and the solvates thereof.
  • the positive allosteric modulator (“PAM”) of metabotropic glutamatergic receptor subtype 2 (“mGluR2”) compound is a compound of Formula (I-B) as defined herein.
  • each R 2 is independently selected from F, Cl, CH 3 , CH 3 O and CF 3 ; and the pharmaceutically acceptable salts and the solvates thereof.
  • the compounds of Formula (I-B) are as defined herein having the Formula (I-Ba)
  • the compounds of Formula (I-B) are as defined herein having the Formula (I-Bb)
  • the compound may be selected from 3-(Cyclopropylmethyl)-7-[(1 S)-1-(2,4-difluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine hydrochloride salt.
  • the orthosteric agonists of mGluR2/mGluR2/3 of the combination of the invention include, but are not limited to, for example, LY-404039; LY-2969822; LY-2934747; LY-379268; DCG-W; LY-354740; LY-314582; LY-544344; LY-2140023; LY-181837; LY-389795; LY-446433; LY-450477; LY-395756; LY-566332; LY-541850; LY-2300559; LY-404040; LY-281223; LY-2979165; talaglumetad; MGS008; MGS0022; MGS0028; MGS0039; ( ⁇ )-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate; (+)-4-amino-2-sulfonylbicyclo[3.1.0]hexane
  • a particular group of mGluR2 agonists include LY-379268; DCG-IV; LY-354740; LY-404039; LY-2969822; LY-2934747; LY-544344; and LY-2140023.
  • orthosteric agonists of metabotropic glutamatergic receptor subtype 2 of the combination of the invention are in particular further selected from those disclosed in WO1997/18199 and WO2003/104217, incorporated herein in their entirety.
  • Particular compounds disclosed therein are ( ⁇ )-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic acid (also known as LY-404039)
  • C 1-3 alkyl As used herein, the notation “C 1-3 alkyl”, “C 1-4 alkyl” or “C 1-6 alkyl” as a group or part of a group defines a saturated, straight or branched, hydrocarbon radical having from 1 to 3 or from 1 to 4 or from 1 to 6 carbon atoms, such as methyl, ethyl, 1-propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methyl-1-propyl, 1,1-dimethylethyl, 3-methyl-1-butyl, 1-pentyl, 1-hexyl and the like.
  • C 3-7 cycloalkyl or “C 3-8 cycloalkyl” as a group or part of a group defines a saturated, cyclic hydrocarbon radical having from 3 to 7 or from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • halo or halogen as used herein as a group or part of a group refers to fluoro, chloro, bromo or iodo, with fluoro or chloro being preferred.
  • substituted is used in the present invention, it is meant, unless otherwise is indicated or is clear from the context, to indicate that one or more hydrogens, preferably from 1 to 3 hydrogens, more preferably from 1 to 2 hydrogens, more preferably 1 hydrogen, on the atom or radical indicated in the expression using “substituted” are replaced with a selection from the indicated group, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.
  • antiepileptic agent and the abbreviation “AED” will be used interchangeably with the term “anticonvulsant agent”, and as used herein, refer to an agent capable of treating, inhibiting or preventing seizure activity or ictogenesis when the agent is administered to a subject or patient.
  • SV2A ligand As used herein, unless otherwise noted, the term “synaptic vesicle protein 2A ligand” and the abbreviation “SV2A ligand” will be used interchangeably.
  • SV2A ligands include, but are not limited to, the compounds included in the publications GB 1,039,113; GB 1,309,692; EP 1 262 036; EP 1 806 339; WO 2001/062726; US 2002/094787; WO 2004/087658; WO 2005/121082; WO 2005/054188; WO 2006/128692; WO 2006/128693; WO 2007/065595; WO 2008/132139, and WO 2008/132142; WO 2011/047860; WO 2012/143116; and WO 2012/143117.
  • Suitable particular examples of SV2A ligands include, but are not limited to: levetiracetam, brivaracetam and seletracetam.
  • the SV2A ligand is selected from levetiracetam, brivaracetam and seletracetam.
  • the SV2A ligand is levetiracetam.
  • the SV2A ligand is brivaracetam.
  • the combination according to the invention comprises (a) a SV2A ligand selected from levetiracetam or brivaracetam; and (b)
  • the pharmaceutical composition according to the invention comprises (a) a pharmaceutically effective amount of levetiracetam or brivaracetam; and (b) a pharmaceutically effective amount of
  • the combination according to the invention comprises (a) a pharmaceutically effective amount of levetiracetam or brivaracetam; and (b) a pharmaceutically effective amount of
  • the pharmaceutical composition according to the invention comprises (a) a pharmaceutically effective amount of levetiracetam or brivaracetam; and (b) a pharmaceutically effective amount of
  • the combination according to the invention comprises (a) a pharmaceutically effective amount of levetiracetam or brivaracetam; and (b) a pharmaceutically effective amount of
  • the pharmaceutical composition according to the invention comprises (a) a pharmaceutically effective amount of levetiracetam or brivaracetam; and (b) a pharmaceutically effective amount of
  • the combination according to the invention comprises (a) a pharmaceutically effective amount of levetiracetam or brivaracetam; and (b) a pharmaceutically effective amount of
  • the pharmaceutical composition according to the invention comprises (a) a pharmaceutically effective amount of levetiracetam or brivaracetam; and (b) a pharmaceutically effective amount of
  • the combination according to the invention comprises (a) a pharmaceutically effective amount of levetiracetam or brivaracetam; and (b) a pharmaceutically effective amount of LY-404039 or a pharmaceutically acceptable salt thereof, in particular the hydrochloride salt thereof, or a solvate thereof.
  • the pharmaceutical composition according to the invention comprises (a) a pharmaceutically effective amount of levetiracetam or brivaracetam; and (b) a pharmaceutically effective amount of LY-404039 or a pharmaceutically acceptable salt thereof, in particular the hydrochloride salt thereof, or a solvate thereof.
  • the combination according to the invention comprises (a) a pharmaceutically effective amount of levetiracetam or brivaracetam; and (b) a pharmaceutically effective amount of LY-2140023 or a pharmaceutically acceptable salt or a solvate thereof, in particular the monohydrate thereof.
  • the pharmaceutical composition according to the invention comprises (a) a pharmaceutically effective amount of levetiracetam or brivaracetam; and (b) a pharmaceutically effective amount of LY-2140023 or a pharmaceutically acceptable salt or a solvate thereof, in particular the monohydrate thereof.
  • the combination product of the present invention in particular, the pharmaceutical composition according to the invention, is especially appropriate for the treatment of epilepsy and related disorders.
  • mGluR2 compounds in particular the mGluR2 PAM/agonist compounds of the invention and their pharmaceutically acceptable addition salts and solvates thereof may contain one or more centres of chirality and exist as stereoisomeric forms.
  • compounds of the invention as used herein, is meant to include the mGluR2 PAM compounds, in particular the compounds of Formula (I)/(I-A)/(I-B), and the mGluR2 agonist compounds as disclosed herein, and the salts and solvates thereof.
  • mGluR2 compound and “mGluR2 PAM/agonist compound” are meant to include the stereoisomers thereof and the tautomeric forms thereof.
  • stereoisomers stereoisomers
  • stereoisomeric forms or “stereochemically isomeric forms” hereinbefore or hereinafter are used interchangeably.
  • the invention includes all stereoisomers of the compounds of the invention either as a pure stereoisomer or as a mixture of two or more stereoisomers.
  • Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture.
  • Diastereomers are stereoisomers that are not enantiomers, i.e. they are not related as mirror images. If a compound contains a double bond, the substituents may be in the E or the Z configuration. Substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration; for example if a compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration. Therefore, the invention includes enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible.
  • the meaning of all those terms, i.e. enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof are known to the skilled person.
  • the absolute configuration is specified according to the Cahn-Ingold-Prelog system.
  • the configuration at an asymmetric atom is specified by either R or S.
  • Resolved stereoisomers whose absolute configuration is not known can be designated by (+) or ( ⁇ ) depending on the direction in which they rotate plane polarized light.
  • resolved enantiomers whose absolute configuration is not known can be designated by (+) or ( ⁇ ) depending on the direction in which they rotate plane polarized light.
  • stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1%, of the other isomers.
  • a mGluR2 compound is for instance specified as (R)
  • S the compound is substantially free of the (S) isomer
  • E the compound is substantially free of the Z isomer
  • a mGluR2 compound is for instance specified as cis, this means that the compound is substantially free of the trans isomer.
  • mGluR2 compounds may also exist in their tautomeric form. Such forms in so far as they may exist, although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
  • the salts of the compounds of this invention refer to non-toxic “pharmaceutically acceptable salts” (salts of the compounds of the present invention wherein the counterion is pharmaceutically acceptable).
  • Other salts may, however, be useful in the preparation or purification of compounds according to this invention or of their pharmaceutically acceptable salts, and may encompass acids and bases which are non-pharmaceutically acceptable. All salts, whether pharmaceutically acceptable or not, are included within the ambit of the present invention.
  • Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e.
  • ethanedioic malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
  • succinic i.e. butanedioic acid
  • maleic fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
  • suitable pharmaceutically acceptable salts thereof may include organic and inorganic bases.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and alkaline earth metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g.
  • the salt form can be converted by treatment with acid into the free acid form.
  • methylamine, ethylamine, propylamine, isopropylamine the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • the salt form can be converted by treatment with acid into the free acid form.
  • solvate comprises the solvent addition forms as well as the salts thereof, which the compounds of Formula (I) are able to form.
  • solvent addition forms are e.g. hydrates, alcoholates and the like.
  • the compounds of Formula (I-B) according to the invention can generally be prepared by a succession of steps, each of which is known to the skilled person.
  • the compounds can be prepared according to the following synthesis methods.
  • the compounds of Formula (I-B) may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures.
  • the racemic compounds of Formula (I-B) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali.
  • An alternative manner of separating the enantiomeric forms of the compounds of Formula (I-B) involves liquid chromatography or supercritical fluid chromatography (SFC) using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • Final compounds according to Formula (I-B) can be prepared by reacting an intermediate compound of Formula (II) with a compound of Formula (III) according to reaction scheme (1), a reaction that is performed under classical Mitsunobu conditions.
  • the reaction is preferably conducted with a phosphine and an azodicarboxylic ester or amide in tetrahydrofuran, 1,4-dioxane, diethyl ether, toluene, benzene, dichloromethane, or mixtures thereof, at ⁇ 30 to 150° C., under thermal heating or microwave irradiation.
  • Phosphines often used are triphenylphosphine and tributylphosphine which are usually combined with dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-(4-chlorobenzyl) azodicarboxylate, dibenzyl azodicarboxylate, di-tert-butyl azodicarboxylate, azodicarboxylic acid bis-(dimethyylamide), azodicarboxylic acid dipiperidide, or azodicarboxylic acid dimorpholide.
  • reaction scheme (1) all variables are as defined in Formula (I-B)
  • Intermediate compounds according to Formula (II) can be prepared by subjecting an intermediate of Formula (IV) to conditions that are known to those skilled in the art. This is illustrated in reaction scheme (2) wherein all variables are defined as mentioned hereinabove. Methods accomplishing these transformations are well known to those skilled in the art.
  • Treatment of the aldehyde of formula (IV) with an organometallic such as methyl lithium or methyl magnesium bromide gives a compound of formula (II).
  • a suitable solvent for this reaction is an ether such as tetrahydrofuran and the reaction is usually carried out at a temperature between ⁇ 78° C. and 40° C.
  • reaction scheme (2) all variables are defined as in Formula (I-B).
  • Intermediate compounds according to Formula (IV) can be prepared by reacting an intermediate of Formula (V) under dihydroxylation and oxidative cleavage conditions that are known to those skilled in the art and can be realized for example with oxone, osmium tetroxide.
  • the process may be carried out optionally in a solvent such as 1,4-dioxane, water and generally at temperatures between about ⁇ 100° C. and about 100° C.
  • a solvent such as 1,4-dioxane
  • reaction scheme (3) wherein all variables are defined as mentioned hereinabove.
  • Intermediate compounds according to Formula (V) can be prepared by coupling reactions, such as Stille or Suzuki reactions of an intermediate of Formula (VI) with a compound of Formula (VII) under conditions that are known to those skilled in the art.
  • the process may be carried out optionally in a solvent such as 1,4-dioxane, water and generally at temperatures between about r.t. and about 200° C. in the presence of a base.
  • a solvent such as 1,4-dioxane
  • reaction scheme (4) wherein all variables are defined as mentioned hereabove, wherein M is trialkyltin, boronic acid or boronate ester, and a palladium catalyst and halo is chloro, bromo or iodo.
  • Intermediate compounds according to Formula (VI) can be prepared following art known procedures by cyclization of an intermediate compound of Formula (VIII) in the presence of a halogenating agent such as for example phosphorus (V) oxychloride (POCl 3 ) in a suitable solvent such as, for example, dichloroethane, stirred under microwave irradiation, for a suitable period of time that allows the completion of the reaction, as for example 5 min at a temperature between 140-200° C.
  • a halogenating agent such as for example phosphorus (V) oxychloride (POCl 3 )
  • a suitable solvent such as, for example, dichloroethane
  • Intermediate compounds according to Formula (VIII) can be prepared by art known procedures by reaction of a hydrazine intermediate of Formula (IX) with acid halides of Formula (X).
  • the reaction can be carried out using an inert-solvent, such as for example DCM, in the presence of a base such as for example triethylamine, for example at r.t. for a suitable period of time that allows completion of the reaction, for example 20 min.
  • R 1 is defined as in Formula (I-B).
  • Intermediate compounds according to Formula (IX) can be prepared by reacting an intermediate compound of Formula (XI) with hydrazine according to reaction scheme (7), a reaction that is performed in a suitable reaction-inert solvent, such as, for example, ethanol, THF or 1,4-dioxane under thermal conditions such as, for example, heating the reaction mixture for example at 160° C. under microwave irradiation for 30 min or classical thermal heating at 70° C. for 16 h.
  • halo is chloro, bromo or iodo.
  • Intermediate compounds according to Formula (XI) can be prepared by reacting an intermediate compound of Formula (XII) with benzyl alcohol according to reaction scheme (8), a reaction that is performed in a suitable reaction-inert solvent, such as, for example, N,N-dimethylformamide in the presence of a suitable base, such as for example sodium hydride at r.t. for a suitable period of time that allows the completion of the reaction, such as for example 1 h.
  • halo is chloro, bromo or iodo.
  • Intermediate compounds of Formula (XII) can be prepared by reacting an intermediate of Formula (XIII), with a suitable trifluoromethylating agent, such as for example fluorosulfonyl(difluoro)acetic acid methyl ester, according to reaction scheme (9).
  • a suitable reaction-inert solvent such as, for example, N,N-dimethylformamide
  • a suitable coupling agent such as for example, copper(I) iodide
  • thermal conditions such as, for example, heating the reaction mixture for example at 160° C. under microwave irradiation for 45 min.
  • halo is chloro, bromo or iodo.
  • the starting materials according to Formulae (II), (VII), (X) or (XIII) are compounds that are either commercially available or may be prepared according to conventional reaction procedures generally known to those skilled in the art.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • the term “subject” refers to an animal, preferably a mammal, most preferably a human adult, child or infant, who is or has been the object of treatment, observation or experiment.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of one or more of the symptoms of the disease or disorder being treated; and/or reduction of the severity of one or more of the symptoms of the disease being treated.
  • the term “fixed-dose ratio of (a) synaptic vesicle protein 2A ligand to (b) compound of Formula (I) of 1:1, calculated on the ED 50 values of the individual compounds (a) and (b)” refers to compositions comprising compounds (a) and (b) in a dose corresponding to 50% of the respective ED 50 dose of the individual compounds (a) and (b) or a multiple of this fixed-dose ratio.
  • fixed-dose ratio of (a) synaptic vesicle protein 2A ligand:(b) compound of Formula (I) of 3:1, calculated on the ED 50 values of the individual compounds (a) and (b)” refers to compositions comprising (b) the compound of Formula (I) in a dose corresponding to 75% of the respective ED 50 dose and compound (a) in a dose corresponding to 25% of the respective ED 50 dose of compound (a) or a multiple of this fixed-dose ratio, and so on.
  • (a) the SV2A ligand and (b) the compound of Formula (I) are present in the pharmaceutical composition in a fixed-dose ratio of (a):(b) of about 1:10 to about 10:1, preferably about 1:5 to about 5:1, more preferably about 1:3 to about 3:1, in another embodiment of about 1:1 to about 3:1; in an alternate embodiment of 1:3; in yet another embodiment of 1:1; further embodiment of 3:1; wherein the fixed-dose ratio is calculated on the ED 50 values of the individual compounds (a) and (b).
  • the present invention is directed to co-therapy or combination therapy, comprising administration of (a) synaptic vesicle protein 2A (“SV2A”) ligand; and (b) a mGluR2 PAM/agonist compound, in particular a compound of Formula (I)/(I-A)/(I-B) as defined herein, pharmaceutically or therapeutically effective amount shall mean that amount of the combination of agents taken together so that the combined effect elicits the desired biological or medicinal response.
  • SV2A synaptic vesicle protein 2A
  • a mGluR2 PAM/agonist compound in particular a compound of Formula (I)/(I-A)/(I-B) as defined herein
  • pharmaceutically or therapeutically effective amount shall mean that amount of the combination of agents taken together so that the combined effect elicits the desired biological or medicinal response.
  • the therapeutically effective amount of co-therapy comprising administration of (a) a SV2A ligand as defined herein and (b) a mGluR2 PAM/agonist compound, in particular a compound of Formula (I)/(I-A)/(I-B) as defined herein would be the amount of the (a) a SV2A ligand as defined herein and the amount of (b) a mGluR2 PAM/agonist compound, in particular compound of Formula (I)/(I-A)/(I-B) that when taken together or sequentially have a combined effect that is therapeutically effective.
  • the amount of the mGluR2 PAM/agonist compound, in particular the compound of Formula (I)/(I-A)/(I-B), and/or the amount of the suitable SV2A ligand individually may or may not be therapeutically effective.
  • the present invention provides methods of prevention or treatment comprising administering to a subject in need thereof, co-therapy with a therapeutically effective amount of a SV2A ligand and a therapeutically effective amount of a mGluR2 PAM/agonist compound, in particular a compound of formula (I)/(I-A)/(I-B), as described herein.
  • a SV2A ligand and a therapeutically effective amount of a mGluR2 PAM/agonist compound, in particular a compound of formula (I)/(I-A)/(I-B), as described herein.
  • a mGluR2 PAM/agonist compound in particular a compound of formula (I)/(I-A)/(I-B), as described herein.
  • the compounds or compositions of this invention must be used in the correct therapeutically effective amount or dose, as described below.
  • Optimal dosages and schedules to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
  • a therapeutically effective dosage of the compounds of the present invention can include repeated doses within a prolonged treatment regimen that will yield clinically significant results.
  • the amounts of the mGluR2 PAM/agonist compound, in particular of the compound of Formula (I)/(I-A)/(I-B), in the combinations of the invention that are administered on a daily basis may vary from about 0.01 to about 2000 mg.
  • Examples of daily amounts of the compound of Formula (I)/(I-A)/(I-B) are 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, 300, 400, 500, 750 and 1000 milligrams for the symptomatic adjustment of the dosage to the patient to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 150.0 mg/kg of body weight per day or any range therein.
  • the range is from about 0.1 to about 100.0 mg/kg of body weight per day, more preferably, from about 0.5 mg/kg to about 50 mg/kg, more preferably, from about 1.0 to about 25.0 mg/kg of body weight per day.
  • the compounds may be administered on a regimen of 1, 2, 3 or 4 times per day.
  • the amounts of SV2A ligand that are administered on a daily basis may vary from about 0.01 to about 7000 mg, preferably will be between 250 and 5000 mg and more preferably will be between 500 and 3000 mg.
  • Examples of daily amount of the SV2A ligand are 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, 500, 750, 1000, 1500 and 3000 milligrams for the symptomatic adjustment of the dosage of the patient to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 150.0 mg/kg of body weight per day or any range therein.
  • the range is from about 0.1 to about 100.0 mg/kg of body weight per day, more preferably, from about 0.5 mg/kg to about 50 mg/kg, more preferably, from about 1.0 to about 25.0 mg/kg of body weight per day.
  • the compounds may be administered on a regimen of 1, 2, 3 or 4 times per day. All amounts mentioned in this and the following paragraphs refer to the free form (i.e. non-salt form). The above values represent free-form equivalents, i.e. quantities as if the free form would be administered. If salts are administered the amounts need to be calculated in function of the molecular weight ratio between the salt and the free form.
  • the above mentioned daily doses are calculated for an average body weight of about 70 kg and should be recalculated in case of paediatric applications, or when used with patients with a substantially diverting body weight.
  • the dosages may be presented as one, two, three or four or more sub-doses administered at appropriate intervals throughout the day.
  • the dosage used preferably corresponds to the daily amount of the mGluR2 PAM/agonist compound, in particular of the compound of Formula (I)/(I-A)/(I-B), or of the SV2A ligand, mentioned above, or a sub-dose thereof, such as 1 ⁇ 2, 1 ⁇ 3, 1 ⁇ 4 thereof.
  • a dosage form may contain the mGluR2 PAM/agonist compound, in particular the compound (I)/(I-A)/(I-B), or the SV2A ligand or both together, in an amount equal to the ranges or quantities mentioned in the previous paragraphs, for example a dosage form may contain 10 mg, 25 mg, 50 mg, 100 mg, 150 mg, or 200 mg of mGluR2 PAM/agonist compound, in particular of compound (I)/(I-A)/(I-B), 10 mg, 25 mg, 50 mg, 100 mg or 250 mg, of SV2A ligand, either in separate formulations or in a combined formulation.
  • the mGluR2 PAM/agonist compound in particular the compound of Formula (I)/(I-A)/(I-B), is administered once daily (q.d.), in particular as one dose per day, and the SV2A ligand is administered once or twice daily (q.d. or b.i.d.), in particular as one or as two doses per day.
  • both compounds are to be administered once daily, this can be accomplished by administering two separate doses, one with the mGluR2 PAM/agonist compound, in particular the compound of Formula (I)/(I-A)/(I-B), one with the SV2A ligand, or by administering a combined dose containing the mGluR2 PAM/agonist compound, in particular the compound of Formula (I)/(I-A)/(I-B), and SV2A ligand.
  • the combinations of the invention may be administered once, twice, three, four, or if desired, multiple times daily. In one embodiment, the combination is administered once daily. In another embodiment, the combination is administered twice daily, or three times per day. Administration of dosages may be by separate dosage forms, i.e. dosage forms only containing mGluR2 PAM/agonist compound, in particular compound of Formula (I)/(I-A)/(I-B), or only SV2A ligand; or by combined dosage forms containing active ingredients mGluR2 PAM/agonist compound, in particular compound of Formula (I)/(I-A)/(I-B), and SV2A ligand. Also, a mix of using a combined dosage form and separate dosage forms can be used. Dosage forms that can be administered are described hereinafter, oral dosage forms, in particular tablets or capsules being preferred.
  • Active ingredients may be formulated in pharmaceutical compositions either separately or as a combined pharmaceutical composition.
  • a pharmaceutical composition comprising a therapeutically effective amount of the mGluR2 PAM/agonist compound, in particular of the compound of Formula (I)/(I-A)/(I-B), or a pharmaceutically acceptable salt thereof, and the SV2A ligand, the foregoing being as specified herein, and a pharmaceutically acceptable carrier.
  • this invention relates to a process for preparing a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of the mGluR2 PAM/agonist compound, in particular of the compound of Formula (I)/(I-A)/(I-B), or a pharmaceutically acceptable salt or a solvate thereof, and a therapeutically effective amount of at least one SV2A ligand.
  • the combinations provided herein may also be formulated as a combined preparation for simultaneous, separate or sequential use in the prevention or treatment of epilepsy and related disorders; neuropathic pain; migraine or resistant headache; bipolar and related disorders; in neuroprotection; or in the prevention of epileptogenesis.
  • the mGluR2 PAM/agonist compound in particular the compound of Formula (I)/(I-A)/(I-B), is formulated in a pharmaceutical composition containing other pharmaceutically acceptable excipients, and the SV2A ligand is formulated separately in a pharmaceutical composition containing other pharmaceutically acceptable excipients.
  • these separate pharmaceutical compositions can be part of a kit for simultaneous, separate, or sequential use.
  • the individual components of the combination of the present invention can be administered simultaneously or separately at different times during the course of therapy or concurrently in divided or single combination forms.
  • the mGluR2 PAM/agonist compounds in particular the compounds of Formula (I)/(I-A)/(I-B), and the SV2A ligand, individually or combined, may be formulated into various pharmaceutical compositions suitable for administration purposes.
  • a therapeutically effective amount of the particular compound, or of both two compounds is combined with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • Pharmaceutical compositions may be prepared as medicaments to be administered orally, parenterally (including subcutaneously (s.c.), intramuscularly (i.m.), and intravenously (i.v.)), rectally, transdermally, bucally, or nasally.
  • compositions may also be prepared to be administered directly to the nervous system by routes including, but not limited to, intracerebral, intraventricular, intracerebroventricular, intrathecal, intracisternal, intraspinal and/or peri-spinal route by delivery via intracranial or intravertebral needles and/or catheters with or without pump devices.
  • Suitable compositions for oral administration include powders, granulates, aggregates, tablets, compressed or coated pills, dragees, sachets, hard or gelatin capsules, syrups and suspensions.
  • compositions for parenteral administration include aqueous or non-aqueous solutions or emulsions, while for rectal administration suitable compositions for administration include suppositories with a hydrophilic or hydrophobic vehicle.
  • suitable transdermal delivery systems can be used and for nasal delivery suitable aerosol delivery systems can be used.
  • any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid compositions such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of solid compositions.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, such as solubilizers, emulsifiers or further auxiliaries may be added thereto.
  • injectable solutions may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of both.
  • Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations intended to be converted, shortly before use, to liquid form preparations such as powders for reconstitution.
  • the carrier optionally comprises a skin penetration enhancing agent and/or a wetting agent, optionally combined with suitable skin-compatible additives in minor proportions.
  • the mGluR2 PAM/agonist compound in particular the compound of Formula (I)/(I-A)/(I-B), or SV2A ligand, or combinations thereof, may also be administered via oral inhalation or insufflation by formulations suited for this type of administration such as a solution, a suspension or a dry powder.
  • Suitable pharmaceutical compositions for administration in the form of aerosols or sprays are, for example, suspensions of the mGluR2 PAM/agonist compound, in particular of the compound of Formula (I)/(I-A)/(I-B), or SV2A ligand, or both, in a pharmaceutically acceptable liquid carrier, such as ethanol or water, or a mixture thereof.
  • a pharmaceutically acceptable liquid carrier such as ethanol or water, or a mixture thereof.
  • the formulation can also additionally contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant.
  • Such a preparation customarily contains the active compound in a concentration from approximately 0.1 to 50%, in particular from approximately 0.3 to 3% by weight.
  • the pharmaceutical compositions may contain the active ingredient mGluR2 PAM/agonist compound, in particular compound of Formula (I)/(I-A)/(I-B), or the SV2A ligand, or both combined in a concentration of about 0.1% to about 50%, or about 1% to about 30%, or about 3% to about 20%, or about 5% to about 20%, all percentages being by weight, wherein the total of all components in said pharmaceutical compositions does not exceed 100%.
  • the mGluR2 PAM/agonist compound in particular the compound of Formula (I)/(I-A)/(I-B), is present in a concentration of about 0.1% to about 50%, or about 1% to about 30%, or about 3% to about 20%, or about 5% to about 20%; and the SV2A ligand is present in a concentration of about 3% to about 50%, or about 5% to about 50%, or about 10% to about 50%, or about 10% to about 40%, or about 10% to about 30%, wherein the total of all components in said pharmaceutical compositions does not exceed 100%.
  • compositions may be conveniently presented in unit dosage form for ease of administration and uniformity of dosage. Examples include tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof. Of interest are solid dosage forms for oral administration such as tablets or capsules.
  • the solid dosage forms in unit dose form may be packed in any known package, blister packs being preferred, in particular for tablets and capsules.
  • the mGluR2 PAM/agonist compound, in particular the compound of Formula (I)/(I-A)/(I-B), and SV2A ligand are formulated separately, they could be packed in separate blisters, but one blister could as well comprise unit dose forms of the mGluR2 PAM/agonist compound, in particular of the compound of Formula (I)/(I-A)/(I-B), and of the SV2A ligand, for example one row with units of mGluR2 PAM/agonist compound, in particular of compound of Formula (I)/(I-A)/(I-B), and another with SV2A ligand.
  • Other possibilities may be possible as well.
  • the combinations of this invention may be used to treat or prevent epilepsy and related disorders; neuropathic pain; migraine or resistant headache; and bipolar and related disorders; or they may be used as a neuroprotectant or to prevent epileptogenesis.
  • treatment is intended to refer to all processes, wherein there may be a slowing, interrupting, arresting or stopping of the progression of a disease or an alleviation of symptoms, but does not necessarily indicate a total elimination of all symptoms
  • epilepsy and related disorders shall mean any disorder in which a subject (preferably a human adult, child or infant) experiences one or more seizures and/or tremors.
  • Suitable examples include, but are not limited to, epilepsy (including, but not limited to, localization-related epilepsies, generalized epilepsies, epilepsies with both generalized and local seizures, and the like), partial-onset seizures with or without generalization, myoclonic seizures, primary generalized tonic-clonic seizures in particular in patients with idiopathic generalized epilepsy, seizures associated with Lennox-Gastaut syndrome, seizures as a complication of a disease or condition (such as seizures associated with encephalopathy, phenylketonuria, juvenile Gaucher's disease, Lundborg's progressive myoclonic epilepsy, stroke, head trauma, stress, hormonal changes, drug use or withdrawal, alcohol use or withdrawal, sleep deprivation, fever, infection, and the like), status epilepticus (convulsive or non convulsive), essential tremor, restless limb syndrome, and the like.
  • epilepsy including, but not limited to, localization-related epilepsies, general
  • the disorder is selected from epilepsy (regardless of type, underlying cause or origin), essential tremor or restless limb syndrome. More preferably, the disorder is epilepsy (regardless of type, underlying cause or origin) or essential tremor.
  • epilepsy is refractory epilepsy, also referred to as treatment or therapy resistant epilepsy. This term is often used when patients have failed three or more anti-epileptic drugs (AEDs).
  • Refractory epilepsy also includes refractory partial epilepsy and refractory generalized epilepsy (including idiopathic or symptomatic).
  • neuropathic pain includes pain resulting from chronic or debilitating conditions or disorders.
  • the chronic or debilitating conditions or disorders which can lead to neuropathic pain include, but are not limited to, painful diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, post-stroke pain, multiple sclerosis-associated pain, neuropathies-associated pain such as in idiopathic or post-traumatic neuropathy and mononeuritis, HIV-associated neuropathic pain, cancer-associated neuropathic pain, carpal tunnel-associated neuropathic pain, spinal cord injury-associated pain, complex regional pain syndrome, fibromyalgia-associated neuropathic pain, lumbar and cervical pain, reflex sympathic dystrophy, phantom limb syndrome and other chronic and debilitating condition-associated pain syndromes.
  • migraine without aura shall mean at least five attacks fulfilling the following criteria: (a) the headache attack lasts 4-72 hours with the headache having at least two of the following features: unilateral location, pulsating quality, moderate or severe intensity with direct influence on activities of daily living, and aggravation by walking up stairs or similar routines: and (b) during the headache at least one of the following occurs: nausea and/or vomiting, and photophobia and phonophobia.
  • migraine with aura shall mean at least two attacks accompanied by at least 3 of the 4 following features: (a) one or more fully reversible aura symptoms: (b) at least one aura symptom which develops gradually over more than four minutes or two or more symptoms which occur in succession; (c) no aura symptom which lasts more than 60 minutes; (d) a headache occurs prior to, simultaneously with or following the aura, with a free interval between aura and headache of less than about 60 minutes.
  • bipolar and related disorders shall include bipolar disorder I (e.g. single manic episode, most recent episode hypomanic, most recent episode manic, most recent episode mixed, most recent episode depressed and most recent episode unspecified), bipolar disorder II, cyclothymic disorder and bipolar disorder not otherwise specified (as these terms are defined by their diagnostic criteria, in the Diagnostic and Statistical manual of Mental Disorders 4th Edition, Text Revision, American Psychiatric Association, 2000 (DSM-IV-TR) or in the 5 th Edition, Text Revision, American Psychiatric Association, 2013 (DSM-5TM).
  • the bipolar disorder is characterized by depressive and manic (or hypomanic) phases, wherein the phases cycle.
  • the bipolar disorder is bipolar disorder I or bipolar disorder II.
  • mania shall include mania or a manic mood phase, regardless of underlying cause.
  • bipolar mania is intended to mean the mania associated with, characteristic of or symptomatic of a bipolar disorder.
  • methods of treating bipolar mania of the present invention are directed to methods which treat the mania and/or manic phase of bipolar disorders.
  • the term “bipolar depression” is intended to mean the depression associated with, characteristic of or symptomatic of a bipolar disorder.
  • methods of treating bipolar depression of the present invention are directed to methods which treat the depression and/or depressed phase of bipolar disorders.
  • cycling or “bipolar cycling” shall refer to the alteration of mood between depressive and manic phases characteristic of bipolar disorders.
  • the present invention includes methods for the stabilization of said cycling, including, but not limited to, decreasing the frequency of the cycling and/or decreasing the magnitude of the manic and/or depressive phases.
  • the pharmaceutical composition of the present invention may be used for mood stabilization, in particular mood stabilization for manic depression.
  • epilepsy refers to the gradual process by which epilepsy develops. This process may occur following brain insults or a variety of conditions, including neurodegenerative diseases, traumatic brain injury, stroke, brain tumor, infections of the central nervous system, and status epilepticus; or it may occur following gene mutations.
  • anxiety refers in particular to generalized anxiety disorder.
  • the term “about” has its conventional meaning. In particular embodiments, when in relation to a numerical value, it may be interpreted to mean the numerical value ⁇ 10%, or ⁇ 5%, or ⁇ 2%, or ⁇ 1%, or ⁇ 0.5%, or ⁇ 0.1%. In other embodiments, the precise value is meant, i.e. by leaving out the word “about”.
  • aq. means aqueous; “DCE” means 1,2-dichloroethane, “DCM” means dichloromethane; “DIPE” means diisopropylether; “DIPEA” means N,N-diisopropylethylamine; “DMF” means N,N-dimethylformamide; “ES” means electrospray; “Et 3 N” means triethylamine; “Et 2 O” means diethyl ether; “EtOAc” means ethyl acetate; “h” means hours; “HPLC” means high performance liquid chromatography; “HRMS” means high-resolution mass spectra/spectrometry; “1” or “L” means liter; “LRMS” means low-resolution mass spectrometry/spectra; “MeOH” means methanol; “min” means minute(s); “mp” means melting point; “Pd(PPh 3 ) 4 ” means tetrakis(
  • Microwave assisted reactions were performed in a single-mode reactor: InitiatorTM Sixty EXP microwave reactor (Biotage AB), or in a multimode reactor: MicroSYNTH Labstation (Milestone, Inc.).
  • TLC Thin layer chromatography
  • silica gel 60 F254 plates Merck
  • Automated flash column chromatography was performed using ready-to-connect cartridges from Merck, on irregular silica gel, particle size 15-40 ⁇ m (normal phase disposable flash columns) on a SPOT or LAFLASH system from Armen Instrument.
  • VCD vibrational circular dichroism
  • RS Whenever the notation “RS” is indicated herein, it denotes that the compound is a racemic mixture, unless otherwise indicated.
  • the stereochemical configuration for some compounds has been designated “R” or “S” when the mixture was separated; for some compounds, the stereochemical configuration has been designated as “*R” or “*S” when the absolute stereochemistry is undetermined although the compound itself has been isolated as a single stereoisomer and is enantiomerically pure.
  • the enantiomeric excess of compounds reported herein was determined by analysis of the racemic mixture by supercritical fluid chromatography (SFC) followed by SFC comparison of the separated enantiomer(s).
  • SFC supercritical fluid chromatography
  • Methylmagnesium bromide (1.4 M in THF, 12.40 mL, 17.37 mmol) was added dropwise to a stirred suspension of intermediate 17 (4.25 g, 15.79 mmol) in THY (281.07 mL) at ⁇ 20° C. under N 2 atmosphere. The mixture was stirred at ⁇ 20° C. for 45 minutes. The crude was treated with a sat. sol. of NH 4 Cl and extracted with EtOAc. The organic layer was separated, dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 4/96).
  • intermediate 21a (racemic mixture) (2.96 g, 66%).
  • Intermediate 21a (1.82 g) was purified by chiral SFC: [Stationary phase: CHIRALPAK AD-H (5 ⁇ m 250 ⁇ 20 mm), Mobile phase: 80% CO 2 , 20% EtOH] yielding 21b (R-enantiomer) (0.453 g, 10%) as a pale grey solid and intermediate 21c (S-enantiomer) (0.439 g, 10%).
  • [ ⁇ ] ⁇ T (100 ⁇ )/(l ⁇ c): where l is the path length in dm and c is the concentration in g/100 ml for a sample at a temperature T (° C.) and a wavelength ⁇ (in nm). If the wavelength of light used is 589 nm (the sodium D line), then the symbol D might be used instead.
  • the sign of the rotation (+ or ⁇ ) should always be given. When using this equation the concentration and solvent are always provided in parentheses after the rotation. The rotation is reported using degrees and no units of concentration are given (it is assumed to be g/100 ml).
  • HPLC High Performance Liquid Chromatography
  • MS Mass Spectrometer
  • tune parameters e.g. scanning range, dwell time . . .
  • ions allowing the identification of the compound's nominal monoisotopic molecular weight (MW).
  • Data acquisition was performed with appropriate software.
  • Compounds are described by their experimental retention times (R t ) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H] + (protonated molecule) and/or [M ⁇ H] ⁇ (deprotonated molecule).
  • the type of adduct is specified (i.e. [M+NH 4 ] + , [M+HCOO] ⁇ , etc. . . . ).
  • the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used.
  • SQL Single Quadrupole Detector, “RT” room temperature, “BEH” bridged ethylsiloxane/silica hybrid, “HSS” High Strength Silica, “DAD” Diode Array Detector.
  • Values are peak values, and are obtained with experimental uncertainties that are commonly associated with this analytical method.
  • melting points were determined in open capillary tubes on a FP 81HT/FP90 apparatus (Mettler-Toledo). Melting points were measured with a temperature gradient of 1, 3, 5 or 10° C./minute. Maximum temperature was 300° C. The melting point was read from a digital display.
  • the SFC measurement was performed using Analytical system from Berger instrument comprising a FCM-1200 dual pump fluid control module for delivering carbon dioxide (CO2) and modifier, a CTC Analytics automatic liquid sampler, a TCM-20000 thermal control module for column heating from room temperature to 80° C.
  • An Agilent 1100 UV photodiode array detector equipped with a high-pressure flow cell standing up to 400 bars was used. Flow from the column was split to a MS spectrometer. The MS detector was configured with an atmospheric pressure ionization source.
  • the following ionization parameters for the Waters ZQ mass spectrophotometer are: corona: 9 ⁇ a, source temp: 140° C., cone: 30 V, probe temp 450° C., extractor 3 V, desolvatation gas 400 L/hr, cone gas 70 L/hr. Nitrogen was used as the nebulizer gas. Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system.
  • Method 1 In addition to the general procedure: The analytical chiral separation in SFC-MS was carried out on a CHIRALPAK AD DAICEL column (10 ⁇ m, 4.6 ⁇ 250 mm) at 35° C. with a flow rate of 3.0 ml/min. The mobile phase is 85% CO 2 , 15% iPrOH (+0.3% iPrNH 2 ) hold 7 min in isocratic mode.
  • Method 2 In addition to the general procedure: The analytical chiral separation in SFC-MS was carried out on a CHIRALPAK AD DAICEL column (10 ⁇ m, 4.6 ⁇ 250 mm) at 35° C. with a flow rate of 3.0 ml/min. The mobile phase is 75% CO2, 15% iPrOH (+0.3% iPrNH 2 ) hold 7 min in isocratic mode.
  • Method 3 In addition to the general procedure: The analytical chiral separation in SFC-MS was carried out on a CHIRALPAK AD DAICEL column (10 ⁇ m, 4.6 ⁇ 250 mm) at 35° C. with a flow rate of 3.0 ml/min. The mobile phase is 80% CO2, 10% Methanol+10% iPrOH (+0.3% iPrNH 2 ) hold 7 min in isocratic mode.
  • the compounds of Formula (I-B) provided in the present invention are positive allosteric modulators of mGluR2. These compounds appear to potentiate glutamate responses by binding to an allosteric site other than the glutamate binding site. The response of mGluR2 to a concentration of glutamate is increased when compounds of Formula (I-B) are present. Compounds of Formula (I-B) are expected to have their effect substantially at mGluR2 by virtue of their ability to enhance the function of the receptor.
  • the effects of positive allosteric modulators tested at mGluR2 using the [ 35 S]GTP ⁇ S binding assay method described below and which is suitable for the identification of such compounds, and more particularly the compounds according to Formula (I-B), are shown in Table E.
  • the [ 35 S]GTP ⁇ S binding assay is a functional membrane-based assay used to study G-protein coupled receptor (GPCR) function whereby incorporation of a non-hydrolysable form of GTP, [ 35 S]GTP ⁇ S (guanosine 5′-triphosphate, labelled with gamma-emitting 35 S), is measured.
  • GPCR G-protein coupled receptor
  • the G-protein a subunit catalyzes the exchange of guanosine 5′-diphosphate (GDP) by guanosine triphosphate (GTP) and on activation of the GPCR by an agonist, [ 35 S]GTP ⁇ S, becomes incorporated and cannot be cleaved to continue the exchange cycle (Harper (1998) Current Protocols in Pharmacology 2.6.1-10, John Wiley & Sons, Inc.).
  • the amount of radioactive [ 35 S]GTP ⁇ S incorporation is a direct measure of the activity of the G-protein and hence the activity of the agonist can be determined.
  • mGlu2 receptors are shown to be preferentially coupled to G ⁇ i-protein, a preferential coupling for this method, and hence it is widely used to study receptor activation of mGlu2 receptors both in recombinant cell lines and in tissues.
  • [ 35 S]GTP ⁇ S binding assay using membranes from cells transfected with the human mGlu2 receptor and adapted from Schaffhauser et al. (Molecular Pharmacology, 2003, 4:798-810) for the detection of the positive allosteric modulation (PAM) properties of the compounds of this invention.
  • CHO-cells were cultured to pre-confluence and stimulated with 5 mM butyrate for 24 h. Cells were then collected by scraping in PBS and cell suspension was centrifuged (10 min at 4000 RPM in benchtop centrifuge). Supernatant was discarded and pellet gently resuspended in 50 mM Tris-HCl, pH 7.4 by mixing with a vortex and pipetting up and down. The suspension was centrifuged at 16,000 RPM (Sorvall RC-5C plus rotor SS-34) for 10 minutes and the supernatant discarded.
  • the pellet was homogenized in 5 mM Tris-HCl, pH 7.4 using an ultra-turrax homogenizer and centrifuged again (18,000 RPM, 20 min, 4° C.). The final pellet was resuspended in 50 mM Tris-HCl, pH 7.4 and stored at ⁇ 80° C. in appropriate aliquots before use. Protein concentration was determined by the Bradford method (Bio-Rad, USA) with bovine serum albumin as standard.
  • Measurement of mGluR2 positive allosteric modulatory activity of test compounds was performed as follows. Test compounds and glutamate were diluted in assay buffer containing 10 mM HEPES acid, 10 mM HEPES salt, pH 7.4, 100 mM NaCl, 3 mM MgCl 2 and 10 ⁇ M GDP. Human mGlu2 receptor-containing membranes were thawed on ice and diluted in assay buffer supplemented with 14 ⁇ g/ml saponin. Membranes were pre-incubated with compound alone or together with a predefined ( ⁇ EC 20 ) concentration of glutamate (PAM assay) for 30 min at 30° C. After addition of [ 35 S]GTP ⁇ S (f.c.
  • concentration-response curves of representative compounds of the present invention obtained in the presence of EC 20 of mGluR2 agonist glutamate to determine positive allosteric modulation (PAM)—were generated using the Lexis software interface (developed at J&J). Data were calculated as % of the control glutamate response, defined as the maximal response that is generated upon addition of glutamate alone. Sigmoid concentration-response curves plotting these percentages versus the log concentration of the test compound were analyzed using non-linear regression analysis. The concentration producing half-maximal effect is then calculated as EC 50 . The pEC 50 values below were calculated as the ⁇ log EC 50 , when the EC 50 is expressed in M. E max is defined as relative maximal effect (i.e. maximal % effect relative to the control glutamate response).
  • Table E shows the pharmacological data obtained for compounds of Formula (I-B) and current pharmacological data obtained for compounds of Formulae (I) and (I-A).
  • n.c. means that the pEC 50 could not be calculated n.t. means not tested pEC 50 values were not calculated in cases where the concentration-response curve did not reach a plateau level.
  • Test compounds were administered using an optimal fluid volume to body fluid ratio. Test compounds were administered to mice in a volume of 0.01 mL/g of body weight (White H. S., et al., General Principles: Experimental selection, quantification, and evaluation of antiepileptic drugs, in Antiepileptic Drugs, Fourth Edition, R. H. Levy, R. H. Mattson, and B. S. Meldrum, Editors. 1995, Raven Press, Ltd.: New York, pp. 99-110). For subcutaneous (s.c.) administration, the test compounds were administered into a loose fold of skin along the back of the animal except compound 6-b, which was administered orally (p.o).
  • Tetracaine (0.5% solution w/v) was added dropwise from a plastic dropper bottle onto the eyes of all animals that would subsequently receive electrical stimulation via corneal electrodes.
  • mice 26-35 g were obtained from Charles River, Portage, Mich. The animals were maintained on an adequate diet (Prolab RMH 3000) and allowed free access to food and water, except during the short time they were removed from their cage for testing Animals newly received in the laboratory were allowed sufficient time to correct for possible food and water restriction incurred during transit before being employed in testing. All mice were housed in plastic cages in specially constructed rooms with controlled humidity, exchange of air and controlled lighting (12 hours on-12 hours off). The animals were housed, fed, and handled in a manner consistent with the recommendations in the National Council Publication, “Guide for the Care and Use of Laboratory Animals”
  • MMI Minimal Motor Impairment
  • Acute MMI was assessed by a combination of direct observations of the animal for overt symptoms of the animal's neurological or muscular function.
  • the rotarod procedure was used to disclose minimal muscular or neurological impairment.
  • the animal can maintain its equilibrium for long periods of time. The animal was considered toxic if it fell off this rotating rod three times during a 1 min period.
  • the first dose administered is usually the same dose as that used in a successful TPE determination.
  • the next dose would be one-half that of the initial dose; if the initial dose was effective or toxic in less than 50% of animals, the following dose would be twice that of the initial dose.
  • Third and fourth doses were selected to produce an evenly spaced dose response line. There should be a minimum of 4 points either including or lying between 0 and 100%.
  • TPE Time of Peak Effect
  • trunk blood and/or brain tissue (whole brains) was collected for quantification of drug levels
  • animals were decapitated and trunk blood was collected into a BD Vacutainer® tube containing K2EDTA and chilled on ice until centrifugation. Following centrifugation (13000-18000 rpm, 5-7 min), the plasma was removed and transferred to a labeled microcentrifuge tube and stored at ⁇ 80° C.
  • brain tissue collection brains were removed immediately following decapitation and flash frozen. The frozen sample was placed in a labeled centrifuge tube and stored at ⁇ 80° C.
  • the 6 Hz seizure test is used as a model of pharmacoresistant limbic seizures.
  • the 6 Hz seizure displays a resistance to phenytoin, carbamazepine, lamotrigine, and topiramate (Barton et al. “Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy” Epilepsy Research 2001, Vol. 47, pp. 217-222).
  • Focal seizures were induced in mice via corneal stimulation (6 Hz, 0.2 msec rectangular pulse, 3 sec duration; Barton et al. 2001). Mice were tested at either 32 mA or 44 mA. Prior to stimulation, drops of 0.5% tetracaine were applied to each eye.
  • the seizures that arise from corneal stimulation in this assay are characterized by a minimal clonic phase followed by stereotyped automatistic behaviors including stun, forelimb clonus, twitching of the vibrissae, and Straub-tail. Animals not displaying these behaviors were considered protected.
  • each compound was tested individually at a dose that displayed minimal activity in the 6 Hz 44 mA test at each compound's TPE.
  • the mGluR2 PAM compounds and levetiracetam were administered in combination (same dose and time-point as individual tests) nearly complete protection was observed in the 6 Hz 44 mA test (Table 2).
  • both plasma and brain samples were collected from each of the groups for pharmacokinetic/pharmacokinetic analysis. No pharmacokinetic interaction was observed based on compound levels in the plasma and brain samples (data not shown).
  • mice were kindled electrically with 3 second, 3 mA, 60 Hz stimulus, twice daily using corneal electrodes until a criterion of 5 consecutive Stage 5 seizures as defined by Racine (Racine “Modification of seizure activity by electrical stimulation” II. motor seizure” Electroenceph Clin Neurophysiol 1972, 32, pp. 281-294).
  • Racine Rost al.
  • the test compound or vehicle was administered and, at the previously determined TPE, each animal was given the electrical stimulus indicated above. Following stimulation, the animals were observed for the presence or absence of the seizure activity scored on the Racine scale (0-5) with 5 representing the highest stage rearing and falling.
  • One dose of LEV and two doses of Co. No. 1 were tested individually and in combination against corneal kindled seizures. Combination of compound 1 with levetiracetam in this model suggests a positive pharmacodynamics interaction (Table 5 below).
  • TPE 32 mA 44 mA kindling 11 0.5 4.77 (3.54- 31.5 (15.1-47.3) 2.8 6.76) (100 mg/kg) 9.41 (1.53-15.1) 2 0.25 3.83 (1.62- 5.89 (3.89-8.45) 3.4 6.71) (40 mg/kg) 1 0.5 2.8 (1.3-4.3) 10.2 (3.1-12.4) 3.7 (20 mg/kg) 25-a 1 7.7 (2.3-18.4) 1 hr TPE: 25.9 n.t.
  • TPE (15.5-33.7) 0.25 hr
  • 2-a 0.5 44.7 (23.4-80.5) 50% protection at 4.4 10.0-31.7) 100 mg/kg (100 mg/kg) 12.2 (8.4-17.4) 21 (17.9-27.4)
  • 6-b 0.5 7.2 (4.2-11.8) 16.1 (13.0-20.1)
  • n.t. LY-404039 0.5 10.2 (3.62-12.4) n.t. 3.1 (100 mg/kg)
  • TPE means time of peak effect
  • CI means confidence interval
  • s.c. means subcutaneous
  • p.o. means orally
  • n.t. means not tested.
  • TPE was determined in 32 mA 6 Hz test. Effects are generally observed at doses that do not produce impairment in rotarod test.
  • For compounds 11 and 2-a the individual values of repeat experiments are provided.
  • For compound 25a both 0.25 and 1 h time points were used for 6 Hz (44 mA)
  • Plasma and brain levels Co. No. 1. in combination study with Levetiracetam (LEV).
  • No. 1 (ng/ml) Protection 6 Hz 44 mA 10 mg/kg 9350 2.5 mg/kg BQL Yes 8580 244 No 10900 314 Yes 10300 382 Yes 9780 416 Yes 9780 377 Yes 13700 2260* No 10100 607 Yes Mean Plasma 10311 657.1 6/8 Level (390) Mean Plasma 1/8 8254 0/8 438 Levels (non- combination) Mean plasma level shown in parenthesis ( ) is calculated with a statistical outlier* removed BQL means below quantifiable limit.
  • FIG. 1 shows the dose-response for the 6 Hz 44 mA ED 50 determinations for the Co. No. 2 and LEV alone and in combination.
  • ED50 (95% CI) Maximum Effect Treatment mg/kg (% Protection) Co. No. 2 alone 6.97 100% (5.44-8.30) Co. No. 2 + 1.35 100% LEV (10 mg/kg) (0.8-1.9) LEV alone ⁇ 200 75% LEV + 1.0 100% Co. No. 2 (3 mg/kg) (0.23-2.24)
  • the isobolographic analysis ( FIG. 2 ) demonstrates that the combination of Co. No. 1 and levetiracetam results in a significantly positive synergistic effect.
  • 25-a produced an ED 50 in the levetiracetam dose-response of 4.9 mg/kg ( ⁇ 70-fold lower compared with levetiracetam alone) and importantly yielded full protection in the 6 Hz 44 mA seizure model.
  • No. 25-a was determined to be 0.25 h (see Table 1).
  • b The time-to-peak effect in the 6 Hz 44 mA assay for Co.
  • No. 25-a was similar for 0.25 h and 1 h; results for 1 h confirmed the ED 50 (95% CI) 25.9 (15.5-33.7) (see Table 1 and 6).
  • Mean plasma level shown in parenthesis ( ) is calculated with a statistical outlier removed. CI means confidence interval
  • 6-b produced an ED 50 in the levetiracetam dose-response of 2.4 mg/kg ( ⁇ 100-fold lower compared with levetiracetam alone) and importantly yielded full protection in the 6 Hz 44 mA seizure model. These results are suggestive of a positive pharmacodynamic interaction in the 6 Hz seizure model between Co. No. 6-b and levetiracetam.
  • LY-404039 was tested alone and in combination with levetiracetam according to the procedures already described hereinabove. The results of the studies performed with LY-404039 are listed in tables 14-15.
  • LY404039 (s.c.) 5 mg/kg tested in combination with LEV (i.p.); LY404039 5 mg/kg was not active when administered alone. Additional LEV (low-dose) control groups were tested at 25 and 6.25 mg/kg (1/8 and 0/6 protected, respectively).
  • Vehicle-treated mice (10% sterile water-NaCl; s.c., 0.5 h TPE and 0.5% MC, i.p., 1 h TPE) showed no protection or rotarod impairment.
  • the current data set indicates that mGlu2 PAM or agonist molecules have anticonvulsant activity in the 6 Hz animal model.
  • mGluR2 PAM metabotropic glutamatergic receptor subtype 2
  • mGluR2 PAM compounds having an EC 50 potency of 1.50 nM as determined in the [ 35 S]GTP ⁇ S assay
  • EC 50 is the concentration producing half-maximal effect in a concentration-response curve obtained in the presence of EC 20 of glutamate
  • appropriate PK parameters and brain penetration result in a synergistic combination with an SV2A ligand, in particular levetiracetam, at non-effective doses of one or both of compound (a) and compound (b) of the combination of the invention.
  • the positive allosteric modulator of metabotropic glutamatergic receptor subtype 2 (mGluR2 PAM) compound of the combination of the invention as defined herein is selected from an mGluR2 PAM compound having an EC 50 potency of ⁇ 150 nM (as determined in the [ 35 S]GTP ⁇ S assay), wherein EC 50 is the concentration producing half-maximal effect in a concentration-response curve obtained in the presence of EC 20 of glutamate.
  • the DSR assay is divided into two models: Reduction of Dominant Behavior Model (RDBM) of mania and Reduction of Submissive Behavior Model (RSBM) of depression.
  • RDBM Dominant Behavior Model
  • RSBM Submissive Behavior Model
  • the RDBM wherein the dominant animals are treated with test compound, is predictive of the ability of the test compound to treat mania.
  • the RSBM wherein the submissive animals are treated with test compound, is predictive of the ability of the test compound to treat depression.
  • Male Sprague Dawley rats (140 to 160 g) from Charles River Laboratories Wilmington, Mass. are used in this assay. Shipments of rats are received at two-week intervals. Each shipment will go through five-day quarantine, one-week acclimation period and one-week selection process, followed by five-weeks of drug or vehicle treatment to those pairs selected.
  • Rats will be housed four per cage. Access to food will be restricted to one hour per day after testing on Monday through Thursday. After testing on Friday, rats will have free access to food until being fasted again on Sunday. At no time will the rats be deprived of water. The food deprivation periods used will have little effect on weight gain as the average weight of rats will be about 300 g by the end of the study. At the conclusion of experiment rats will be sacrificed by decapitation, the trunk blood and brains will be collected for in vitro experiments and drug concentration measurements.
  • the basic testing apparatus consisted of two chambers connected with a tunnel only large enough to allow one rat to pass through at a time. On the floor, at the mid-point of the tunnel will be a container of sweetened milk. This basic apparatus will be replicated, so that a total of four pairs of rats can be video tracked simultaneously. The camera can distinguish rats marked by different colors. Thus, the rats' heads will be colored for the purpose of video tracking, red in one cage and yellow in the other cage. Only one animal at a time can have comfortable access to the feeder, but both animals can drink milk during the five-minute daily session. During the five-minute daily sessions, time spent in the feeder zone by each rat will be recorded by the video tracking software and saved into a text file.
  • the test will begin with a random assignment of rats into pairs. Each member of a pair will be placed in an opposite chamber of the testing apparatus. The time spent in the feeder zone by each animal will be recorded. During the first week (five days) of testing the animals habituate to the new environment. Dominance will be assigned to the animal with the highest score during the second week of testing if three criteria are achieved. First, there must be a significant difference (two-tailed t-test, P ⁇ 0.05) between the average daily drinking scores of both animals. Second, the dominant animal score must be at least 25% greater than the submissive animal's score. Finally, there must be no “reversals” during the pair selection week where the putative submissive rat out-scored its dominant partner on isolated occasions. Ideally there will be minimal reversals during the acclimation week as well. Only animal pairs that achieve these criteria will be continued in the study.
  • Dominance ⁇ ⁇ Level ⁇ ⁇ ( week ⁇ ⁇ n ⁇ ⁇ in ⁇ ⁇ % ) ( Dominance ⁇ ⁇ Level ⁇ ⁇ ( week ⁇ ⁇ n ) ) / ( Dominance ⁇ ⁇ Level ⁇ ⁇ ( week ⁇ ⁇ 2 )
  • the statistical significance of the difference in dominance level between the control group (pairs of rats where both dominant and submissive animals will be treated with vehicle) and the treatment group (submissive rats will be treated with drug and dominant rats with vehicle) will be determined by ANOVA, followed by a t-test.
  • the activity onset time value at 50% of response (AOT-50) and the minimum and maximum response to drug will be calculated based on the reduction of the dominance level value using non-linear regression analysis (GraphPad Software, Inc., San Diego, Calif.).
  • the normalized DL values will be used for this calculation, where DL values for treatment weeks will be normalized as a percent of the second week (pretreatment) value of that pair according the above formula.
  • the minimum of the response determines drug positive activity, corresponding to efficacy, since DL values will be reduced if the response to a drug is positive.
  • DL values will be increased. If the drug does not have such activity the maximum of the response will not exceed 100%. Any maximal DL value significantly higher than control value (about 100%) indicates drug negative activity.
  • Levetiracetam and mGluR2 PAM/agonist compound (e.g. compounds 2, 2-a, 25-a, 6-b or LY-404039) will be evaluated in the rat RDBM according to the procedure described in more detail below.
  • Groups of dominant rats will be treated p.o. QD with levetiracetam 10 mg/kg and mGluR2 PAM/agonist compound at various concentrations from approximately 0.05 mg/kg (n ⁇ 3), at 0.5 mg/kg (n ⁇ 3), at 2.5 mg/kg (n ⁇ 3), at 5.0 mg/kg (n ⁇ 3) and at 50.0 mg/kg (n ⁇ 3).
  • a vehicle control group of dominant rats will be treated with 0.5% methylcellulose (n ⁇ 3) and a second control group of dominant rats will be treated i.p. QD with sodium valproate at 30 mg/kg (n ⁇ 6 from 2 studies of n ⁇ 3 each).
  • AOT activity onset time
  • the activity onset time will be estimated from the non-linear regression fit.
  • the non-linear regression model will fit for each drug, combination and dose normalized daily DL values.
  • the combination of levetiracetam and mGlu2 PAM/agonist compounds is expected to reduce dominant behavior indicating that the combination is active as an anti-manic.
  • 100 mg of a mGluR2 PAM/agonist compound is formulated with sufficiently finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gel capsule.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Cell Biology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The present invention relates to combinations comprising a positive allosteric modulator (“PAM”) of metabotropic glutamatergic receptor subtype 2 (“mGluR2”) or a pharmaceutically acceptable salt or a solvate thereof, or an orthosteric agonist of metabotropic glutamatergic receptor subtype 2 compound or a pharmaceutically acceptable salt or a solvate thereof, and a synaptic vesicle protein 2A (“SV2A”) ligand.

Description

    FIELD OF THE INVENTION
  • The present invention relates to combinations comprising a positive allosteric modulator (“PAM”) of metabotropic glutamatergic receptor subtype 2 (“mGluR2”) or a pharmaceutically acceptable salt or a solvate thereof, or an orthosteric agonist of metabotropic glutamatergic receptor subtype 2 compound or a pharmaceutically acceptable salt or a solvate thereof, and a synaptic vesicle protein 2A (“SV2A”) ligand.
    • BACKGROUND OF THE INVENTION
  • Epilepsy describes a condition in which a person has recurrent seizures due to a chronic, underlying process. Epilepsy refers to a clinical phenomenon rather than a single disease entity, since there are many forms and causes of epilepsy. Using a definition of epilepsy as two or more unprovoked seizures, the incidence of epilepsy is estimated at approximately 0.3 to 0.5 percent in different populations throughout the world, with the prevalence of epilepsy estimated at 5 to 10 people per 1000.
  • An essential step in the evaluation and management of a patient with a seizure is to determine the type of seizure that has occurred. The main characteristic that distinguishes the different categories of seizures is whether the seizure activity is partial (synonymous with focal) or generalized.
  • Partial seizures are those in which the seizure activity is restricted to discrete areas of the cerebral cortex. If consciousness is fully preserved during the seizure, the clinical manifestations are considered relatively simple and the seizure is termed a simple-partial seizure. If consciousness is impaired, the seizure is termed a complex-partial seizure. An important additional subgroup comprises those seizures that begin as partial seizures and then spread diffusely throughout the cortex, which are known as partial seizures with secondary generalization.
  • Generalized seizures involve diffuse regions of the brain simultaneously in a bilaterally symmetric fashion. Absence or petit mal seizures are characterized by sudden, brief lapses of consciousness without loss of postural control. Atypical absence seizures typically include a longer duration in the lapse of consciousness, less abrupt onset and cessation, and more obvious motor signs that may include focal or lateralizing features. Generalized tonic-clonic or grand mal seizures, the main type of generalized seizures, are characterized by abrupt onset, without warning. The initial phase of the seizure is usually tonic contraction of muscles, impaired respiration, a marked enhancement of sympathetic tone leading to increased heart rate, blood pressure, and pupillary size. After 10-20 s, the tonic phase of the seizure typically evolves into the clonic phase, produced by the superimposition of periods of muscle relaxation on the tonic muscle contraction. The periods of relaxation progressively increase until the end of the ictal phase, which usually lasts no more than 1 min. The postictal phase is characterized by unresponsiveness, muscular flaccidity, and excessive salivation that can cause stridorous breathing and partial airway obstruction. Atonic seizures are characterized by sudden loss of postural muscle tone lasting 1-2 s. Consciousness is briefly impaired, but there is usually no postictal confusion. Myoclonic seizures are characterized by a sudden and brief muscle contraction that may involve one part of the body or the entire body.
  • The synaptic vesicle protein 2A (“SV2A”) has been identified as a broad spectrum anticonvulsant target in models of partial and generalized epilepsy. Studies performed in animal models and human tissue suggest that changes in the expression of SV2A are implicated in epilepsy (for a review see for instance: (a) Mendoza-Torreblanca et al. “Synaptic vesicle protein 2A: basic facts and role in synaptic function” European Journal of Neuroscience 2013, pp. 1-11; (b) Kaminski R M, et al. “Targeting SV2A for Discovery of Antiepileptic Drugs”. In: Noebels J L, Avoli M, Rogawski M A, et al., editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (Md.): National Center for Biotechnology Information (US); 2012. Available from: http://www.ncbi.nlm.nih.gov/books/NBK98183/).
  • The exact role of SV2A remains unclear but studies suggest that changes in the expression of SV2A affect synaptic function (Nowack et al. “Levetiracetam reverses synaptic deficits produced by overexpression of SV2A” PLoS One 2011, Volume 6 (12), e29560). It has also been suggested that SV2A is a key player in exocytosis and is involved in neurotransmission (Crowder et al. “Abnormal neurotransmission in mice lacking synaptic vesicle protein 2A (SV2A)” Proc Nat Acad Sci USA 1999, 96, pp. 15268-15273) and studies in knock-out mice suggest that lack of SV2A results in an imbalance between glutamatergic and GABAergic neurotransmission (Venkatesan et al. “Altered balance between excitatory and inhibitory inputs onto CA pyramidal neurons from SV2A-deficient but not SV2B-deficient mice” J Neurosci Res 2012, 90, pp. 2317-2327). Decreased expression of SV2A may be a consequence of seizure activity and may be involved in the progression of epilepsy (van Vliet et al. “Decreased expression of synaptic vesicle protein 2A, the binding site for levetiracetam, during epileptogenesis and chronic epilepsy” Epilepsia 2009, 50, pp. 422-433; Feng et al. “Down-regulation of synaptic vesicle protein 2A in the anterior temporal neocortex of patients with intractable epilepsy” J Mol Neurosci 2009, 39, pp. 354-359; Toering et al. “Expression patterns of synaptic vesicle protein 2A in focal cortical dysplasia and TSC-cortical tubers” Epilepsia 2009, 50, pp. 1409-1418) and epileptogenesis in patients with brain tumours (de Groot et al. “Expression of synaptic vesicle protein 2A in epilepsy-associated brain tumors and in the peritumoral cortex” Neuro-Oncology 2010, 12, pp. 265-273).
  • SV2A ligands include levetiracetam (Lynch et al. “The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam” Proc. Natl. Acad. Sci. USA 2004, Vol. 101, pp. 9861-9866), brivaracetam and seletracetam (Kaminski R M, et al. “Targeting SV2A for Discovery of Antiepileptic Drugs”. In: Noebels J L, Avoli M, Rogawski M A, et al., editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (Md.): National Center for Biotechnology Information (US); 2012. Available from: http://www.ncbi.nlm.nih.gov/books/NBK98183/; Nowack et al. “Levetiracetam reverses synaptic deficits produced by overexpression of SV2A” PLoSone December 2011, Vol. 6(12), e29560).
  • Levetiracetam, (−)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide or (S)-2-(2-oxopyrrolidin-1-yl)butanamide,
  • Figure US20220143141A1-20220512-C00001
  • is an antiepileptic drug. It showed no activity in traditional acute models (maximal electroshock and pentylenetetrazol seizure tests) but was found potent in chronic epilepsy models and in genetic models of generalized epilepsy. It has shown a high safety margin compared to other antiepileptic drugs (Klitgaard “Levetiracetam: the preclinical profile of a new class of antiepileptic drugs” Epilepsia 2001, 42 (Supplement 4), pp. 13-18). It is commercialized under the trademark Keppra®, available as tablets, as an oral solution, and as a concentrate made up into a solution for infusion. Keppra® has been approved in Europe as a monotherapy in patients from 16 years of age with newly diagnosed epilepsy, in the treatment of partial-onset seizures (fits) with or without secondary generalization and as an add-on therapy for use with other anti-epileptic drugs in the treatment of partial-onset seizures with or without generalization in patients from 1 month of age; myoclonic seizures in patients from 12 years of age with juvenile myoclonic epilepsy; and primary generalized tonic-clonic seizures in patients from 12 years of age with idiopathic generalized epilepsy (www.ema.europa.eu). Keppra® has also been approved in the USA as an add-on therapy for the treatment of partial onset seizures in patients from 1 month of age; myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy; and primary generalized tonic-clonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy. Keppra XR®, available as extended-release tablets, has been approved in the USA for the add-on treatment of partial onset seizures in patients 16 years of age and older with epilepsy (http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm).
  • Brivaracetam, the 4-n-propyl analog of levetiracetam, (2S)-2-[(4R)-oxo-4-propyl-pyrrolidin-1-yl]butanamide,
  • Figure US20220143141A1-20220512-C00002
  • is in clinical trials and investigated as monotherapy in partial onset seizures and post-herpetic neuralgia and as add-on therapy in refractory partial onset seizures, Unverricht-Lundborg disease in adolescents and adults and in photosensitive epilepsy (www.clinicaltrials.gov).
  • Seletracetam, (2S)-2-[(4S)-4-(2,2-difluorovinyl)-2-oxo-pyrrolidin-1-yl]butanamide,
  • Figure US20220143141A1-20220512-C00003
  • has been tested in clinical trials.
  • Processes for the preparation of the three compounds are known in the literature. For instance, processes for making Levetiracetam are disclosed for instance, in EP 0 162 036 and in GB 2 225 322. A process for the preparation of Brivaracetam is disclosed for instance in WO 01/62726. A process for the preparation of Seletracetam is known for instance from WO2005/121082. Alternative processes for making the three compounds are disclosed in EP1806339.
  • Antiepileptic drugs have found usefulness in neurological and psychiatric disorders, including neuropathic pain, migraine, essential tremor and in anxiety, schizophrenia and bipolar disorder (Landmarck “Antiepileptic drugs in non-epilepsy disorders. Relations between mechanisms of action and clinical efficacy” CNS Drugs 2008, Vol. 22(1), pp. 27-47; Calabresi et al. “Antiepileptic drugs in migraine: from clinical aspects to cellular mechanisms” Trends in Pharmacological Sciences 2007, Vol. 28(4), pp. 188-195; Rogawski and Loscher “The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions” Nat Med 2004, Vol. 10, pp. 685-692).
  • Levetiracetam has been found effective or potentially effective in a wide-spectrum of neuropsychiatric disorders including mood disorders (Muralidharan and Bhagwagar “Potential of levetiracetam in mood disorders: a preliminary review” CNS Drugs 2006, Vol. 20, pp. 969-979; Mula et al. “The role of anticonvulsant drugs in anxiety disorders: a critical review of the evidence” J Clin Pshycopharmacol 2007, Vol. 27, pp. 263-272), anxiety disorders (Kinrys et al. “Levetiracetam as adjunctive therapy for refractory anxiety disorders” J Clin Psychiatry 2007, Vol. 68, pp. 1010-1013; Zhang et al. “Levetiracetam in social phobia: a placebo controlled pilot study” J Psychopharmacol 2005, Vol. 19, pp. 551-553; Kinrys et al. “Levetiracetam for treatment-refractory posttraumatic stress disorder” J Clin Psychiatry 2006, Vol. 67, pp. 211-214), pain (Enggaard et al. “Specific effect of levetiracetam in experimental human pain models” Eur J Pain 2006, Vol. 10, pp. 193-198; Dunteman “Levetiracetam as an adjunctive analgesic in neoplastic plexopathies: case series and commentary” J Pain Palliative Care Pharmacother 2005, Vol. 19, pp. 35-43; Price “Levetiracetam in the treatment of neuropathic pain: three case studies” Clin J Pain 2004, Vol. 20, pp. 33-36), movement disorders (Bushara et al. “The effect of levetiracetam on essential tremor” Neurology 2005, Vol. 64, pp. 1078-1080; McGavin et al “Levetiracetam as a treatment for tardive dyskinesia: a case report” Neurology 2003, Vol. 61, pp. 419; Woods et al. “Effects of levetiracetam on tardive dyskinesia: a randomized, double-blind, placebo-controlled study” J Clin Psychiatry 2008, Vol. 69, pp. 546-554; Zivkovic et al. “Treatment of tardive dyskinesia with levetiracetam in a transplant patient” Acta Neurol Scand 2008, Vol. 117, pp. 351-353; Striano et al. “Dramatic response to levetiracetam in post-ischaemic Holmes' tremor” J Neurol Neurosurg Psychiatry 2007, Vol. 78, pp. 438-439) and it is suspected to show potentially beneficial effects in cognitive functioning (Piazzini et al. “Levetiracetam: An improvement of attention and of oral fluency in patients with partial epilepsy” Epilepsy Research 2006, Vol. 68, pp. 181-188; de Groot et al. “Levetiracetam improves verbal memory in high-grade glioma patients” Neuro-oncology 2013, Vol. 15(2), pp. 216-223; Bakker et al. “Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment” Neuron 2012, Vol. 74, pp. 467-474; for a review: Eddy et al. “The cognitive impact of antiepileptic drugs” Ther Adv Neurol Disord 2011, Vol. 4(6), pp. 385-407 and references cited therein; Wheless “Levetiracetam in the treatment of childhood epilepsy” Neuropsychiatric Disease and Treatment 2007, Vol. 3(4), pp. 409-421), and behavioral symptoms in dementia (Dolder and Nealy “The efficacy and safety of newer anticonvulsants in patients with dementia” Drugs Aging 2012, Vol. 29(8), pp. 627-637). Animal data and some preliminary clinical trials suggest that levetiracetam may have potential for restraining post-traumatic epilepsy, such as those caused by status epilepticus, traumatic brain injury and ischemic stroke, and it appears to have neuroprotective effects. The potential of levetiracetam in easing epileptogenesis or cognitive dysfunction remains to be ascertained by conclusive animal and clinical studies (for reviews: Loscher and Brandt “Prevention or modification of epileptogenesis after brain insults: experimental approaches and translational research” Pharmacol Rev 2010, Vol. 62, 668-700; Shetty “Prospects of levetiracetam as a neuroprotective drug against status epilepticus, traumatic brain injury and stroke” Front. Neur. 2013, 4:172. Doi: 10.3389/fneur.2013.00172) as it has displayed antiepileptogenic activity in the kindling model in mice and rats. It has also been suggested that levetiracetam inhibits glutamate release (Lee et al. “Levetiracetam inhibits glutamate transmission through presynaptic P/Q-type calcium channels on the granule cells of the dentate gyrus” British Journal of Pharmacology 2009, Vol. 158, pp. 1753-1762).
  • Seletracetam and Brivaracetam, have been found to reduce the severity of dystonia in the dtsz mutant hamster model and may be helpful in some patients suffering from dyskinetic and dystonic movement disorders (Hamann et al. “Brivaracetam and seletracetam, two new SV2A ligands, improve paroxysmal dystonia in the dtsz mutant hamster” European Journal of Pharmacology 2008, Vol. 601, pp. 99-102).
  • Positive allosteric modulators of mGluR2 have emerged recently as promising novel therapeutic approaches for the treatment of several CNS disorders, including epilepsy, and some mGluR2 PAMs are currently undergoing clinical trials for the treatment of schizophrenia, and anxiety-depression (www.clinicaltrials.gov, see for instance: JNJ-40411813/ADX71149 by Addex Therapeutics and Janssen Pharmaceuticals, Inc.). The initial suggestion that drugs that dampen glutamatergic transmission may be efficacious in the treatment of epilepsy came from acute non-clinical studies with mixed mGlu2/3 receptor agonists (Moldrich et al. “Glutamate metabotropic receptors as targets for drug therapy in epilepsy” Eur J Pharmacol. 2003, Vol. 476, pp. 3-16). LY379268 and LY389795, two mGlu2/3 receptor agonists, were found ineffective in blocking MES seizures up to doses producing motor impairment but were found effective in the 6 Hz model in a dose-dependent manner (Barton et al. “Comparison of the effect of glutamate receptor modulators in the 6 Hz and maximal electroshock seizure models” Epilepsy Research 2003, Vol. 56, pp. 17-26). Continued administration of an mGlu2/3 agonist paradoxically induced seizure activity in long-term toxicology studies (Dunayevich et al. “Efficacy and tolerability of an mGlu2/3 agonist in the treatment of generalized anxiety disorder” Neuropsychopharmacology. 2008, Vol. 33(7), pp. 1603-10). This paradoxical effect may be related to agonist-induced changes in the sensitivity of the receptor system (tachyphylaxis), but has not been reported however in preclinical models of epilepsy. Positive allosteric modulators, in contrast, modulate ongoing neurotransmission but are not directly stimulatory, thereby reducing the risk for tachyphylaxis.
  • Prior to seizure activity, increases in extracellular glutamate are measured in human hippocampus and the increase is sustained during epileptogenic activity (During and Spencer “Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain” Lancet 1993, Vol. 341(8861), pp. 1607-10), thus lending support to the idea that a reduction in glutamate levels may be of benefit in the treatment of epilepsy. In fact, during seizure activity glutamate levels increase to potentially neurotoxic levels. Seizure activity results in progressive structural damage in human brain inducing further abnormalities in glutamate metabolism (Petroff et al. “Glutamate-glutamine cycling in the epileptic human hippocampus” Epilepsia 2002, Vol. 43(7), pp. 703-10). Thus, an mGluR2 positive allosteric modulator or an mGluR2 orthosteric agonist may be expected to protect against seizure-induced neuronal damage.
  • WO2009/033704 and WO2010/130424 disclose mGluR2 positive allosteric modulators, uses thereof and processes for synthesizing the compounds. WO1997/18199 and WO2003/104217 disclose excitatory amino acid receptor modulator compounds that later were shown to have mGlu2/3 orthosteric agonist activity (see for example Rorick-Kehn et al. (2007) The Journal of Pharmacology and Experimental therapeutics Vol. 321, No. 1, pp. 308-317), further scientific and patent literature disclose additional examples of compounds having mGlu2/3 orthosteric agonist activity, and WO2008/150233 discloses compounds with mGluR2 allosteric activator activity.
  • Currently available anti-epileptic drugs do not solely affect glutamatergic transmission. Their mechanism of action is generally conceptualized as altering the balance between excitatory (glutamate-mediated) and inhibitory (GABA-mediated) transmission (Johannessen Landmark “Antiepileptic drugs in non-epilepsy disorders: relations between mechanisms of action and clinical efficacy” CNS Drugs 2008, Vol. 22(1), pp. 27-47).
  • A significant limiting factor in the use of SV2A ligands is tolerability and side-effect profile. For example the effective dose of levetiracetam for partial onset seizures is dosed at 1000 mg, 2000 mg, and 3000 mg, given as twice-daily. The side effects reported for levetiracetam include aggressive or angry behavior, anxiety, change in personality, chills, cough or hoarseness, crying, depersonalization, diarrhea, dry mouth, euphoria, fever, general feeling of discomfort or illness, headache, hyperventilation, irregular heartbeats, irritability, joint pain, loss of appetite, lower back or side pain, mental depression, muscle aches and pains, nausea, painful or difficult urination, paranoia, quick to react or overreact emotionally, rapidly changing moods, restlessness, shaking, shivering, shortness of breath, sleepiness or unusual drowsiness, sore throat, stuffy or runny nose, sweating, trouble sleeping, unusual tiredness or weakness and vomiting. Thus, there is still a need to provide an effective treatment with a lower effective dose of levetiracetam and a more favourable side effect profile for the treatment of epilepsy and related disorders, not only in the adult but also in the pediatric population.
    • BRIEF DESCRIPTION OF THE FIGURES
  • FIG. 1: Dose response for the 6 Hz 44 mA ED50 determination for the Co. No. 2 and LEV alone and in combination.
  • FIG. 2: Isobolographic analysis for the combination of Co. No. 1 with levetiracetam (LEV) in the 6 Hz (44 mA) assay. Initial ED50 values (shown below) were determined for both Co. No. 1 and LEV (data points on x- and y-axes; filled diamonds). The theoretical line of additivity connects the calculated ED50 values for the two compounds (solid black line). Theoretical ED50 (+SEM) for three fixed dose ratio combinations (LEV:Co. No. 1) are plotted: 1:3—filled squares/solid black line, 1:1—filled upward triangles/solid black line, and 3:1—filled downward triangles/solid black line. Experimental treatment doses were initially derived from theoretical values and adjusted according to observed effects. Experimentally-determined ED50 (+SEM) values for each fixed dose-ratio combination are also shown: 1:3′—open squares/dotted line, 1:1′—open upward triangles/dotted line, and 3:1′—open downward triangles/dotted line. Comparisons between theoretical and experimentally-determined ED50 values were compared using a t-test (***P<0.001). N=8 per group. In FIG. 2, the ratio of LEV to Co. No. 1 is depicted as follows:
  • LEV:Co. No. 1 ratio
     
    Figure US20220143141A1-20220512-P00001
          		1:3 ED50 (LEV) = 345 mg/kg (211-485)
     
    Figure US20220143141A1-20220512-P00002
          		1:1 (intraperitoneally, i.p.)
     
    Figure US20220143141A1-20220512-P00003
          		3:1 ED50 (Co. No. 1) = 10.2 mg/kg (3.1-12.4) (s.c.)
     
    Figure US20220143141A1-20220512-P00004
          		1:3′
     
    Figure US20220143141A1-20220512-P00005
          		1:1′
     
    Figure US20220143141A1-20220512-P00006
          		3:1′
  • FIG. 3: Combination Studies for Co. No. 25-a with levetiracetam (LEV) in the 6 Hz Assay (44 mA). At a dose of 10 mg/kg s.c., Co. No. 25-a increases the potency of LEV, leading to an approximate 70-fold shift in the ED50. This suggests a positive pharmacodynamic relationship.
  • FIG. 4: Combination Studies for Co. No. 2-a with levetiracetam (LEV) in the 6 Hz Assay (44 mA). At a dose of 10 mg/kg s.c., Co. No. 2-a increases the potency of LEV, leading to an approximate 35-fold shift in the ED50. This suggests a positive pharmacodynamic relationship.
  • FIG. 5: Combination Studies for Co. No. 6-b with levetiracetam (LEV) in the 6 Hz Assay (44 mA). At a dose of 10 mg/kg p.o., Co. No. 6-b increases the potency of LEV, leading to an approximate 100-fold shift in the ED50. This suggests a positive pharmacodynamic relationship.
  • FIG. 6: Combination Studies for LY-404039 with levetiracetam (LEV) in the 6 Hz Assay (44 mA). At a dose of 5 mg/kg s.c., LY-404039 increases the potency of LEV, leading to an approximate 27-fold shift in the ED50. This suggests a positive pharmacodynamic relationship.
    •  DESCRIPTION OF THE INVENTION
  • The present invention relates to a combination comprising
      • (a) a synaptic vesicle protein 2A (“SV2A”) ligand; and
      • (b) a positive allosteric modulator (“PAM”) of metabotropic glutamatergic receptor subtype 2 (“mGluR2”) compound or a pharmaceutically acceptable salt or a solvate thereof, or an orthosteric agonist of metabotropic glutamatergic receptor subtype 2 compound or a pharmaceutically acceptable salt or a solvate thereof.
  • In a particular embodiment, the invention as described herein relates to a pharmaceutical combination, in particular a pharmaceutical combination product, comprising
      • (a) a synaptic vesicle protein 2A (“SV2A”) ligand; and
      • (b) a positive allosteric modulator (“PAM”) of metabotropic glutamatergic receptor subtype 2 (“mGluR2”) compound or a pharmaceutically acceptable salt or a solvate thereof, or an orthosteric agonist of metabotropic glutamatergic receptor subtype 2 compound or a pharmaceutically acceptable salt or a solvate thereof; and
      • (c) at least one pharmaceutically acceptable carrier.
  • In a further embodiment, the invention relates to the combination described herein for use as a medicament.
  • A further embodiment of this invention relates to the use of the combination described herein for the manufacture of a medicament or a pharmaceutical product for the treatment or prevention of epilepsy and related disorders; neuropathic pain; migraine or resistant headache and bipolar and related disorders.
  • A further embodiment of this invention relates to the use of the combination described herein for the manufacture of a medicament or a pharmaceutical product for neuroprotection.
  • A further embodiment of this invention relates to the use of the combination described herein for the manufacture of a medicament or a pharmaceutical product for the prevention of epileptogenesis.
  • A further embodiment relates to the treatment or prevention of epilepsy and related disorders; neuropathic pain; migraine or resistant headache; and bipolar and related disorders of a subject comprising administering concurrently or sequentially to the subject in need thereof a synaptic vesicle protein 2A (“SV2A”) ligand; and a positive allosteric modulator (“PAM”) of metabotropic glutamatergic receptor subtype 2 (“mGluR2”) compound or a pharmaceutically acceptable salt or a solvate thereof, or an orthosteric agonist of metabotropic glutamatergic receptor subtype 2 compound or a pharmaceutically acceptable salt or a solvate thereof, in amounts that would be therapeutically effective when the SV2A ligand and mGluR2 compound are administered together.
  • A further embodiment relates to a combination as described herein for neuroprotection; or to a combination as described herein for use in neuroprotection.
  • A further embodiment relates to a combination as described herein for the prevention of epileptogenesis; or to a combination as described herein for use in the prevention of epileptogenesis.
  • In a further embodiment the invention relates to a method of treating or preventing epilepsy and related disorders; neuropathic pain; migraine or resistant headache; bipolar and related disorders in patients comprising administering a fixed dose combination of
      • (a) a synaptic vesicle protein 2A (“SV2A”) ligand; and
      • (b) a positive allosteric modulator (“PAM”) of metabotropic glutamatergic receptor subtype 2 (“mGluR2”) compound or a pharmaceutically acceptable salt or a solvate thereof, or an orthosteric agonist of metabotropic glutamatergic receptor subtype 2 compound or a pharmaceutically acceptable salt or a solvate thereof,
        in amounts that would be therapeutically effective when the SV2A ligand and mGluR2 compound are administered together.
  • In a further embodiment the invention relates to a method of neuroprotection with a combination as defined herein.
  • In a further embodiment the invention relates to a method of anti-epileptogenesis with a combination as defined herein.
  • A further embodiment relates to a method for the treatment or prevention of epilepsy and related disorders; neuropathic pain; migraine or resistant headache; bipolar and related disorders said method comprising administering a therapeutically effective amount of a combination or a combination product comprising
      • (a) a synaptic vesicle protein 2A (“SV2A”) ligand; and
      • (b) a positive allosteric modulator (“PAM”) of metabotropic glutamatergic receptor subtype 2 (“mGluR2”) compound or a pharmaceutically acceptable salt or a solvate thereof, or an orthosteric agonist of metabotropic glutamatergic receptor subtype 2 compound or a pharmaceutically acceptable salt or a solvate thereof,
      • to a subject in need thereof, such as a warm-blooded animal, in particular a human.
  • A further embodiment relates to a method of neuroprotection, said method comprising administering a therapeutically effective amount of a combination or a combination product comprising
      • (a) a synaptic vesicle protein 2A (“SV2A”) ligand; and
      • (b) a positive allosteric modulator (“PAM”) of metabotropic glutamatergic receptor subtype 2 (“mGluR2”) compound or a pharmaceutically acceptable salt or a solvate thereof, or an orthosteric agonist of metabotropic glutamatergic receptor subtype 2 compound or a pharmaceutically acceptable salt or a solvate thereof,
      • to a subject in need thereof, such as a warm-blooded animal, in particular a human.
  • A further embodiment relates to a method of anti-epileptogenesis, said method comprising administering a therapeutically effective amount of a combination or a combination product comprising
      • (a) a synaptic vesicle protein 2A (“SV2A”) ligand; and
      • (b) a positive allosteric modulator (“PAM”) of metabotropic glutamatergic receptor subtype 2 (“mGluR2”) compound or a pharmaceutically acceptable salt or a solvate thereof, or an orthosteric agonist of metabotropic glutamatergic receptor subtype 2 compound or a pharmaceutically acceptable salt or a solvate thereof,
      • to a subject in need thereof, such as a warm-blooded animal, in particular a human.
  • In an additional embodiment, the present invention relates to a pharmaceutical product or a commercial package comprising a combination according to the invention as described herein, in particular together with instructions, for simultaneous, separate or sequential use thereof in the treatment or prevention of epilepsy and related disorders; neuropathic pain; migraine or resistant headache bipolar; and related disorders.
  • In an additional embodiment, the present invention relates to a pharmaceutical product or a commercial package comprising a combination according to the invention as described herein, in particular together with instructions, for simultaneous, separate or sequential use thereof in neuroprotection.
  • In an additional embodiment, the present invention relates to a pharmaceutical product or a commercial package comprising a combination according to the invention as described herein, in particular together with instructions, for simultaneous, separate or sequential use thereof in anti-epileptogenesis.
  • In a further embodiment the invention relates to a combination comprising a quantity which is jointly therapeutically effective against epilepsy and related disorders; neuropathic pain; migraine or resistant headache; bipolar and related disorders; of
      • (a) a synaptic vesicle protein 2A (“SV2A”) ligand; and
      • (b) a positive allosteric modulator (“PAM”) of metabotropic glutamatergic receptor subtype 2 (“mGluR2”) compound or a pharmaceutically acceptable salt or a solvate thereof, or an orthosteric agonist of metabotropic glutamatergic receptor subtype 2 compound or a pharmaceutically acceptable salt or a solvate thereof, and at least one pharmaceutically acceptable carrier.
  • In a further embodiment the invention relates to a combination comprising a quantity which is jointly therapeutically effective as neuroprotectant, of
      • (a) a synaptic vesicle protein 2A (“SV2A”) ligand; and
      • (b) a positive allosteric modulator (“PAM”) of metabotropic glutamatergic receptor subtype 2 (“mGluR2”) compound or a pharmaceutically acceptable salt or a solvate thereof, or an orthosteric agonist of metabotropic glutamatergic receptor subtype 2 compound or a pharmaceutically acceptable salt or a solvate thereof, and at least one pharmaceutically acceptable carrier.
  • In a further embodiment the invention relates to a combination comprising a quantity which is jointly therapeutically effective in the prevention of epileptogenesis, of
      • (a) a synaptic vesicle protein 2A (“SV2A”) ligand; and
      • (b) a positive allosteric modulator (“PAM”) of metabotropic glutamatergic receptor subtype 2 (“mGluR2”) compound or a pharmaceutically acceptable salt or a solvate thereof, or an orthosteric agonist of metabotropic glutamatergic receptor subtype 2 compound or a pharmaceutically acceptable salt or a solvate thereof, and at least one pharmaceutically acceptable carrier.
  • In a further embodiment, the invention relates to the use of
      • (a) a synaptic vesicle protein 2A (“SV2A”) ligand; and
      • (b) a positive allosteric modulator (“PAM”) of metabotropic glutamatergic receptor subtype 2 (“mGluR2”) compound or a pharmaceutically acceptable salt or a solvate thereof, or an orthosteric agonist of metabotropic glutamatergic receptor subtype 2 compound or a pharmaceutically acceptable salt or a solvate thereof,
      • for the preparation of a combination product according to the present invention.
  • The (b) components of the combination of the invention are in general referred to herein as “mGluR2 compounds” or “mGluR2 PAM/agonist compounds”, or “positive allosteric modulator of mGluR2/mGluR2 orthosteric agonist compound” meaning that the compounds have mainly activity at the metabotropic glutamatergic receptor subtype 2, and are in particular selected from positive allosteric modulators (PAMs) of metabotropic glutamatergic receptor subtype 2, and orthosteric agonists of metabotropic glutamatergic receptor subtype 2. A skilled person will be familiar with the large homology of mGluR2 and mGluR3, due to which some mGluR2 orthosteric agonists also display activity as mGluR3 orthosteric agonists. Such is the case for example, of (−)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic acid (also known as LY-404,039 [CAS 635318-11-5]), with a Ki=149 nM (mGlu2 receptor) and Ki=92 nM (mGlu3 receptor), 100-fold selectivity for mGlu2 and mGlu3 over mGlu4a, -6, -7a, and -8a, and no activity at mGlu1a and mGlu5a (Rorick-Kehn et al. (2007) The Journal of Pharmacology and Experimental Therapeutics Vol. 321, No. 1, pp. 308-317). The term “mGluR2 compounds” or “mGluR2 PAM/agonist compounds”, or “positive allosteric modulator of mGluR2/mGluR2 orthosteric agonist compound” does therefore not exclude compounds displaying some other additional minor activity in vitro or in vivo.
  • The mGluR2 PAM compounds of the combination of the invention are in particular selected from those disclosed in WO2010/130424. A particular subgroup of said compounds disclosed in WO2010/130424 can be defined by the following Formula (I)
  • Figure US20220143141A1-20220512-C00004
  • or a stereoisomeric form thereof; wherein
    R1 is selected from the group consisting of (C3-7 cycloalkyl)C1-3 alkyl-, mono- or
    polyhaloC1-4alkyl, and (C1-4alkyl)-O—(C1-4alkyl);
    R2 is halo or polyhaloC1-4alkyl;
    A is a covalent bond or a —CH2—;
    L is selected from the radicals (a), (b) and (c):
  • Figure US20220143141A1-20220512-C00005
  • wherein
    R3a is selected from unsubstituted phenyl or phenyl substituted with 1 or 2 halo substituents;
    R4a is selected from the group of hydrogen, C1-3alkyl and halo;
    or R3a—C—R4a together represent a radical of formula (a-1)
  • Figure US20220143141A1-20220512-C00006
  • wherein R5a is hydrogen or halo;
    R3b is selected from the group of phenyl substituted with 1 or 2 halo substituents, pyridinyl substituted with 1 or 2 halo substituents, unsubstituted pyrimidinyl and pyrimidinyl substituted with 1 or 2 C1-3alkyloxy substituents;
    or a pharmaceutically acceptable salt or a solvate thereof.
  • Thus, according to a particular embodiment of the invention, the positive allosteric modulator (“PAM”) of metabotropic glutamatergic receptor subtype 2 (“mGluR2”) compound is a compound of Formula (I) as defined herein.
  • In a particular embodiment, the compounds of Formula (I) are as defined herein wherein
  • R1 is selected from the group consisting of cyclopropylmethyl-, 2,2,2-trifluoroethyl, and CH3—O—CH2—;
    R2 is chloro or CF3;
    A is a covalent bond or a —CH2—;
    L is selected from the radicals (a), (b) and (c):
  • Figure US20220143141A1-20220512-C00007
  • wherein
    R3a is selected from unsubstituted phenyl or phenyl substituted with 1 or 2 fluoro substituents;
    R4a is selected from the group of hydrogen, methyl and fluoro;
    or R3a—C—R4a together represent a radical of formula (a-1)
  • Figure US20220143141A1-20220512-C00008
  • wherein R5a is hydrogen or fluoro;
  • R3b is selected from the group of phenyl substituted with 1 or 2 fluoro substituents, pyridinyl substituted with 1 or 2 fluoro substituents, unsubstituted pyrimidinyl and pyrimidinyl substituted with 1 or 2 methoxy substituents;
  • or a pharmaceutically acceptable salt or a solvate thereof.
  • In a particular embodiment, the compounds of Formula (I) are as defined herein wherein
  • (i) when A is CH2; and R2 is trifluoromethyl; then
      • R1 is cyclopropylmethyl-; and
      • L is selected from
  • Figure US20220143141A1-20220512-C00009
  • (ii) when A is CH2; and R2 is chloro; then
      • R1 is cyclopropylmethyl-; and
      • L is
  • Figure US20220143141A1-20220512-C00010
  • (iii) when A is a covalent bond; and R2 is trifluoromethyl; then
      • R1 is cyclopropylmethyl; and
      • L is selected from
  • Figure US20220143141A1-20220512-C00011
  • (iv) when A is a covalent bond and R2 is Cl; then
      • (iv-a) R1 is cyclopropylmethyl and L is
  • Figure US20220143141A1-20220512-C00012
      • or
      • (iv-b) R1 is 2,2,2-trifluoroethyl and L is selected from
  • Figure US20220143141A1-20220512-C00013
  • (v) when A is CH2 and R1 is —CH2—O—CH3; then
    R2 is —CF3 and L is
  • Figure US20220143141A1-20220512-C00014
  • or a pharmaceutically acceptable salt or a solvate thereof.
  • The compounds of Formula (I) are disclosed in WO2010/130424 and may be prepared according to the processes described therein, which are hereby incorporated by reference in their totality.
  • Particular compounds of Formula (I) include
  • Figure US20220143141A1-20220512-C00015
    Figure US20220143141A1-20220512-C00016
    Figure US20220143141A1-20220512-C00017
  • In an embodiment of the invention, the compound of Formula (I) is
  • Figure US20220143141A1-20220512-C00018
  • Co. No. 1; or a pharmaceutically acceptable salt thereof, preferably a hydrochloride salt thereof.
  • In an additional embodiment of the invention, the compound of Formula (I) is
  • Figure US20220143141A1-20220512-C00019
  • Co. No. 2; or a pharmaceutically acceptable salt thereof, preferably a hydrochloride salt thereof (.HCl).
  • The mGluR2 PAM compounds of the combination of the invention are also in particular selected from those disclosed in WO2009/033704. Said compounds disclosed in WO2009/033704 can be defined by the following Formula (I-A)
  • Figure US20220143141A1-20220512-C00020
  • and the stereochemically isomeric forms thereof, wherein
    R1 is C1-6 alkyl; or C1-3 alkyl substituted with C3-7 cycloalkyl, phenyl, or phenyl substituted with halo, trifluoromethyl or trifluoromethoxy;
    R2 is halo, trifluoromethyl, C1-3 alkyl or cyclopropyl;
    R3 is hydrogen, fluoro, hydroxyl, hydroxyC1-3 alkyl, hydroxyC1-3 alkyloxy, fluoroC1-3 alkyl, fluoroC1-3 alkyloxy or cyano; and
    Ar is unsubstituted phenyl; or phenyl substituted with n radicals R4, wherein n is 1, 2 or 3;
    R4 is selected from the group consisting of hydrogen, halo, C1-3alkyl, hydroxyC1-3 alkyl, polyhaloC1-3 alkyl, cyano, hydroxyl, amino, carboxyl, C1-3alkyloxyC1-3alkyl, C1-3 alkyloxy, polyhaloC1-3 alkyloxy, C1-3alkylcarbonyl, mono- and di(C1-3 alkyl)amino, and morpholinyl; or
    two vicinal R4 radicals taken together form a bivalent radical of formula

  • —N═CH—NH—  (i),

  • —CH═CH—NH—  (ii), or

  • —O—CH2—CH2—NH—  (iii); or
  • R3 and a R4 radical in ortho position taken together form a bivalent radical of formula

  • —CH2—O—  (iv), or

  • —O—CH2—  (v);
      • and the pharmaceutically acceptable salts and the solvates thereof.
  • In a particular embodiment, the compounds of Formula (I-A) are as defined herein wherein
  • R1 is C1-6 alkyl; or C1-3 alkyl substituted with C3-7 cycloalkyl, phenyl, or phenyl substituted with halo, trifluoromethyl or trifluoromethoxy;
    R2 is halo, trifluoromethyl, C1-3 alkyl or cyclopropyl;
    R3 is hydrogen, fluoro, hydroxyl, hydroxyC1-3 alkyl, hydroxyC1-3 alkyloxy, fluoroC1-3 alkyl, fluoroC1-3 alkyloxy or cyano; and
    Ar is unsubstituted phenyl, or phenyl substituted with n radicals R4, wherein n is 1, 2 or 3;
    R4 is selected from the group consisting of hydrogen, halo, C1-3alkyl, hydroxyC1-3 alkyl, polyhaloC1-3 alkyl, cyano, hydroxyl, amino, carboxyl, C1-3alkyloxyC1-3alkyl, C1-3 alkyloxy, polyhaloC1-3 alkyloxy; C1-3 alkylcarbonyl, mono- and di(C1-3 alkyl)amino, and morpholinyl; or
    two vicinal R4 radicals taken together form a bivalent radical of formula

  • —N═CH—NH—  (i),

  • —CH═CH—NH—  (ii), or

  • —O—CH2—CH2—NH—  (iii);
  • and the pharmaceutically acceptable salts and solvates thereof.
  • In a particular embodiment, the compounds of Formula (I-A) are as defined herein wherein
  • R1 is C1-6alkyl; or C1-3 alkyl substituted with C3-7 cycloalkyl, phenyl or phenyl substituted with halo, trifluoromethyl or trifluoromethoxy;
    R2 is halo, trifluoromethyl, C1-3 alkyl or cyclopropyl;
    R3 is hydrogen, fluoro, hydroxyl, hydroxyC1-3 alkyl, hydroxyC1-3 alkyloxy, fluoroC1-3alkyl, fluoroC1-3 alkyloxy or cyano; and
    Ar is unsubstituted phenyl;
    and the pharmaceutically acceptable salts and solvates thereof.
  • In an additional embodiment, the compounds of Formula (I-A) are as defined herein wherein
  • R1 is 1-butyl, 2-methyl-1-propyl, 3-methyl-1-butyl, (cyclopropyl)methyl or 2-(cyclopropyl)-3-ethyl;
    R3 is hydrogen, fluoro or cyano; and
    Ar is unsubstituted phenyl;
    and the pharmaceutically acceptable salts and solvates thereof.
  • In an additional embodiment, the compounds of Formula (I-A) are as defined herein wherein
  • R1 is 1-butyl, 3-methyl-1-butyl, (cyclopropyl)methyl or 2-(cyclopropyl)-1-ethyl;
    R2 is chloro;
    R3 is hydrogen or fluoro; and
    Ar is unsubstituted phenyl;
    and the pharmaceutically acceptable salts and the solvates thereof.
  • In a further embodiment, the compounds of Formula (I-A) are as defined herein wherein
  • R1 is C1-6alkyl; or C1-3 alkyl substituted with C3-7 cycloalkyl, phenyl, or phenyl substituted with halo, trifluoromethyl or trifluoromethoxy;
    R2 is halo, trifluoromethyl, C1-3 alkyl or cyclopropyl;
    R3 is hydrogen, fluoro, hydroxyl, hydroxyC1-3 alkyl, hydroxyC1-3 alkyloxy, fluoroC1-3alkyl, fluoroC1-3alkyloxy or cyano; and
    Ar is phenyl substituted with n radicals R4, wherein n is 1, 2, or 3;
    R4 is selected from the group consisting of halo, C1-3alkyl, hydroxyC1-3 alkyl, C1-3 alkyloxy, polyhaloC1-3 alkyloxy, C1-3 alkylcarbonyl, mono- and di(C1-3 alkyl)amino, and morpholinyl; or
    two vicinal R4 radicals taken together form a bivalent radical of formula

  • —N═CH—NH—  (i),

  • —CH═CH—NH—  (ii), or

  • —O—CH2—CH2—NH—  (iii); or
  • R3 and a R4 radical in ortho position taken together form a bivalent radical of formula

  • —CH2—O—  (iv),

  • —O—CH2—  (v);
  • and the pharmaceutically acceptable salts and solvates thereof.
  • In an additional embodiment, the compounds of Formula (I-A) are as defined herein wherein
  • R1 is 1-butyl, 2-methyl-1-propyl, 3-methyl-1-butyl, (cyclopropyl)methyl or 2-(cyclopropyl)-1-ethyl;
    R3 is hydrogen, fluoro or cyano; and
    Ar is phenyl substituted with halo, trifluoromethyl, morpholinyl or hydroxyC1-3 alkyl;
    and the pharmaceutically acceptable salts and solvates thereof.
  • In an additional embodiment, the compounds of Formula (I-A) are as defined herein wherein
  • R1 is 1-butyl, 3-methyl-1-butyl, (cyclopropyl)methyl or 2-(cyclopropyl)-1-ethyl;
    R2 is chloro;
    R3 is hydrogen or fluoro; and
    Ar is phenyl substituted with at least one halo group;
    and the pharmaceutically acceptable salts and solvates thereof.
  • In an additional embodiment, the compounds of Formula (I-A) are as defined herein wherein
  • R1 is 1-butyl, 3-methyl-1-butyl, (cyclopropyl)methyl or 2-(cyclopropyl)-1-ethyl;
    R2 is chloro;
    R3 is hydrogen or fluoro; and
    Ar is phenyl substituted with at least two fluoro groups;
    and the pharmaceutically acceptable salts and solvates thereof.
  • The compounds of Formula (I-A) are disclosed in WO2009/033704 and may be prepared according to the processes described therein, which are hereby incorporated by reference in their totality.
  • Particular compounds of Formula (I-A) include
  • Figure US20220143141A1-20220512-C00021
    Figure US20220143141A1-20220512-C00022
    Figure US20220143141A1-20220512-C00023
    Figure US20220143141A1-20220512-C00024
    Figure US20220143141A1-20220512-C00025
    Figure US20220143141A1-20220512-C00026
    Figure US20220143141A1-20220512-C00027
    Figure US20220143141A1-20220512-C00028
  • and the pharmaceutically acceptable salts and the solvates thereof.
  • In an embodiment of the invention, the compound of Formula (I-A) is
  • Figure US20220143141A1-20220512-C00029
  • or a pharmaceutically acceptable salt or a solvate thereof.
  • The mGluR2 PAM compounds of the combination of the invention are also in particular selected from those disclosed in PCT/EP2014/068676. Said compounds disclosed in PCT/EP2014/068676 can be defined by the following Formula (I-B)
  • Figure US20220143141A1-20220512-C00030
  • and the stereochemically isomeric forms thereof, wherein
    R1 is selected from the group consisting of C1-6 alkyl, (C3-8cycloalkyl)C1-3alkyl, and (C1-3 alkyloxy)C1-3 alkyl;
    each R2 is independently selected from F, Cl, C1-3alkyl, C1-3alkyloxy, mono- or polyhaloC1-3 alkyl, and mono- or polyhaloC1-3 alkyloxy;
    n is an integer selected from 1, 2, and 3;
    and the pharmaceutically acceptable salts and the solvates thereof.
  • The mGluR2 PAM compounds of the combination of the invention are in particular selected from compounds of Formula (I-B) as defined hereinabove, and stereoisomeric forms thereof, wherein R1 is selected from the group consisting of CH3CH2, CH3CH2CH2, (cyclopropyl)methyl, (cyclobutyl)methyl, ethyloxymethyl and methyloxymethyl; and the rest of variables are as defined herein; and the pharmaceutically acceptable salts and the solvates thereof.
  • In a further embodiment, the mGluR2 PAM compounds of the combination of the invention are in particular selected from compounds of Formula (I-B) as defined hereinabove, and stereoisomeric forms thereof, wherein R1 is selected from the group consisting of CH3CH2, (cyclopropyl)methyl, (cyclobutyl)methyl and methyloxymethyl; and the rest of variables are as defined herein; and the pharmaceutically acceptable salts and the solvates thereof.
  • In a further embodiment, the mGluR2 PAM compounds of the combination of the invention are in particular selected from compounds of Formula (I-B) as defined hereinabove, and stereoisomeric forms thereof, wherein R1 is selected from the group consisting of CH3CH2, (cyclopropyl)methyl, (cyclobutyl)methyl and ethyloxymethyl; and the rest of variables are as defined herein; and the pharmaceutically acceptable salts and the solvates thereof.
  • Thus, according to a particular embodiment of the invention, the positive allosteric modulator (“PAM”) of metabotropic glutamatergic receptor subtype 2 (“mGluR2”) compound is a compound of Formula (I-B) as defined herein.
  • In an additional embodiment, the compounds of Formula (I-B) are as defined herein, wherein
  • each R2 is independently selected from F, Cl, CH3, CH3O and CF3; and the pharmaceutically acceptable salts and the solvates thereof.
  • In a further embodiment, the compounds of Formula (I-B) are as defined herein having the Formula (I-Ba)
  • Figure US20220143141A1-20220512-C00031
  • wherein the variables are as defined in Formula (I-B) herein, and the pharmaceutically acceptable salts and the solvates thereof.
  • In a further embodiment, the compounds of Formula (I-B) are as defined herein having the Formula (I-Bb)
  • Figure US20220143141A1-20220512-C00032
  • wherein the variables are as defined in Formula (I-B) herein, and the pharmaceutically acceptable salts and the solvates thereof.
  • Particular compounds of formula (I-B) include
    • 3-(Cyclopropylmethyl)-7-[1-(4-fluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo-[4,3-a]pyridine;
    • 3-(Cyclopropylmethyl)-7-[(1*R)-1-(4-fluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;
    • 3-(Cyclopropylmethyl)-7-[(1*S)-1-(4-fluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;
    • 3-(Cyclopropylmethyl)-7-[(1S)-1-(2,4-difluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;
    • 3-(Cyclopropylmethyl)-7-[(1R)-1-(2,4-difluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;
    • 3-(Cyclopropylmethyl)-7-[1-(2,4-difluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo-[4,3-a]pyridine;
    • 3-(Cyclopropylmethyl)-7-[(1S)-1-(3,5-difluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;
    • 3-(Cyclopropylmethyl)-7-[(1 S)-1-(3,4-difluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;
    • 3-(Cyclopropylmethyl)-7-[(1S)-1-(2,3-difluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;
    • 3-(Cyclopropylmethyl)-7-[(1S)-1-(2,5-difluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;
    • 3-(Cyclopropylmethyl)-7-[(1S)-1-(2,6-difluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;
    • 3-(Cyclopropylmethyl)-7-[(1S)-1-(4-fluoro-2-methoxyphenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;
    • 3-(Cyclobutylmethyl)-7-[1-(2,4-difluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo-[4,3-a]pyridine;
    • 7-[(1S)-1-(2-Chloro-4-methylphenoxy)ethyl]-3-(cyclopropylmethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;
    • 3-(Cyclopropylmethyl)-7-[(1S)-1-(4-fluoro-2-methylphenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;
    • 3-(Cyclopropylmethyl)-8-(trifluoromethyl)-7-[(1S)-1-(2,4,6-trifluorophenoxy)ethyl][1,2,4]triazolo[4,3-a]pyridine;
    • 7-[1-(2,4-Difluorophenoxy)ethyl]-3-(ethoxymethyl)-8-(trifluoromethyl)[1,2,4]triazolo-[4,3-a]pyridine;
    • 3-Ethyl-8-(trifluoromethyl)-7-[1-(2,4,6-trifluorophenoxy)ethyl][1,2,4]triazolo[4,3-a]pyridine;
    • 7-[1-(2,4-Difluorophenoxy)ethyl]-3-ethyl-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;
    • 3-(Cyclobutylmethyl)-7-[(1*R)-1-(2,4-difluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;
    • 3-(Cyclobutylmethyl)-7-[(1*S)-1-(2,4-difluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;
    • 3-(Ethoxymethyl)-8-(trifluoromethyl)-7-[(1*R)-1-(2,4,6-trifluorophenoxy)ethyl][1,2,4]triazolo[4,3-a]pyridine;
    • 3-(Ethoxymethyl)-8-(trifluoromethyl)-7-[(1*S)-1-(2,4,6-trifluorophenoxy)ethyl][1,2,4]triazolo[4,3-a]pyridine;
    • 7-[(1*S)-1-(2,4-Difluorophenoxy)ethyl]-3-(ethoxymethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;
    • 7-[(1*R)-1-(2,4-Difluorophenoxy)ethyl]-3-(ethoxymethyl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;
    • 7-[(1*R)-1-(2,4-Difluorophenoxy)ethyl]-3-ethyl-8-(trifluoromethyl)[1,2,4]triazolo-[4,3-a]pyridine;
    • 7-[(1*S)-1-(2,4-Difluorophenoxy)ethyl]-3-ethyl-8-(trifluoromethyl)[1,2,4]triazolo-[4,3-a]pyridine;
    • 7-[1-(2,4-Difluorophenoxy)ethyl]-3-propyl-8-(trifluoromethyl) [1,2,4]triazolo[4,3-a]pyridine;
    • 3-Ethyl-8-(trifluoromethyl)-7-[(1*R)-1-(2,4,6-trifluorophenoxy)ethyl]-[1,2,4]triazolo-[4,3-a]pyridine;
    • 3-Ethyl-8-(trifluoromethyl)-7-[(1*S)-1-(2,4,6-trifluorophenoxy)ethyl]-[1,2,4]triazolo-[4,3-a]pyridine;
    • 7-[(1*R)-(2,4-difluorophenoxy)ethyl]-3-propyl-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine; and
    • 7-[(1*S)-(2,4-difluorophenoxy)ethyl]-3-propyl-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine.
  • Included within the scope of this list are stereoisomeric forms, the pharmaceutically acceptable salts and the solvates thereof.
  • In an additional embodiment, the compound may be selected from 3-(Cyclopropylmethyl)-7-[(1 S)-1-(2,4-difluorophenoxy)ethyl]-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine hydrochloride salt.
  • The orthosteric agonists of mGluR2/mGluR2/3 of the combination of the invention include, but are not limited to, for example, LY-404039; LY-2969822; LY-2934747; LY-379268; DCG-W; LY-354740; LY-314582; LY-544344; LY-2140023; LY-181837; LY-389795; LY-446433; LY-450477; LY-395756; LY-566332; LY-541850; LY-2300559; LY-404040; LY-281223; LY-2979165; talaglumetad; MGS008; MGS0022; MGS0028; MGS0039; (−)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate; (+)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid; (+)-2-amino-4-fluorobicyclo-[3.1.0]hexane-2,6-dicarboxylic acid; 1S,2R,5S,6S-2-amino-6-fluoro-4-oxobicyclo-[3.1.0]hexane-2,6-dicarboxylic acid; 1S,2R,4S,5S,6S-2-amino-6-fluoro-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid; 1S,2R,3R,5S,6S-2-amino-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid; 1S,2R,3S,5S,6S-2-amino-6-fluoro-3-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid; (+)-4-amino-2-sulfonylbicyclo-[3.1.0]hexane-4,6-dicarboxylic acid; (+)-2-amino-4-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid; 1S,2R,5S,6S-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid; 1S,2R,4S,5S,6S-2-amino-6-fluoro-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid; 1S,2R,3R,5S,6S-2-amino-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid; or 1S,2R,3S,5S,6S-2-amino-6-fluoro-3-hydroxybicyclo-[3.1.0]hexane-2,6-dicarboxylic acid.
  • A particular group of mGluR2 agonists include LY-379268; DCG-IV; LY-354740; LY-404039; LY-2969822; LY-2934747; LY-544344; and LY-2140023.
  • The orthosteric agonists of metabotropic glutamatergic receptor subtype 2 of the combination of the invention are in particular further selected from those disclosed in WO1997/18199 and WO2003/104217, incorporated herein in their entirety. Particular compounds disclosed therein are (−)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic acid (also known as LY-404039)
  • Figure US20220143141A1-20220512-C00033
  • or a salt or a solvate thereof, and (1R,4S,5S,6S)-4-[[(2S)-2-amino-4-(methylthio)-1-oxobutyl]amino]-2-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid 2,2-dioxide (also known as LY-2140023 [CAS 635318-55-7])
  • Figure US20220143141A1-20220512-C00034
  • or a salt or a solvate thereof, for example the monohydrate thereof.
  • The names of the compounds of the present invention were generated according to the nomenclature rules agreed upon by the Chemical Abstracts Service (C.A.S.) using Advanced Chemical Development, Inc., software (ACD/Name product version 10.01.0.14105, October 2006). In case of tautomeric forms, the name of the depicted tautomeric form of the structure was generated. However it should be clear that the other non-depicted tautomeric form is also included within the scope of the present invention.
  • As used herein, the notation “C1-3alkyl”, “C1-4alkyl” or “C1-6alkyl” as a group or part of a group defines a saturated, straight or branched, hydrocarbon radical having from 1 to 3 or from 1 to 4 or from 1 to 6 carbon atoms, such as methyl, ethyl, 1-propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methyl-1-propyl, 1,1-dimethylethyl, 3-methyl-1-butyl, 1-pentyl, 1-hexyl and the like.
  • The notation “C3-7cycloalkyl” or “C3-8cycloalkyl” as a group or part of a group defines a saturated, cyclic hydrocarbon radical having from 3 to 7 or from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • The notation “halo” or “halogen” as used herein as a group or part of a group refers to fluoro, chloro, bromo or iodo, with fluoro or chloro being preferred.
  • The notation “mono- and polyhaloC1-3alkyl” or “mono- and polyhaloC1-4alkyl” shall denote C1-3alkyl or C1-4alkyl respectively, as defined before, substituted with 1, 2, 3 or where possible with more halo atoms as defined before.
  • Whenever the term “substituted” is used in the present invention, it is meant, unless otherwise is indicated or is clear from the context, to indicate that one or more hydrogens, preferably from 1 to 3 hydrogens, more preferably from 1 to 2 hydrogens, more preferably 1 hydrogen, on the atom or radical indicated in the expression using “substituted” are replaced with a selection from the indicated group, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.
  • As used herein, unless otherwise noted, the term “antiepileptic agent” and the abbreviation “AED” will be used interchangeably with the term “anticonvulsant agent”, and as used herein, refer to an agent capable of treating, inhibiting or preventing seizure activity or ictogenesis when the agent is administered to a subject or patient.
  • As used herein, unless otherwise noted, the term “synaptic vesicle protein 2A ligand” and the abbreviation “SV2A ligand” will be used interchangeably. Examples of SV2A ligands include, but are not limited to, the compounds included in the publications GB 1,039,113; GB 1,309,692; EP 1 262 036; EP 1 806 339; WO 2001/062726; US 2002/094787; WO 2004/087658; WO 2005/121082; WO 2005/054188; WO 2006/128692; WO 2006/128693; WO 2007/065595; WO 2008/132139, and WO 2008/132142; WO 2011/047860; WO 2012/143116; and WO 2012/143117. Suitable particular examples of SV2A ligands include, but are not limited to: levetiracetam, brivaracetam and seletracetam.
  • Therefore, in an embodiment of the invention, the SV2A ligand is selected from levetiracetam, brivaracetam and seletracetam.
  • In a particular embodiment, the SV2A ligand is levetiracetam.
  • In a particular embodiment, the SV2A ligand is brivaracetam.
  • Processes for the preparation of the above SV2A ligands are known from the literature and described for instance in EP 1 806 339; in EP 0 162 036 and in GB 2 225 322 (levetiracetam); in WO 01/62726 (brivaracetam); and in WO 2005/121082 (seletracetam); such processes are hereby incorporated by reference in their totality.
  • In an additional embodiment, the combination according to the invention comprises (a) a SV2A ligand selected from levetiracetam or brivaracetam; and (b)
  • Figure US20220143141A1-20220512-C00035
  • or a pharmaceutically acceptable salt thereof, preferably a hydrochloride salt thereof, or a solvate thereof.
  • In an additional embodiment, the pharmaceutical composition according to the invention comprises (a) a pharmaceutically effective amount of levetiracetam or brivaracetam; and (b) a pharmaceutically effective amount of
  • Figure US20220143141A1-20220512-C00036
  • or a pharmaceutically acceptable salt thereof, preferably a hydrochloride salt thereof, or a solvate thereof.
  • In an additional embodiment, the combination according to the invention comprises (a) a pharmaceutically effective amount of levetiracetam or brivaracetam; and (b) a pharmaceutically effective amount of
  • Figure US20220143141A1-20220512-C00037
  • or a pharmaceutically acceptable salt, or a solvate thereof.
  • In an additional embodiment, the pharmaceutical composition according to the invention comprises (a) a pharmaceutically effective amount of levetiracetam or brivaracetam; and (b) a pharmaceutically effective amount of
  • Figure US20220143141A1-20220512-C00038
  • or a pharmaceutically acceptable salt, or a solvate thereof.
  • In an additional embodiment, the combination according to the invention comprises (a) a pharmaceutically effective amount of levetiracetam or brivaracetam; and (b) a pharmaceutically effective amount of
  • Figure US20220143141A1-20220512-C00039
  • or a pharmaceutically acceptable salt, or a solvate thereof.
  • In an additional embodiment, the pharmaceutical composition according to the invention comprises (a) a pharmaceutically effective amount of levetiracetam or brivaracetam; and (b) a pharmaceutically effective amount of
  • Figure US20220143141A1-20220512-C00040
  • or a pharmaceutically acceptable salt, or a solvate thereof.
  • In an additional embodiment, the combination according to the invention comprises (a) a pharmaceutically effective amount of levetiracetam or brivaracetam; and (b) a pharmaceutically effective amount of
  • Figure US20220143141A1-20220512-C00041
  • or a pharmaceutically acceptable salt thereof, in particular the hydrochloride salt thereof, or a solvate thereof.
  • In an additional embodiment, the pharmaceutical composition according to the invention comprises (a) a pharmaceutically effective amount of levetiracetam or brivaracetam; and (b) a pharmaceutically effective amount of
  • Figure US20220143141A1-20220512-C00042
  • or a pharmaceutically acceptable salt thereof, in particular the hydrochloride salt thereof, or a solvate thereof.
  • In an additional embodiment, the combination according to the invention comprises (a) a pharmaceutically effective amount of levetiracetam or brivaracetam; and (b) a pharmaceutically effective amount of LY-404039 or a pharmaceutically acceptable salt thereof, in particular the hydrochloride salt thereof, or a solvate thereof.
  • In an additional embodiment, the pharmaceutical composition according to the invention comprises (a) a pharmaceutically effective amount of levetiracetam or brivaracetam; and (b) a pharmaceutically effective amount of LY-404039 or a pharmaceutically acceptable salt thereof, in particular the hydrochloride salt thereof, or a solvate thereof.
  • In an additional embodiment, the combination according to the invention comprises (a) a pharmaceutically effective amount of levetiracetam or brivaracetam; and (b) a pharmaceutically effective amount of LY-2140023 or a pharmaceutically acceptable salt or a solvate thereof, in particular the monohydrate thereof.
  • In an additional embodiment, the pharmaceutical composition according to the invention comprises (a) a pharmaceutically effective amount of levetiracetam or brivaracetam; and (b) a pharmaceutically effective amount of LY-2140023 or a pharmaceutically acceptable salt or a solvate thereof, in particular the monohydrate thereof.
  • The combination product of the present invention, in particular, the pharmaceutical composition according to the invention, is especially appropriate for the treatment of epilepsy and related disorders.
  • It will be appreciated that some of the mGluR2 compounds, in particular the mGluR2 PAM/agonist compounds of the invention and their pharmaceutically acceptable addition salts and solvates thereof may contain one or more centres of chirality and exist as stereoisomeric forms.
  • The term “compounds of the invention” as used herein, is meant to include the mGluR2 PAM compounds, in particular the compounds of Formula (I)/(I-A)/(I-B), and the mGluR2 agonist compounds as disclosed herein, and the salts and solvates thereof.
  • As used herein, any chemical formula with bonds shown only as solid lines and not as solid wedged or hashed wedged bonds, or otherwise indicated as having a particular configuration (e.g. R, S) around one or more atoms, contemplates each possible stereoisomer, or mixture of two or more stereoisomers.
  • Hereinbefore and hereinafter, the terms “mGluR2 compound” and “mGluR2 PAM/agonist compound” are meant to include the stereoisomers thereof and the tautomeric forms thereof. The terms “stereoisomers”, “stereoisomeric forms” or “stereochemically isomeric forms” hereinbefore or hereinafter are used interchangeably. The invention includes all stereoisomers of the compounds of the invention either as a pure stereoisomer or as a mixture of two or more stereoisomers. Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture. Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e. they are not related as mirror images. If a compound contains a double bond, the substituents may be in the E or the Z configuration. Substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration; for example if a compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration. Therefore, the invention includes enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible. The meaning of all those terms, i.e. enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof are known to the skilled person. The absolute configuration is specified according to the Cahn-Ingold-Prelog system. The configuration at an asymmetric atom is specified by either R or S. Resolved stereoisomers whose absolute configuration is not known can be designated by (+) or (−) depending on the direction in which they rotate plane polarized light. For instance, resolved enantiomers whose absolute configuration is not known can be designated by (+) or (−) depending on the direction in which they rotate plane polarized light.
  • When a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1%, of the other isomers. Thus, when a mGluR2 compound is for instance specified as (R), this means that the compound is substantially free of the (S) isomer; when a mGluR2 compound is for instance specified as E, this means that the compound is substantially free of the Z isomer; when a mGluR2 compound is for instance specified as cis, this means that the compound is substantially free of the trans isomer.
  • Some of the mGluR2 compounds may also exist in their tautomeric form. Such forms in so far as they may exist, although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
  • It follows that a single compound may exist in both stereisomeric and tautomeric forms.
  • For use in medicine, the salts of the compounds of this invention refer to non-toxic “pharmaceutically acceptable salts” (salts of the compounds of the present invention wherein the counterion is pharmaceutically acceptable). Other salts may, however, be useful in the preparation or purification of compounds according to this invention or of their pharmaceutically acceptable salts, and may encompass acids and bases which are non-pharmaceutically acceptable. All salts, whether pharmaceutically acceptable or not, are included within the ambit of the present invention.
  • The pharmaceutically acceptable acid and base addition salts as mentioned hereinabove or hereinafter are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of the invention are able to form. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. Conversely, said salt forms can be converted by treatment with an appropriate base into the free base form. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and alkaline earth metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely, the salt form can be converted by treatment with acid into the free acid form.
  • The term “solvate” comprises the solvent addition forms as well as the salts thereof, which the compounds of Formula (I) are able to form. Examples of such solvent addition forms are e.g. hydrates, alcoholates and the like.
    • Preparation of the Compounds of Formula (I-B)
  • The compounds of Formula (I-B) according to the invention can generally be prepared by a succession of steps, each of which is known to the skilled person. In particular, the compounds can be prepared according to the following synthesis methods.
  • The compounds of Formula (I-B) may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of Formula (I-B) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of Formula (I-B) involves liquid chromatography or supercritical fluid chromatography (SFC) using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
    • A. Preparation of the Final Compounds of Formula (I-B)
  • Final compounds according to Formula (I-B), can be prepared by reacting an intermediate compound of Formula (II) with a compound of Formula (III) according to reaction scheme (1), a reaction that is performed under classical Mitsunobu conditions. The reaction is preferably conducted with a phosphine and an azodicarboxylic ester or amide in tetrahydrofuran, 1,4-dioxane, diethyl ether, toluene, benzene, dichloromethane, or mixtures thereof, at −30 to 150° C., under thermal heating or microwave irradiation. Phosphines often used are triphenylphosphine and tributylphosphine which are usually combined with dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-(4-chlorobenzyl) azodicarboxylate, dibenzyl azodicarboxylate, di-tert-butyl azodicarboxylate, azodicarboxylic acid bis-(dimethyylamide), azodicarboxylic acid dipiperidide, or azodicarboxylic acid dimorpholide. In reaction scheme (1), all variables are as defined in Formula (I-B)
  • Figure US20220143141A1-20220512-C00043
    • B. Preparation of the Intermediates Experimental Procedure 2
  • Intermediate compounds according to Formula (II) can be prepared by subjecting an intermediate of Formula (IV) to conditions that are known to those skilled in the art. This is illustrated in reaction scheme (2) wherein all variables are defined as mentioned hereinabove. Methods accomplishing these transformations are well known to those skilled in the art. Treatment of the aldehyde of formula (IV) with an organometallic such as methyl lithium or methyl magnesium bromide gives a compound of formula (II). A suitable solvent for this reaction is an ether such as tetrahydrofuran and the reaction is usually carried out at a temperature between −78° C. and 40° C. In reaction scheme (2), all variables are defined as in Formula (I-B).
  • Figure US20220143141A1-20220512-C00044
    • Experimental Procedure 3
  • Intermediate compounds according to Formula (IV) can be prepared by reacting an intermediate of Formula (V) under dihydroxylation and oxidative cleavage conditions that are known to those skilled in the art and can be realized for example with oxone, osmium tetroxide. The process may be carried out optionally in a solvent such as 1,4-dioxane, water and generally at temperatures between about −100° C. and about 100° C. A summary of such methods is found in “Comprehensive Organic Transformations”, VCH Publishers, (1989), R. C. Larock, pp. 595-596. This is illustrated in reaction scheme (3) wherein all variables are defined as mentioned hereinabove.
  • Figure US20220143141A1-20220512-C00045
    • Experimental Procedure 4
  • Intermediate compounds according to Formula (V) can be prepared by coupling reactions, such as Stille or Suzuki reactions of an intermediate of Formula (VI) with a compound of Formula (VII) under conditions that are known to those skilled in the art. The process may be carried out optionally in a solvent such as 1,4-dioxane, water and generally at temperatures between about r.t. and about 200° C. in the presence of a base. This is illustrated in reaction scheme (4) wherein all variables are defined as mentioned hereabove, wherein M is trialkyltin, boronic acid or boronate ester, and a palladium catalyst and halo is chloro, bromo or iodo.
  • Figure US20220143141A1-20220512-C00046
    • Experimental Procedure 5
  • Intermediate compounds according to Formula (VI) can be prepared following art known procedures by cyclization of an intermediate compound of Formula (VIII) in the presence of a halogenating agent such as for example phosphorus (V) oxychloride (POCl3) in a suitable solvent such as, for example, dichloroethane, stirred under microwave irradiation, for a suitable period of time that allows the completion of the reaction, as for example 5 min at a temperature between 140-200° C. In reaction scheme (5), R1 is defined as in Formula (I-B) and halo is chloro, bromo or iodo.
  • Figure US20220143141A1-20220512-C00047
    • Experimental Procedure 6
  • Intermediate compounds according to Formula (VIII) can be prepared by art known procedures by reaction of a hydrazine intermediate of Formula (IX) with acid halides of Formula (X). The reaction can be carried out using an inert-solvent, such as for example DCM, in the presence of a base such as for example triethylamine, for example at r.t. for a suitable period of time that allows completion of the reaction, for example 20 min. In reaction scheme (6), R1 is defined as in Formula (I-B).
  • Figure US20220143141A1-20220512-C00048
    • Experimental Procedure 7
  • Intermediate compounds according to Formula (IX) can be prepared by reacting an intermediate compound of Formula (XI) with hydrazine according to reaction scheme (7), a reaction that is performed in a suitable reaction-inert solvent, such as, for example, ethanol, THF or 1,4-dioxane under thermal conditions such as, for example, heating the reaction mixture for example at 160° C. under microwave irradiation for 30 min or classical thermal heating at 70° C. for 16 h. In reaction scheme (7), halo is chloro, bromo or iodo.
  • Figure US20220143141A1-20220512-C00049
    • Experimental Procedure 8
  • Intermediate compounds according to Formula (XI) can be prepared by reacting an intermediate compound of Formula (XII) with benzyl alcohol according to reaction scheme (8), a reaction that is performed in a suitable reaction-inert solvent, such as, for example, N,N-dimethylformamide in the presence of a suitable base, such as for example sodium hydride at r.t. for a suitable period of time that allows the completion of the reaction, such as for example 1 h. In reaction scheme (8), halo is chloro, bromo or iodo.
  • Figure US20220143141A1-20220512-C00050
    • Experimental Procedure 9
  • Intermediate compounds of Formula (XII), can be prepared by reacting an intermediate of Formula (XIII), with a suitable trifluoromethylating agent, such as for example fluorosulfonyl(difluoro)acetic acid methyl ester, according to reaction scheme (9). This reaction is performed in a suitable reaction-inert solvent such as, for example, N,N-dimethylformamide in the presence of a suitable coupling agent such as for example, copper(I) iodide, under thermal conditions such as, for example, heating the reaction mixture for example at 160° C. under microwave irradiation for 45 min. In reaction scheme (9), halo is chloro, bromo or iodo.
  • Figure US20220143141A1-20220512-C00051
  • The starting materials according to Formulae (II), (VII), (X) or (XIII) are compounds that are either commercially available or may be prepared according to conventional reaction procedures generally known to those skilled in the art.
  • As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • As used herein, the term “subject” refers to an animal, preferably a mammal, most preferably a human adult, child or infant, who is or has been the object of treatment, observation or experiment.
  • The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of one or more of the symptoms of the disease or disorder being treated; and/or reduction of the severity of one or more of the symptoms of the disease being treated.
  • The combination of compounds (a) SV2A ligand and (b) positive allosteric modulator (“PAM”) of metabotropic glutamatergic receptor subtype 2 (“mGluR2”) or a pharmaceutically acceptable salt or a solvate thereof, or orthosteric agonist of metabotropic glutamatergic receptor subtype 2 or a pharmaceutically acceptable salt or a solvate thereof, whether the compounds (a) and (b) are given simultaneously, separately or sequentially, may be beneficial compared to the effect of the compounds (a) or (b) administered alone. In particular, there may be at least one beneficial effect, e.g. a mutual enhancement of the effect of the compounds (a) and (b), a more than additive effect, in particular a synergic effect; additional advantageous effects, include for example, a significantly reduced effective dose for the combination of (a) and (b); a further therapeutic effect not observed for any of the compounds (a) or (b) alone, a more beneficial side effect profile, or a combined therapeutic effect in a non-effective dosage of one or both of (a) and (b).
  • As defined herein, the term “fixed-dose ratio of (a) synaptic vesicle protein 2A ligand to (b) compound of Formula (I) of 1:1, calculated on the ED50 values of the individual compounds (a) and (b)” refers to compositions comprising compounds (a) and (b) in a dose corresponding to 50% of the respective ED50 dose of the individual compounds (a) and (b) or a multiple of this fixed-dose ratio. The term “fixed-dose ratio of (a) synaptic vesicle protein 2A ligand:(b) compound of Formula (I) of 3:1, calculated on the ED50 values of the individual compounds (a) and (b)” refers to compositions comprising (b) the compound of Formula (I) in a dose corresponding to 75% of the respective ED50 dose and compound (a) in a dose corresponding to 25% of the respective ED50 dose of compound (a) or a multiple of this fixed-dose ratio, and so on.
  • Thus, in another embodiment of the invention, (a) the SV2A ligand and (b) the compound of Formula (I) are present in the pharmaceutical composition in a fixed-dose ratio of (a):(b) of about 1:10 to about 10:1, preferably about 1:5 to about 5:1, more preferably about 1:3 to about 3:1, in another embodiment of about 1:1 to about 3:1; in an alternate embodiment of 1:3; in yet another embodiment of 1:1; further embodiment of 3:1; wherein the fixed-dose ratio is calculated on the ED50 values of the individual compounds (a) and (b).
  • Wherein the present invention is directed to co-therapy or combination therapy, comprising administration of (a) synaptic vesicle protein 2A (“SV2A”) ligand; and (b) a mGluR2 PAM/agonist compound, in particular a compound of Formula (I)/(I-A)/(I-B) as defined herein, pharmaceutically or therapeutically effective amount shall mean that amount of the combination of agents taken together so that the combined effect elicits the desired biological or medicinal response. For example, the therapeutically effective amount of co-therapy comprising administration of (a) a SV2A ligand as defined herein and (b) a mGluR2 PAM/agonist compound, in particular a compound of Formula (I)/(I-A)/(I-B) as defined herein would be the amount of the (a) a SV2A ligand as defined herein and the amount of (b) a mGluR2 PAM/agonist compound, in particular compound of Formula (I)/(I-A)/(I-B) that when taken together or sequentially have a combined effect that is therapeutically effective. Further, it will be recognized by one skilled in the art that in the case of co-therapy with a therapeutically effective amount, as in the example above, the amount of the mGluR2 PAM/agonist compound, in particular the compound of Formula (I)/(I-A)/(I-B), and/or the amount of the suitable SV2A ligand individually may or may not be therapeutically effective.
  • The present invention provides methods of prevention or treatment comprising administering to a subject in need thereof, co-therapy with a therapeutically effective amount of a SV2A ligand and a therapeutically effective amount of a mGluR2 PAM/agonist compound, in particular a compound of formula (I)/(I-A)/(I-B), as described herein. In order to accomplish this objective the compounds or compositions of this invention must be used in the correct therapeutically effective amount or dose, as described below.
  • Optimal dosages and schedules to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
  • One skilled in the art will recognize that a therapeutically effective dosage of the compounds of the present invention can include repeated doses within a prolonged treatment regimen that will yield clinically significant results.
  • The amounts of the mGluR2 PAM/agonist compound, in particular of the compound of Formula (I)/(I-A)/(I-B), in the combinations of the invention that are administered on a daily basis may vary from about 0.01 to about 2000 mg. Examples of daily amounts of the compound of Formula (I)/(I-A)/(I-B) are 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, 300, 400, 500, 750 and 1000 milligrams for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 150.0 mg/kg of body weight per day or any range therein. Preferably, the range is from about 0.1 to about 100.0 mg/kg of body weight per day, more preferably, from about 0.5 mg/kg to about 50 mg/kg, more preferably, from about 1.0 to about 25.0 mg/kg of body weight per day. The compounds may be administered on a regimen of 1, 2, 3 or 4 times per day. The amounts of SV2A ligand that are administered on a daily basis may vary from about 0.01 to about 7000 mg, preferably will be between 250 and 5000 mg and more preferably will be between 500 and 3000 mg. Examples of daily amount of the SV2A ligand are 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, 500, 750, 1000, 1500 and 3000 milligrams for the symptomatic adjustment of the dosage of the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 150.0 mg/kg of body weight per day or any range therein. Preferably, the range is from about 0.1 to about 100.0 mg/kg of body weight per day, more preferably, from about 0.5 mg/kg to about 50 mg/kg, more preferably, from about 1.0 to about 25.0 mg/kg of body weight per day. The compounds may be administered on a regimen of 1, 2, 3 or 4 times per day. All amounts mentioned in this and the following paragraphs refer to the free form (i.e. non-salt form). The above values represent free-form equivalents, i.e. quantities as if the free form would be administered. If salts are administered the amounts need to be calculated in function of the molecular weight ratio between the salt and the free form.
  • The above mentioned daily doses are calculated for an average body weight of about 70 kg and should be recalculated in case of paediatric applications, or when used with patients with a substantially diverting body weight.
  • The dosages may be presented as one, two, three or four or more sub-doses administered at appropriate intervals throughout the day. The dosage used preferably corresponds to the daily amount of the mGluR2 PAM/agonist compound, in particular of the compound of Formula (I)/(I-A)/(I-B), or of the SV2A ligand, mentioned above, or a sub-dose thereof, such as ½, ⅓, ¼ thereof. A dosage form may contain the mGluR2 PAM/agonist compound, in particular the compound (I)/(I-A)/(I-B), or the SV2A ligand or both together, in an amount equal to the ranges or quantities mentioned in the previous paragraphs, for example a dosage form may contain 10 mg, 25 mg, 50 mg, 100 mg, 150 mg, or 200 mg of mGluR2 PAM/agonist compound, in particular of compound (I)/(I-A)/(I-B), 10 mg, 25 mg, 50 mg, 100 mg or 250 mg, of SV2A ligand, either in separate formulations or in a combined formulation. In one embodiment, the mGluR2 PAM/agonist compound, in particular the compound of Formula (I)/(I-A)/(I-B), is administered once daily (q.d.), in particular as one dose per day, and the SV2A ligand is administered once or twice daily (q.d. or b.i.d.), in particular as one or as two doses per day. In the instance where both compounds are to be administered once daily, this can be accomplished by administering two separate doses, one with the mGluR2 PAM/agonist compound, in particular the compound of Formula (I)/(I-A)/(I-B), one with the SV2A ligand, or by administering a combined dose containing the mGluR2 PAM/agonist compound, in particular the compound of Formula (I)/(I-A)/(I-B), and SV2A ligand.
  • The combinations of the invention may be administered once, twice, three, four, or if desired, multiple times daily. In one embodiment, the combination is administered once daily. In another embodiment, the combination is administered twice daily, or three times per day. Administration of dosages may be by separate dosage forms, i.e. dosage forms only containing mGluR2 PAM/agonist compound, in particular compound of Formula (I)/(I-A)/(I-B), or only SV2A ligand; or by combined dosage forms containing active ingredients mGluR2 PAM/agonist compound, in particular compound of Formula (I)/(I-A)/(I-B), and SV2A ligand. Also, a mix of using a combined dosage form and separate dosage forms can be used. Dosage forms that can be administered are described hereinafter, oral dosage forms, in particular tablets or capsules being preferred.
  • Active ingredients may be formulated in pharmaceutical compositions either separately or as a combined pharmaceutical composition. In the latter instance, there is provided a pharmaceutical composition comprising a therapeutically effective amount of the mGluR2 PAM/agonist compound, in particular of the compound of Formula (I)/(I-A)/(I-B), or a pharmaceutically acceptable salt thereof, and the SV2A ligand, the foregoing being as specified herein, and a pharmaceutically acceptable carrier.
  • In a further aspect, this invention relates to a process for preparing a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of the mGluR2 PAM/agonist compound, in particular of the compound of Formula (I)/(I-A)/(I-B), or a pharmaceutically acceptable salt or a solvate thereof, and a therapeutically effective amount of at least one SV2A ligand.
  • The combinations provided herein may also be formulated as a combined preparation for simultaneous, separate or sequential use in the prevention or treatment of epilepsy and related disorders; neuropathic pain; migraine or resistant headache; bipolar and related disorders; in neuroprotection; or in the prevention of epileptogenesis. In such a case, the mGluR2 PAM/agonist compound, in particular the compound of Formula (I)/(I-A)/(I-B), is formulated in a pharmaceutical composition containing other pharmaceutically acceptable excipients, and the SV2A ligand is formulated separately in a pharmaceutical composition containing other pharmaceutically acceptable excipients. Conveniently, these separate pharmaceutical compositions can be part of a kit for simultaneous, separate, or sequential use.
  • The individual components of the combination of the present invention can be administered simultaneously or separately at different times during the course of therapy or concurrently in divided or single combination forms.
  • Therefore, the mGluR2 PAM/agonist compounds, in particular the compounds of Formula (I)/(I-A)/(I-B), and the SV2A ligand, individually or combined, may be formulated into various pharmaceutical compositions suitable for administration purposes. In these, a therapeutically effective amount of the particular compound, or of both two compounds, is combined with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. Pharmaceutical compositions may be prepared as medicaments to be administered orally, parenterally (including subcutaneously (s.c.), intramuscularly (i.m.), and intravenously (i.v.)), rectally, transdermally, bucally, or nasally. The pharmaceutical compositions may also be prepared to be administered directly to the nervous system by routes including, but not limited to, intracerebral, intraventricular, intracerebroventricular, intrathecal, intracisternal, intraspinal and/or peri-spinal route by delivery via intracranial or intravertebral needles and/or catheters with or without pump devices. Suitable compositions for oral administration include powders, granulates, aggregates, tablets, compressed or coated pills, dragees, sachets, hard or gelatin capsules, syrups and suspensions. Suitable compositions for parenteral administration include aqueous or non-aqueous solutions or emulsions, while for rectal administration suitable compositions for administration include suppositories with a hydrophilic or hydrophobic vehicle. For topical administration suitable transdermal delivery systems can be used and for nasal delivery suitable aerosol delivery systems can be used.
  • For example, in preparing the compositions for oral administration, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid compositions such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of solid compositions. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, such as solubilizers, emulsifiers or further auxiliaries may be added thereto. Injectable solutions may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of both. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations intended to be converted, shortly before use, to liquid form preparations such as powders for reconstitution. In the compositions suitable for percutaneous administration, the carrier optionally comprises a skin penetration enhancing agent and/or a wetting agent, optionally combined with suitable skin-compatible additives in minor proportions. The mGluR2 PAM/agonist compound, in particular the compound of Formula (I)/(I-A)/(I-B), or SV2A ligand, or combinations thereof, may also be administered via oral inhalation or insufflation by formulations suited for this type of administration such as a solution, a suspension or a dry powder. Suitable pharmaceutical compositions for administration in the form of aerosols or sprays are, for example, suspensions of the mGluR2 PAM/agonist compound, in particular of the compound of Formula (I)/(I-A)/(I-B), or SV2A ligand, or both, in a pharmaceutically acceptable liquid carrier, such as ethanol or water, or a mixture thereof. If required, the formulation can also additionally contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant. Such a preparation customarily contains the active compound in a concentration from approximately 0.1 to 50%, in particular from approximately 0.3 to 3% by weight.
  • The pharmaceutical compositions may contain the active ingredient mGluR2 PAM/agonist compound, in particular compound of Formula (I)/(I-A)/(I-B), or the SV2A ligand, or both combined in a concentration of about 0.1% to about 50%, or about 1% to about 30%, or about 3% to about 20%, or about 5% to about 20%, all percentages being by weight, wherein the total of all components in said pharmaceutical compositions does not exceed 100%. In the compositions containing both two compounds mGluR2 PAM/agonist compound, in particular compound of Formula (I)/(I-A)/(I-B), and SV2A ligand, the mGluR2 PAM/agonist compound, in particular the compound of Formula (I)/(I-A)/(I-B), is present in a concentration of about 0.1% to about 50%, or about 1% to about 30%, or about 3% to about 20%, or about 5% to about 20%; and the SV2A ligand is present in a concentration of about 3% to about 50%, or about 5% to about 50%, or about 10% to about 50%, or about 10% to about 40%, or about 10% to about 30%, wherein the total of all components in said pharmaceutical compositions does not exceed 100%.
  • The pharmaceutical compositions may be conveniently presented in unit dosage form for ease of administration and uniformity of dosage. Examples include tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof. Of interest are solid dosage forms for oral administration such as tablets or capsules.
  • The solid dosage forms in unit dose form may be packed in any known package, blister packs being preferred, in particular for tablets and capsules. Where the mGluR2 PAM/agonist compound, in particular the compound of Formula (I)/(I-A)/(I-B), and SV2A ligand are formulated separately, they could be packed in separate blisters, but one blister could as well comprise unit dose forms of the mGluR2 PAM/agonist compound, in particular of the compound of Formula (I)/(I-A)/(I-B), and of the SV2A ligand, for example one row with units of mGluR2 PAM/agonist compound, in particular of compound of Formula (I)/(I-A)/(I-B), and another with SV2A ligand. Other possibilities may be possible as well.
  • The combinations of this invention may be used to treat or prevent epilepsy and related disorders; neuropathic pain; migraine or resistant headache; and bipolar and related disorders; or they may be used as a neuroprotectant or to prevent epileptogenesis.
  • As used herein, the term “treatment” is intended to refer to all processes, wherein there may be a slowing, interrupting, arresting or stopping of the progression of a disease or an alleviation of symptoms, but does not necessarily indicate a total elimination of all symptoms
  • As used herein, unless otherwise noted, the terms “epilepsy and related disorders” or “epilepsy or related disorder” shall mean any disorder in which a subject (preferably a human adult, child or infant) experiences one or more seizures and/or tremors. Suitable examples include, but are not limited to, epilepsy (including, but not limited to, localization-related epilepsies, generalized epilepsies, epilepsies with both generalized and local seizures, and the like), partial-onset seizures with or without generalization, myoclonic seizures, primary generalized tonic-clonic seizures in particular in patients with idiopathic generalized epilepsy, seizures associated with Lennox-Gastaut syndrome, seizures as a complication of a disease or condition (such as seizures associated with encephalopathy, phenylketonuria, juvenile Gaucher's disease, Lundborg's progressive myoclonic epilepsy, stroke, head trauma, stress, hormonal changes, drug use or withdrawal, alcohol use or withdrawal, sleep deprivation, fever, infection, and the like), status epilepticus (convulsive or non convulsive), essential tremor, restless limb syndrome, and the like. Preferably, the disorder is selected from epilepsy (regardless of type, underlying cause or origin), essential tremor or restless limb syndrome. More preferably, the disorder is epilepsy (regardless of type, underlying cause or origin) or essential tremor. A particular example of epilepsy is refractory epilepsy, also referred to as treatment or therapy resistant epilepsy. This term is often used when patients have failed three or more anti-epileptic drugs (AEDs). Refractory epilepsy also includes refractory partial epilepsy and refractory generalized epilepsy (including idiopathic or symptomatic).
  • As used herein, the term “neuropathic pain” includes pain resulting from chronic or debilitating conditions or disorders. The chronic or debilitating conditions or disorders which can lead to neuropathic pain include, but are not limited to, painful diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, post-stroke pain, multiple sclerosis-associated pain, neuropathies-associated pain such as in idiopathic or post-traumatic neuropathy and mononeuritis, HIV-associated neuropathic pain, cancer-associated neuropathic pain, carpal tunnel-associated neuropathic pain, spinal cord injury-associated pain, complex regional pain syndrome, fibromyalgia-associated neuropathic pain, lumbar and cervical pain, reflex sympathic dystrophy, phantom limb syndrome and other chronic and debilitating condition-associated pain syndromes.
  • As used herein, the term “migraine” shall mean a chronic, episodic and debilitating clinical condition that is diagnosed by the presence of moderate to severe pulsating unilateral headaches lasting between 4 and 72 h, which includes migraine without aura and migraine with aura. As used herein, “migraine without aura” shall mean at least five attacks fulfilling the following criteria: (a) the headache attack lasts 4-72 hours with the headache having at least two of the following features: unilateral location, pulsating quality, moderate or severe intensity with direct influence on activities of daily living, and aggravation by walking up stairs or similar routines: and (b) during the headache at least one of the following occurs: nausea and/or vomiting, and photophobia and phonophobia. As used herein, “migraine with aura” shall mean at least two attacks accompanied by at least 3 of the 4 following features: (a) one or more fully reversible aura symptoms: (b) at least one aura symptom which develops gradually over more than four minutes or two or more symptoms which occur in succession; (c) no aura symptom which lasts more than 60 minutes; (d) a headache occurs prior to, simultaneously with or following the aura, with a free interval between aura and headache of less than about 60 minutes.
  • As used herein, the term “bipolar and related disorders” shall include bipolar disorder I (e.g. single manic episode, most recent episode hypomanic, most recent episode manic, most recent episode mixed, most recent episode depressed and most recent episode unspecified), bipolar disorder II, cyclothymic disorder and bipolar disorder not otherwise specified (as these terms are defined by their diagnostic criteria, in the Diagnostic and Statistical manual of Mental Disorders 4th Edition, Text Revision, American Psychiatric Association, 2000 (DSM-IV-TR) or in the 5th Edition, Text Revision, American Psychiatric Association, 2013 (DSM-5™). Preferably, the bipolar disorder is characterized by depressive and manic (or hypomanic) phases, wherein the phases cycle. Preferably, the bipolar disorder is bipolar disorder I or bipolar disorder II. As used herein “mania” shall include mania or a manic mood phase, regardless of underlying cause. As used herein, the term “bipolar mania” is intended to mean the mania associated with, characteristic of or symptomatic of a bipolar disorder. Thus, methods of treating bipolar mania of the present invention are directed to methods which treat the mania and/or manic phase of bipolar disorders. As used herein, the term “bipolar depression” is intended to mean the depression associated with, characteristic of or symptomatic of a bipolar disorder. Thus, methods of treating bipolar depression of the present invention are directed to methods which treat the depression and/or depressed phase of bipolar disorders. As used herein, unless otherwise noted the terms “cycling” or “bipolar cycling” shall refer to the alteration of mood between depressive and manic phases characteristic of bipolar disorders. Thus, the present invention includes methods for the stabilization of said cycling, including, but not limited to, decreasing the frequency of the cycling and/or decreasing the magnitude of the manic and/or depressive phases.
  • Thus, in an embodiment, the pharmaceutical composition of the present invention may be used for mood stabilization, in particular mood stabilization for manic depression.
  • As used herein, the term “epileptogenesis” refers to the gradual process by which epilepsy develops. This process may occur following brain insults or a variety of conditions, including neurodegenerative diseases, traumatic brain injury, stroke, brain tumor, infections of the central nervous system, and status epilepticus; or it may occur following gene mutations.
  • As used herein, the term “anxiety” refers in particular to generalized anxiety disorder.
  • As used herein, the term “about” has its conventional meaning. In particular embodiments, when in relation to a numerical value, it may be interpreted to mean the numerical value ±10%, or ±5%, or ±2%, or ±1%, or ±0.5%, or ±0.1%. In other embodiments, the precise value is meant, i.e. by leaving out the word “about”.
  • “And/or” means that each one or both or all of the components or features of a list are possible variants, especially two or more thereof in an alternative or cumulative way.
  • As used herein, the term “a”, “an”, “the” and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.
    • EXAMPLES
  • The following Examples are set forth to aid in the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter.
  • A) Compounds of Formula (I-B)—Chemistry and In Vitro Testing
  • Several methods for preparing the compounds of Formula (I-B) of this invention are illustrated in the following Examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification.
  • Hereinafter, “aq.” means aqueous; “DCE” means 1,2-dichloroethane, “DCM” means dichloromethane; “DIPE” means diisopropylether; “DIPEA” means N,N-diisopropylethylamine; “DMF” means N,N-dimethylformamide; “ES” means electrospray; “Et3N” means triethylamine; “Et2O” means diethyl ether; “EtOAc” means ethyl acetate; “h” means hours; “HPLC” means high performance liquid chromatography; “HRMS” means high-resolution mass spectra/spectrometry; “1” or “L” means liter; “LRMS” means low-resolution mass spectrometry/spectra; “MeOH” means methanol; “min” means minute(s); “mp” means melting point; “Pd(PPh3)4” means tetrakis(triphenylphosphine)palladium(0); “RP” means reverse phase; “r.t.” means room temperature; “s” means seconds; “sat.” means saturated; “SFC” means supercritical fluid chromatography; “sol.” means solution; “THF” means tetrahydrofuran.
  • Microwave assisted reactions were performed in a single-mode reactor: Initiator™ Sixty EXP microwave reactor (Biotage AB), or in a multimode reactor: MicroSYNTH Labstation (Milestone, Inc.).
  • Thin layer chromatography (TLC) was carried out on silica gel 60 F254 plates (Merck) using reagent grade solvents. Open column chromatography was performed on silica gel, particle size 60 Å, mesh=230-400 (Merck) using standard techniques. Automated flash column chromatography was performed using ready-to-connect cartridges from Merck, on irregular silica gel, particle size 15-40 μm (normal phase disposable flash columns) on a SPOT or LAFLASH system from Armen Instrument.
  • The absolute stereochemical configuration for some of the compounds was determined using vibrational circular dichroism (VCD). They were measured on a Bruker Equinox 55 equipped with a PMA 37, in a KBr liquid cell using CD2Cl2 as solvent (PEM: 1350 cm-1, LIA: 1 mV, resolution: 4 cm−1). A description on the use of VCD for the determination of absolute configuration can be found in Dyatkin A. B. et. al, Chirality, 14:215-219 (2002).
  • Whenever the notation “RS” is indicated herein, it denotes that the compound is a racemic mixture, unless otherwise indicated. The stereochemical configuration for some compounds has been designated “R” or “S” when the mixture was separated; for some compounds, the stereochemical configuration has been designated as “*R” or “*S” when the absolute stereochemistry is undetermined although the compound itself has been isolated as a single stereoisomer and is enantiomerically pure. The enantiomeric excess of compounds reported herein was determined by analysis of the racemic mixture by supercritical fluid chromatography (SFC) followed by SFC comparison of the separated enantiomer(s).
    • Preparation of Intermediates Description 1—Intermediate 1
  • Figure US20220143141A1-20220512-C00052
  • Cyclopropylacetic acid ([CAS 5239-82-7], 50 g, 500 mmol) was dissolved in CH2Cl2 (300 mL) then SOCl2 (100 mL) was added. The reaction mixture was stirred at 60° C. for 2 h and then the solvent was evaporated to yield intermediate 1 (53 g, 90%), which was used without further purification.
    • Description 2—Intermediate 2
  • Figure US20220143141A1-20220512-C00053
  • To a solution of 2,4-dichloro-3-iodopyridine ([CAS 343781-36-2], 290 g, 1058 mmol) in DMF (1.7 L) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate ([CAS 680-15-9], 403 g, 2098 mmol) and CuI (403 g, 2.13 mol), the reaction was then heated at 100° C. for 5 h.
  • The reaction was cooled and filtered. The filtrate was diluted with H2O and extracted with Et2O and washed with a NH3 solution. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to yield intermediate 2 (160 g), which was used without further purification.
    • Description 3—Intermediate 3
  • Figure US20220143141A1-20220512-C00054
  • To a solution of NaH (60% in oil, 24 g, 600 mmol) in DMF (2 L) at 0° C. was added benzyl alcohol (35 g, 325 mmol), then the reaction was stirred for 2 min. Intermediate 2 (160 mg, 741 mmol) was added in one portion, and stirred at 0° C. for 1 h. The reaction was diluted by the addition of H2O and extracted with Et2O. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography over silica gel (eluent: petroleum ether/EtOAc=20/1). The pure fractions were collected and the solvent was evaporated to yield intermediate 3 (100 g, 38%).
    • Description 4—Intermediate 4
  • Figure US20220143141A1-20220512-C00055
  • To a solution of intermediate 3 (100 g, 277 mmol) in 1,4-dioxane (1.5 L) was added NH2NH2 hydrate (85% solution in water, 300 g, 9.11 mol), the reaction was then heated in sealed tube at 160° C. for 2 h. The mixture was concentrated in vacuo, dissolved in DCM, washed with NaHCO3. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to yield intermediate 4 (90 g, 90%), which was used without further purification.
    • Description 5—Intermediate 5
  • Figure US20220143141A1-20220512-C00056
  • To a solution of intermediate 4 (90 g, 318 mmol) in CH2Cl2 (1.5 L) was added triethylamine (64.3 g, 636 mmol), the mixture was cooled to 0° C., then a solution of intermediate 1 (53 g, 449 mmol) in CH2Cl2 was added. The solution was stirred at RT for 1 h. The reaction mixture was washed with a sat. aq. sol. of NaHCO3, and extracted with CH2Cl2. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to yield intermediate 5 (104.4 g, 90%).
  • The following intermediates were synthesized following a synthetic sequence analogous to that reported in Description 5 (D51.
  • Intermediate Acid chloride Conditions
    Figure US20220143141A1-20220512-C00057
         		propionyl chloride ([CAS 79-03-8]) Addition run at RT.
    Intermediate 6
    Figure US20220143141A1-20220512-C00058
         		cyclobutaneacetyl chloride ([CAS 59543-38-3]) Conditions as in D5.
    Intermediate 7
    Figure US20220143141A1-20220512-C00059
         		2-ethoxy-acetyl chloride ([CAS 14077-58-8]) Conditions as in D5.
    Intermediate 8
    Figure US20220143141A1-20220512-C00060
         		butyryl chloride ([CAS 141-75-3]) Conditions as in D5.
    Intermediate 25
    • Description 6 (a) Intermediate 9
  • Figure US20220143141A1-20220512-C00061
  • To a solution of intermediate 5 (101 g, 277 mmol) in CH3CN (1.2 L) were added phosphorus(V) oxychloride (84.7 g, 553 mmol) and N,N-diisopropylethylamine (71.3 g, 553 mmol). The reaction mixture was stirred at 90° C. for 38 h. The reaction was then diluted with DCM and washed with a Na2CO3 solution. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography over silica gel (eluent: petroleum ether/EtOAc=4/1). The pure fractions were collected and the solvent was evaporated to yield intermediate 9 (31.39 g, 41%).
    • (b) Intermediate 10
  • Figure US20220143141A1-20220512-C00062
  • The reaction was performed in 4 batches then combined for work up and purification. To a solution of intermediate 6 (7 g, 20.6 mmol) in DCE (50 mL), was added N,N-diisopropylethylamine (3.96 mL, 22.69 mmol) and then phosphorus oxychloride (2.12 mL, 22.69 mmol) and the reaction mixture was heated in a microwave at 150° C. for 5 min. Then DCM was added and the organic layer was washed with a sat. sol. of NaHCO3, dried (Na2SO4) and concentrated in vacuo to afford the desired compound, which was purified by column chromatography (gradient elution: DCM 100% to MeOH.NH 3 2% in DCM) to yield intermediate 10 (2.5 g, 49%).
  • The following intermediates were synthesized following a synthetic sequence analogous to that reported in Description 6(a) or (b).
  • Intermediate Starting material Conditions
    Figure US20220143141A1-20220512-C00063
         		Intermediate 7 Reaction performed as in (a) but in CH3CN. After the reaction was complete, the reaction mixture was poured into ice/water then washed with NaHCO3 sat. sol. And extracted with DCM, dried (Na2SO4), filtered and concentrated. Purification was performed in Spot (Si cartridge, eluent DCM/EtOAc up to 10-20%).
    Figure US20220143141A1-20220512-C00064
         		Intermediate 8 Reaction performed as in (b). Purification by flash column chromatography (silica; EtOAc in DCM 0/100 to 40/60).
    Figure US20220143141A1-20220512-C00065
         		Intermediate 25 Reaction performed as in (a). Purification by flash column chromatography (silica; MeOH in CH2Cl2, from 0/100 to 4/96).
    • Description 7—Intermediate 13
  • Figure US20220143141A1-20220512-C00066
  • (Ph3P)4Pd (2.096 g, 1.81 mmol) was added to a stirred solution of intermediate 9 (10 g, 36.28 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxoborolane ([CAS 75927-49-0], 7.77 mL, 43.53 mmol) in deoxygenated dioxane (30 mL) and a deoxygenated NaHCO3 saturated solution (30 mL) under nitrogen. The mixture was stirred at 100° C. for 18 h. The mixture was diluted with EtOAc/water and filtered through a pad of diatomaceous earth. The filtrate was treated with brine and extracted with EtOAc. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in CH2Cl2 0/100 to 5/95). The desired fractions were collected and concentrated in vacuo to yield intermediate 13 (6.08, 63%) as a yellow solid.
  • The following intermediates were synthesized following a synthetic sequence analogous to that reported in Description 7.
  • Intermediate Starting material Conditions
    Figure US20220143141A1-20220512-C00067
         		Intermediate 10 Reaction performed at 150° C. Purification by flash column chromatography (silica; 7N solution of ammonia in methanol in DCM 0/100 to 1/9).
    Figure US20220143141A1-20220512-C00068
         		Intermediate 11 Extraction with DCM, purification by flash column chromatography (silica; MeOH in DCM 4/96).
    Figure US20220143141A1-20220512-C00069
         		Intermediate 12 Purification by flash column chromatography (silica; EtOAc in DCM 0/100 to 10/90).
    Figure US20220143141A1-20220512-C00070
         		Intermediate 26 Reaction mixture performed at 150° C. in microwave. Purification by flash column chromatography (silica; EtOAc in DCM 0/100 to 10/90).
    • Description 8 (a) Intermediate 17
  • Figure US20220143141A1-20220512-C00071
  • Osmium tetraoxide (2.5% in t-BuOH, 10.103 mL, 0.781 mmol) and then, sodium periodate 12.53 g, 58.58 mmol) in water (48.5 mL) were added to a suspension of Intermediate 13 (6.08 g, 20.02 mmol) in dioxane (192 mL). The mixture was stirred at room temperature for 2 h.
  • The mixture was treated with water and EtOAc and it was filtered off through a pad of diatomaceous earth. The filtrate was extracted with EtOAc. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was washed with Et2O and it was filtered and dried to yield intermediate 17 (4.25 g, 79%) as a brown solid.
    • (b) Intermediate 18
  • Figure US20220143141A1-20220512-C00072
  • A suspension of sodium periodate (5.04 g, 23.54 mmol) in distilled water (19 mL) was added to a stirred solution of osmium tetraoxide (2.5% in t-BuOH, 4.06 mL, 0.31 mmol) and intermediate 14 (2.08 g, 7.85 mmol) in dioxane (75 mL). The mixture was stirred at room temperature for 150 min, and then the mixture was treated with sat NaHCO3 and brine, and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The product was triturated with Et2O and filtered in vacuo, and finally put in desiccator at 50° C. for 18 h, to yield intermediate 18 (1.6 g, 80%) as a brown solid.
  • The following intermediates were synthesized following a synthetic sequence analogous to that reported in Description 8.
  • Intermediate Starting material Conditions
    Figure US20220143141A1-20220512-C00073
         		Intermediate 15 Procedure as in (a).
    Figure US20220143141A1-20220512-C00074
         		Intermediate 16 Procedure as in (a).
    Figure US20220143141A1-20220512-C00075
         		Intermediate 27 Procedure as in (a), order of addition: osmium tetroxide was added to a stirred solution of intermediate 27 in 1,4-dioxane, then a suspension of sodium periodate in water was added and the reaction mixture was stirred for 2 h at RT. No filtration through a pad of diatomaceous earth.
    • Description 9 (a) Intermediates 21a, 21b and 21c
  • Figure US20220143141A1-20220512-C00076
  • Methylmagnesium bromide (1.4 M in THF, 12.40 mL, 17.37 mmol) was added dropwise to a stirred suspension of intermediate 17 (4.25 g, 15.79 mmol) in THY (281.07 mL) at −20° C. under N2 atmosphere. The mixture was stirred at −20° C. for 45 minutes. The crude was treated with a sat. sol. of NH4Cl and extracted with EtOAc. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 4/96). The desired fractions were collected and concentrated in vacuo to yield intermediate 21a (racemic mixture) (2.96 g, 66%). Intermediate 21a (1.82 g) was purified by chiral SFC: [Stationary phase: CHIRALPAK AD-H (5 μm 250×20 mm), Mobile phase: 80% CO2, 20% EtOH] yielding 21b (R-enantiomer) (0.453 g, 10%) as a pale grey solid and intermediate 21c (S-enantiomer) (0.439 g, 10%).
    • (b) Intermediate 22
  • Figure US20220143141A1-20220512-C00077
  • Methylmagnesium bromide (1.4 M in THF, 3.97 mL, 5.56 mmol) was added dropwise to a stirred suspension of intermediate 18 (1.23 g, 5.06 mmol) in THY (90 mL) at −20° C. under N2 atmosphere. The mixture was stirred at −20° C. for 45 minutes. The crude was treated with a sat. sol. of NH4Cl and extracted with EtOAc. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 4/96). The desired fractions were collected and concentrated in vacuo. The residue thus obtained was triturated with Et2O to yield intermediate 22 (620 mg, 35%) as a pale yellow solid. The following intermediates were synthesized following a synthetic sequence analogous to that reported in Description 9.
  • Intermediate Starting material Conditions
    Figure US20220143141A1-20220512-C00078
         		Intermediate 19 Procedure (b).
    Figure US20220143141A1-20220512-C00079
         		Intermediate 20 Procedure (b).
    Figure US20220143141A1-20220512-C00080
         		Intermediate 28 Procedure (b).
  • Intermediate 24a was further separated into Intermediate 24b and Intermediate 24c:
  •
    Figure US20220143141A1-20220512-C00081
         		Intermediate 24b
    Figure US20220143141A1-20220512-C00082
         		Intermediate 24c
    Chiral SFC conditions: Stationary phase Chiralpak AD-H 5 μm
    250*30 mm; Mobile phase: 80% CO2, 15% EtOH
    • Preparation of the Final Compounds of Formula (I-B) Example 1 (a) Synthesis of Compounds 4-b, 6-b and 5-b
  • Figure US20220143141A1-20220512-C00083
  • DIAD (2.07 mL, 10.52 mmol) was added dropwise to a stirred solution of intermediate 21a (2 g, 7.01 mmol), 2,4-difluorophenol (1.00 mL, 10.52 mmol) and triphenylphosphine (2.76 g, 10.52 mmol) in THF (74.18 mL) at 0° C. and under nitrogen atmosphere. The mixture was stirred at 100° C. for 10 minutes under microwave irradiation. The mixture was diluted with EtOAc and washed with a sat. sol. of NaHCO3. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 97/3). The desired fractions were collected and concentrated in vacuo. The residue was triturated with DIPE to give compound 4-b (1.46 g, 52%) as a white solid, which was purified by chiral SFC [Stationary phase: Chiralpak AD (5 μm 250*30 mm, Mobile phase: 85% CO2, 15% iPrOH)], yielding compound 6-b (0.659 g, 24%) and compound 5-b (0.693 g, 25%).
    • (b) Alternative Synthesis of Compound 6-b
  • Figure US20220143141A1-20220512-C00084
  • DIAD (31.06 μL, 0.16 mmol) was added dropwise to a stirred solution of intermediate 21b (30 mg, 0.11 mmol), 2,4-difluorophenol (15.07 μL, 0.16 mmol) and triphenylphosphine (41.38 mg, 0.16 mmol) in THF (1.11 mL) at 0° C. and under nitrogen atmosphere. The mixture was stirred at 100° C. for 10 minutes under microwave irradiation. The mixture was diluted with EtOAc and washed with a sat. sol. of NaHCO3. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 97/3). The desired fractions were collected and concentrated in vacuo. The residue was triturated with DIPE to give compound 6-b (40 mg, 96%) as a white solid.
    • (c) Synthesis of Compound 6-b Hydrochloride Salt (.HCl)
  • DIAD (207.06 μL, 1.05 mmol) was added dropwise to a stirred solution of intermediate 21b (200 mg, 0.70 mmol), 2,4-difluorophenol (100.45 μL, 1.05 mmol) and triphenylphosphine (275.84 mg, 1.0516 mmol) in THF (4 mL) at 0° C. and under nitrogen atmosphere. The mixture was stirred at 100° C. for 15 minutes under microwave irradiation. The mixture was diluted with EtOAc and washed with a sat. sol. of NaHCO3. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by RP HPLC (Stationary phase: C18)(Bridge 30×100 mm 5 μm, Mobile phase: Gradient from 60% 0.1% NH4CO3H/NH4OH pH 9 solution in Water, 40% CH3CN to 43% 0.1% NH4CO3H/NH4OH pH 9 solution in Water, 57% CH3CN), yielding a white solid residue that was dissolved in Et2O (8 mL) and 1,4-dioxane (0.5 mL). To the solution thus obtained HCl (4M in dioxane, 200 μL) was added dropwise. The white solid precipitate was filtered, washed with Et2O, dried (Na2SO4) and evaporated under vacuum. The white residue thus obtained was triturated with Et2O to give compound 6-b .HCl (110 mg, 36%) as a white solid.
  • The following compounds were synthesized following a synthetic sequence analogous to that reported in Example 1(b), starting from intermediate 21b.
  • Figure US20220143141A1-20220512-C00085
    Co. No.
    Figure US20220143141A1-20220512-C00086
     9-b
    Figure US20220143141A1-20220512-C00087
    10-b
    Figure US20220143141A1-20220512-C00088
    11-b
    Figure US20220143141A1-20220512-C00089
    12-b
    Figure US20220143141A1-20220512-C00090
    13-b
    Figure US20220143141A1-20220512-C00091
    14-b
    Figure US20220143141A1-20220512-C00092
    • Example 2 Synthesis of Compound 7-b
  • Figure US20220143141A1-20220512-C00093
  • Procedure (a): DIAD (31.06 μL, 0.158 mmol) was added dropwise to a stirred solution of intermediate 21b (30 mg, 0.105 mmol), 3,5-difluorophenol (20.52 mg, 0.158 mmol) and triphenylphosphine (41.38 mg, 0.158 mmol) in THF (1.113 mL) at 0° C. and under nitrogen atmosphere. The mixture was stirred at 100° C. for 10 minutes under microwave irradiation. The mixture was diluted with EtOAc and washed with a sat. sol. of NaHCO3. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 96/4). The desired fractions were collected and concentrated in vacuo. The residue was triturated with DIPE to give compound 7-b (21 mg, 50%) as a white solid.
  • Procedure (b): Alternatively, compound 7 was also synthesized following a synthetic sequence analogous to that reported in Example 1(b), starting from intermediate 21b.
    • Example 3 Synthesis of Compound 8-b
  • Figure US20220143141A1-20220512-C00094
  • Procedure (a): DIAD (31.06 μL, 0.158 mmol) was added dropwise to a stirred solution of intermediate 21b (30 mg, 0.105 mmol), 3,4-difluorophenol (20.52 mg, 0.158 mmol) and triphenylphosphine (41.38 mg, 0.158 mmol) in THF (1.11 mL) at 0° C. and under nitrogen atmosphere. The mixture was stirred at 100° C. for 10 minutes under microwave irradiation. The mixture was diluted with EtOAc and washed with a sat. sol. of NaHCO3. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 96/4). The desired fractions were collected and concentrated in vacuo. The residue was triturated with DIPE to give compound 8-b (10.6 mg, 25%) as a white solid.
  • Procedure (b): Alternatively, compound 8-b was also synthesized following a synthetic sequence analogous to that reported in Example 1(b), starting from intermediate 21b.
    • Example 4 Synthesis of Compound 15-b
  • Figure US20220143141A1-20220512-C00095
  • Procedure (a): DIAD (155.3 μL, 0.789 mmol) was added dropwise to a stirred solution of intermediate 21b (150 mg, 0.526 mmol), 2,4,6-trifluorophenol (116.8 mg, 0.789 mol) and triphenylphosphine (206.88 mg, 0.789 mmol) in THF (5.56 mL) at 0° C. and under nitrogen atmosphere. The mixture was stirred at 100° C. for 10 minutes under microwave. The mixture was diluted with DCM and washed with a sat. sol. of NaHCO3. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo, then purified by flash column chromatography (silica; MeOH/NH3 7 N in DCM 0/100 to 90/10). The desired fractions were collected and concentrated in vacuo. The was purified by RP HPLC (Stationary phase: C18 XBridge 30×100 mm 5 μm, Mobile phase: Gradient from 54% 0.1% NH4CO3H/NH4OH pH 9 solution in Water, 46% CH3CN to 64% 0.1% NH4CO3H/NH4OH pH 9 solution in Water, 36% CH3CN) yielding a colourless oil that was crystallized upon standing (2 days). The solid was triturated with heptane to give compound 15-b (129.8 mg, 59%) as a white solid. Procedure (b): Alternatively, compound 15-b was also synthesized following a synthetic sequence analogous to that reported in Example 1(b), starting from intermediate 21b.
    • Example 5 Synthesis of Compounds 1-b, 2-b and 3-b
  • Figure US20220143141A1-20220512-C00096
  • Compounds 1-b, 2-b and 3-b were synthesized following the procedure described in Example 1(a). Thus, reaction of DIAD (500.05 μL, 2.54 mmol), intermediate 21a (483 mg, 1.69 mmol), 4-fluorophenol (227.77 mg, 2.03 mmol) and triphenylphosphine (666.14 mg, 2.54 mmol) in THF (17.91 mL) as described in Example 1(a) yielded a residue that was purified by flash column chromatography (silica; EtOAc in DCM 0/100 to 90/10). The desired fractions were collected and concentrated in vacuo. The resulting residue was triturated with DIPE to yield compound 1-b (320 mg, 50%) as a white solid, which was purified by chiral SFC [Stationary phase: Chiralpak AD (5 μm 250*30 mm, Mobile phase: 77% CO2, 23% MeOH)], yielding compound 2-b (131 mg, 20%) and compound 3-b (129 mg, 20%) as white solids.
    • Example 6 Synthesis of Compounds 24-b, 26-b, and 27-b
  • Figure US20220143141A1-20220512-C00097
  • Compounds 24-b, 26-b and 27-b were synthesized following the procedure described in Example 1(a). Thus, reaction of DIAD (364.57 μL, 1.85 mmol), intermediate 22 (320 mg, 1.23 mmol), 2,4-difluorophenol (176.86 μL, 1.85 mmol) and triphenylphosphine (485.67 mg, 1.85 mmol) in THF (13.06 mL) as described in Example 1(a) yielded a residue that was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 96/4). The desired fractions were collected and concentrated in vacuo to yield a colourless oil that crystallized with DIPE to give compound 24 as a white solid, which was purified by RP HPLC (Stationary phase: C18 XBridge 30×100 mm 5 μm; mobile phase: Gradient from 54% 0.1% NH4CO3H/NH4OH pH 9 solution in Water, 46% CH3CN to 64% 0.1% NH4CO3H/NH4OH pH 9 solution in Water, 36% CH3CN) yielding a colourless oil that was crystallized upon trituration with heptane to give 240 mg (52%) of compound 24-b as a white solid, which was then purified by chiral SFC (Stationary phase: CHIRALPAK AD-H 5 μm 250×20 mm; mobile phase: 85% CO2, 15% iPOH (0.3% iPrNH2)), yielding compound 26-b (103 mg, 22%) and compound 27-b (107 mg, 23%).
  • The following compounds were obtained following a synthetic sequence similar to that reported in Example 1(a).
  •
    Figure US20220143141A1-20220512-C00098
         		Compound 25-b
    Figure US20220143141A1-20220512-C00099
         		Compound 28-b
    Figure US20220143141A1-20220512-C00100
         		Compound 29-b
    Starting material: Intermediate 22
    Chiral SFC conditions: Stationary phase: Chiralpak AD-H 5 μm
    250 × 20 mm); Mobile phase: 85% CO2, 15% mixture of EtOH/iPrOH
    50/50 v/v (+0.3% iPrNH2)
    Figure US20220143141A1-20220512-C00101
         		Compound 16-b
    Figure US20220143141A1-20220512-C00102
         		Compound 17-b
    Figure US20220143141A1-20220512-C00103
         		Compound 18-b
    Starting material: Intermediate 23
    Chiral SFC conditions: Stationary phase: Chiralpak AD-H (5 μm
    250*30 mm); Mobile phase: 80% CO2, 20% mixture MeOH/iPrOH
    50/50 v/v (+0.3% iPrNH2)
  • The following compounds were synthesized following a synthetic sequence as reported in Example 1(b), starting from the indicated intermediates.
  •
    Figure US20220143141A1-20220512-C00104
    Figure US20220143141A1-20220512-C00105
    Figure US20220143141A1-20220512-C00106
    Figure US20220143141A1-20220512-C00107
    Figure US20220143141A1-20220512-C00108
    Figure US20220143141A1-20220512-C00109
    Figure US20220143141A1-20220512-C00110
    Figure US20220143141A1-20220512-C00111
    Starting material: Intermediate 30
    Chiral SFC conditions: Stationary phase: Chiralpak AD-H 5 μm 250 × 20 mm);
    Mobile phase: 85% CO2, 15% iPrOH.
  • Table A below lists additional compounds of Formula (I-B) which were prepared by analogy to the above examples (Exp. no.).
  • TABLE A
    Example compounds according to Formula (I-B).
    # indicates that the experimental procedure is described in the examples.
    Figure US20220143141A1-20220512-C00112
    Co.
    no. Exp no. R1 Ar Stereo-chem.
    1-b E5#
    Figure US20220143141A1-20220512-C00113
    Figure US20220143141A1-20220512-C00114
         		RS
    2-b E5#
    Figure US20220143141A1-20220512-C00115
    Figure US20220143141A1-20220512-C00116
         		*R
    3-b E5#
    Figure US20220143141A1-20220512-C00117
    Figure US20220143141A1-20220512-C00118
         		*S
    4-b E1#
    Figure US20220143141A1-20220512-C00119
    Figure US20220143141A1-20220512-C00120
         		RS
    5-b E1#
    Figure US20220143141A1-20220512-C00121
    Figure US20220143141A1-20220512-C00122
         		R
    6-b   6- b•HCl E1(a) and (b)# E1(c)#
    Figure US20220143141A1-20220512-C00123
    Figure US20220143141A1-20220512-C00124
         		S
    7-b E2#
    Figure US20220143141A1-20220512-C00125
    Figure US20220143141A1-20220512-C00126
         		S
    8-b E3#
    Figure US20220143141A1-20220512-C00127
    Figure US20220143141A1-20220512-C00128
         		S
    9-b E1(b)
    Figure US20220143141A1-20220512-C00129
    Figure US20220143141A1-20220512-C00130
         		S
    10-b E1(b)
    Figure US20220143141A1-20220512-C00131
    Figure US20220143141A1-20220512-C00132
         		S
    11-b E1(b)
    Figure US20220143141A1-20220512-C00133
    Figure US20220143141A1-20220512-C00134
         		S
    12-b E1(b)
    Figure US20220143141A1-20220512-C00135
    Figure US20220143141A1-20220512-C00136
         		S
    13-b E1(b)
    Figure US20220143141A1-20220512-C00137
    Figure US20220143141A1-20220512-C00138
         		S
    14-b E1(b)
    Figure US20220143141A1-20220512-C00139
    Figure US20220143141A1-20220512-C00140
         		S
    15-b E4#
    Figure US20220143141A1-20220512-C00141
    Figure US20220143141A1-20220512-C00142
         		S
    16-b E1(a)
    Figure US20220143141A1-20220512-C00143
    Figure US20220143141A1-20220512-C00144
         		RS
    17-b E1(a)
    Figure US20220143141A1-20220512-C00145
    Figure US20220143141A1-20220512-C00146
         		*R
    18-b E1(a)
    Figure US20220143141A1-20220512-C00147
    Figure US20220143141A1-20220512-C00148
         		*S
    19-b E1(b)
    Figure US20220143141A1-20220512-C00149
    Figure US20220143141A1-20220512-C00150
         		RS
    20-b E1(b)
    Figure US20220143141A1-20220512-C00151
    Figure US20220143141A1-20220512-C00152
         		*R
    21-b E1(b)
    Figure US20220143141A1-20220512-C00153
    Figure US20220143141A1-20220512-C00154
         		*S
    22-b E1(b)
    Figure US20220143141A1-20220512-C00155
    Figure US20220143141A1-20220512-C00156
         		*R
    23-b E1(b)
    Figure US20220143141A1-20220512-C00157
    Figure US20220143141A1-20220512-C00158
         		*S
    24-b E6#
    Figure US20220143141A1-20220512-C00159
    Figure US20220143141A1-20220512-C00160
         		RS
    25-b E1(a)
    Figure US20220143141A1-20220512-C00161
    Figure US20220143141A1-20220512-C00162
         		RS
    26-b E6#
    Figure US20220143141A1-20220512-C00163
    Figure US20220143141A1-20220512-C00164
         		*R
    27-b E6#
    Figure US20220143141A1-20220512-C00165
    Figure US20220143141A1-20220512-C00166
         		*S
    28-b E1(a)
    Figure US20220143141A1-20220512-C00167
    Figure US20220143141A1-20220512-C00168
         		*R
    29-b E1(a)
    Figure US20220143141A1-20220512-C00169
    Figure US20220143141A1-20220512-C00170
         		*S
    30-b E1(b)
    Figure US20220143141A1-20220512-C00171
    Figure US20220143141A1-20220512-C00172
         		RS
    31-b E1(b)
    Figure US20220143141A1-20220512-C00173
    Figure US20220143141A1-20220512-C00174
         		*R
    32-b E1(b)
    Figure US20220143141A1-20220512-C00175
    Figure US20220143141A1-20220512-C00176
         		*S
    • Analytical Part Optical Rotations
  • Optical rotations were measured on a Perkin-Elmer 341 polarimeter with a sodium lamp and reported as follows: [α]° (λ, c g/100 ml, solvent, T° C.).
  • [α]λ T=(100α)/(l×c): where l is the path length in dm and c is the concentration in g/100 ml for a sample at a temperature T (° C.) and a wavelength λ (in nm). If the wavelength of light used is 589 nm (the sodium D line), then the symbol D might be used instead. The sign of the rotation (+ or −) should always be given. When using this equation the concentration and solvent are always provided in parentheses after the rotation. The rotation is reported using degrees and no units of concentration are given (it is assumed to be g/100 ml).
    • LCMS
  • For (LC)MS-characterization of the compounds of the present invention, the following methods were used.
    • General Procedure
  • The High Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below).
  • Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time . . . ) in order to obtain ions allowing the identification of the compound's nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software. Compounds are described by their experimental retention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H]+ (protonated molecule) and/or [M−H]− (deprotonated molecule). In case the compound was not directly ionizable the type of adduct is specified (i.e. [M+NH4]+, [M+HCOO]−, etc. . . . ). For molecules with multiple isotopic patterns (Br, Cl . . . ), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used. Hereinafter, “SQD” means Single Quadrupole Detector, “RT” room temperature, “BEH” bridged ethylsiloxane/silica hybrid, “HSS” High Strength Silica, “DAD” Diode Array Detector.
  • TABLE B
    LCMS Method codes (Flow expressed in mL/min; column temperature (T) in
    ° C.; Run time in minutes).
    Flow
    — Run LCMS
    Instrument Column Mobile phase Gradient Col T time Method
    Waters: Agilent: A: 95% From 95% 1 5 1
    Acquity ® Eclipse Plus CH3COONH4 A to 5% A —
    UPLC ®- C18 RRHD 6.5 mM + 5% in 4.6 min, 50
    DAD and (1.8 μm, 2.1 × 50 mm) CH3CN, B: CH3CN held for
    SQD 0.4 min
    Waters: Waters: A: 95% From 95%
    Acquity ® CSH ™ C18 CH3COONH4 A to 5% A 1 5 2
    UPLC ®- (1.7 μm, 6.5 mM + 5% in 4.6 min, —
    DAD and 2.1 × 50 mm) CH3CN, B: held for 50
    SQD CH3CN 0.4 min
    Waters: Waters: BEH A: 95% 84.2% A for 0.343 6.2 3
    Acquity ® C18 (1.7 μm, CH3COONH4 0.49 min, to —
    UPLC ®- 2.1 × 100 mm) 7 mM/5% 10.5% A in 40
    DAD and CH3CN, 2.18 min,
    Quattro B: CH3CN held for
    Micro ™ 1.94 min,
    back to
    84.2% A in
    0.73 min,
    held for
    0.73 min.
    Waters: Waters: A: 95% From 95% 1 9 4
    Acquity ® CSH ™ C18 CH3COONH4 A to5% A in —
    UPLC ®- (1.7 μm, 2.1 × 50 mm) 6.5 mM + 5% 7.8 min, held 50
    DAD and CH3CN, B: for 1.2 min
    SQD CH3CN
    • Melting Points
  • Values are peak values, and are obtained with experimental uncertainties that are commonly associated with this analytical method.
    • Mettler FP 81HT/FP90 Apparatus
  • For a number of compounds, melting points were determined in open capillary tubes on a FP 81HT/FP90 apparatus (Mettler-Toledo). Melting points were measured with a temperature gradient of 1, 3, 5 or 10° C./minute. Maximum temperature was 300° C. The melting point was read from a digital display.
  • TABLE C
    Physico-chemical data for some compounds,
    retention time (Rt) in min, [M + H] peak (protonated
    molecule), LCMS method and mp (melting point in ° C.).
    Co. Mp Rt LCMS
    no. (° C.) (min) [MH+] method Optical Rotation
     1-b 156.3 2.32 380 1
     2-b 176.9 2.93 380 3 −58.5° (589 nm, c 0.53
    w/v %, DMF, 20° C.)
     3-b 177.3 2.93 380 3 +59.4° (589 nm, c 0.52
    w/v %, DMF, 20° C.)
     4-b 121.7 2.41 398 1
     5-b 142 2.99 398.3 3 +95.7° (589 nm, c 0.69
    w/v %, DMF, 20° C.)
     6-b 142.4 2.99 398.2 3 −95.4° (589 nm, c 0.7
    w/v %, DMF, 20° C.)
     7-b 170.08 2.37 398 2 −55.7° (589 nm, c 0.96
    w/v %, DMF, 20° C.)
     8-b n.d. 2.32 398 2 n.d.
     9-b n.d. 2.32 398 2 n.d.
    10-b n.d. 2.25 398 2 n.d.
    11-b n.d. 2.28 398 2 n.d.
    12-b n.d. 2.16 410 2 n.d.
    13-b 144.1 2.68 410 2 n.d.
    14-b 161.7 2.51 394 2 n.d.
    15-b 80.3 2.37 416 2 −167.0° (589 nm, c
    0.55 w/v %, DMF,
    20° C.)
    16-b n.d. 2.50 412 2 n.d.
    17-b n.d. 3.12 412 3 n.d.
    18-b n.d. 3.12 412 3 n.d.
    19-b n.d. 2.39 402 2 n.d.
    20-b n.d. 2.3 402 2 n.d.
    21-b n.d. 3.36 402 n.d.
    22-b n.d. 2.35 420 2 n.d.
    23-b n.d. 2.35 420 2 n.d.
    24-b 135.7 2.05 372 2 n.d.
    25-b 138.3 2.13 390 2 n.d.
    26-b n.d. 2.80 372 3 −83.9° (589 nm, c 0.52
    w/v %, DMF, 25° C.)
    27-b n.d. 2.80 372 3 +92.1° (589 nm, c 0.55
    w/v %, DMF, 25° C.)
    28-b n.d. 2.85 390 3 −129.2° (589 nm, c 0.5
    w/v %, DMF, 25° C.)
    29-b n.d. 2.85 390 3 +137.3° (589 nm, c
    0.51 w/v %, DMF, 25° C.)
    30-b 130.6 2.29 386 2 n.d.
    31-b 127.85 2.29 386 2 −67.5° (589 nm, c 0.83
    w/v %, DMF, 20° C.)
    32-b 127.69 2.29 386 2 +89.5° (589 nm, c 0.83
    w/v %, DMF, 20° C.)
    (n.d. = not determined).
    • SFC-MS General Procedure
  • The SFC measurement was performed using Analytical system from Berger instrument comprising a FCM-1200 dual pump fluid control module for delivering carbon dioxide (CO2) and modifier, a CTC Analytics automatic liquid sampler, a TCM-20000 thermal control module for column heating from room temperature to 80° C. An Agilent 1100 UV photodiode array detector equipped with a high-pressure flow cell standing up to 400 bars was used. Flow from the column was split to a MS spectrometer. The MS detector was configured with an atmospheric pressure ionization source. The following ionization parameters for the Waters ZQ mass spectrophotometer are: corona: 9 μa, source temp: 140° C., cone: 30 V, probe temp 450° C., extractor 3 V, desolvatation gas 400 L/hr, cone gas 70 L/hr. Nitrogen was used as the nebulizer gas. Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system.
  • Method 1: In addition to the general procedure: The analytical chiral separation in SFC-MS was carried out on a CHIRALPAK AD DAICEL column (10 μm, 4.6×250 mm) at 35° C. with a flow rate of 3.0 ml/min. The mobile phase is 85% CO2, 15% iPrOH (+0.3% iPrNH2) hold 7 min in isocratic mode.
  • Method 2: In addition to the general procedure: The analytical chiral separation in SFC-MS was carried out on a CHIRALPAK AD DAICEL column (10 μm, 4.6×250 mm) at 35° C. with a flow rate of 3.0 ml/min. The mobile phase is 75% CO2, 15% iPrOH (+0.3% iPrNH2) hold 7 min in isocratic mode.
  • Method 3: In addition to the general procedure: The analytical chiral separation in SFC-MS was carried out on a CHIRALPAK AD DAICEL column (10 μm, 4.6×250 mm) at 35° C. with a flow rate of 3.0 ml/min. The mobile phase is 80% CO2, 10% Methanol+10% iPrOH (+0.3% iPrNH2) hold 7 min in isocratic mode.
  • TABLE D
    Analytical SFC data
    Co. Isomer Elution
    Nr. Rt [M + H]+ UV Area % Method Order*
     6-b 4.28 398 100 1 A
     5-b 5.98 398 100 1 B
     2-b 2.13 380 100 2 A
     3-b 2.97 380 100 2 B
    17-b 2.46 412 100 3 A
    18-b 3.12 412 100 3 B
    31-b 2.93 386 100 1 A
    32-b 3.81 386 100 1 B
    *A means the first isomer that elutes. B means the second isomer that elutes.
    Rt means retention time (in minutes), [M + H]+ means the protonated mass of the compound, method refers to the method used for SFC/MS analysis of enantiomerically pure compounds. The measurement was compared against the mixture.
    • Nuclear Magnetic Resonance (NMR)
  • For a number of compounds, 1H NMR spectra were recorded either on a Bruker DPX-400 or on a Bruker AV-500 spectrometer with standard pulse sequences, operating at 400 MHz and 500 MHz respectively. Chemical shifts (δ) are reported in parts per million (ppm) downfield from tetramethylsilane (TMS), which was used as internal standard.
  • Co. No. 6-b: 1H NMR (400 MHz, CDCl3) δ ppm 0.30-0.38 (m, 2H), 0.59-0.68 (m, 2H), 1.14-1.22 (m, 1H), 1.72 (d, J=6.5 Hz, 3H), 3.02-3.14 (m, 2H), 5.84 (q, J=6.3 Hz, 1H), 6.67-6.73 (m, 1H), 6.80-6.89 (m, 2H), 7.30 (d, J=7.4 Hz, 1H), 8.11 (d, J=7.4 Hz, 1H)
  • Co. No. 7-b: 1H NMR (400 MHz, CDCl3) δ ppm 0.30-0.39 (m, 2H), 0.59-0.68 (m, 2H), 1.11-1.23 (m, 1H), 1.70 (d, J=6.5 Hz, 3H), 3.01-3.14 (m, 2H), 5.83 (q, J=6.2 Hz, 1H), 6.35-6.45 (m, 3H), 7.13 (d, J=7.2 Hz, 1H), 8.08 (d, J=7.4 Hz, 1H)
  • Co. No. 8-b: 1H NMR (400 MHz, CDCl3) δ ppm 0.30-0.38 (m, 2H), 0.58-0.68 (m, 2H), 1.11-1.22 (m, 1H), 1.69 (d, J=6.2 Hz, 3H), 3.01-3.13 (m, 2H), 5.79 (q, J=6.2 Hz, 1H), 6.53 (dtd, J=9.2, 3.1, 3.1, 1.7 Hz, 1H), 6.72 (ddd, J=11.6, 6.5, 3.1 Hz, 1H), 6.95-7.04 (m, 1H), 7.15 (d, J=7.4 Hz, 1H), 8.07 (d, J=7.4 Hz, 1H)
  • Co. No. 15-b: 1H NMR (500 MHz, CDCl3) δ ppm 0.30-0.41 (m, 2H), 0.59-0.71 (m, 2H), 1.16-1.25 (m, 1H), 1.70 (d, J=6.4 Hz, 3H), 3.05-3.16 (m, 2H), 5.80 (q, J=6.4 Hz, 1H), 6.62-6.70 (m, 2H), 7.45 (d, J=7.5 Hz, 1H), 8.16 (d, J=7.2 Hz, 1H)
  • Co. No. 13-b: 1H NMR (500 MHz, CDCl3) δ ppm 0.27-0.39 (m, 2H), 0.58-0.67 (m, 2H), 1.12-1.21 (m, 1H), 1.73 (d, J=6.4 Hz, 3H), 2.22 (s, 3H), 3.06 (qd, J=15.4, 6.6 Hz, 2H), 5.92 (q, J=6.4 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 6.89 (dd, J=8.4, 1.4 Hz, 1H), 7.18 (d, J=1.7 Hz, 1H), 7.32 (d, J=7.2 Hz, 1H), 8.07 (d, J=7.2 Hz, 1H)
  • Co. No. 14-b: 1H NMR (500 MHz, CDCl3) δ ppm 0.28-0.39 (m, 2H), 0.57-0.69 (m, 2H), 1.12-1.21 (m, 1H), 1.70 (d, J=6.6 Hz, 3H), 2.31 (s, 3H), 3.01-3.12 (m, 2H), 5.79 (q, J=6.6 Hz, 1H), 6.55 (dd, J=9.0, 4.3 Hz, 1H), 6.69 (td, J=8.5, 3.0 Hz, 1H), 6.87 (dd, J=9.0, 2.9 Hz, 1H), 7.17 (d, J=7.5 Hz, 1H), 8.06 (d, J=7.2 Hz, 1H)
  • Co. No. 20-b: 1H NMR (500 MHz, CDCl3) δ ppm 1.22 (t, J=7.1 Hz, 3H), 1.72 (d, J=6.4 Hz, 3H), 3.58 (q, J=7.1 Hz, 2H), 5.03-5.10 (m, 2H), 5.84 (q, J=6.5 Hz, 1H), 6.67-6.74 (m, 1H), 6.81-6.88 (m, 2H), 7.34 (d, J=7.2 Hz, 1H), 8.40 (d, J=7.5 Hz, 1H)
  • Co. No. 22-b: 1H NMR (500 MHz, CDCl3) δ ppm 1.23 (t, J=6.9 Hz, 3H), 1.70 (d, J=6.4 Hz, 3H), 3.58 (q, J=7.0 Hz, 2H), 5.05-5.12 (m, 2H), 5.81 (q, J=6.6 Hz, 1H), 6.62-6.70 (m, 2H), 7.48 (d, J=7.5 Hz, 1H), 8.45 (d, J=7.2 Hz, 1H)
  • Co. No. 31-b: 1H NMR (400 MHz, CDCl3) δ ppm 1.07 (t, J=7.40 Hz, 3H) 1.72 (d, J=6.24 Hz, 3H) 1.92 (sxt, J=7.63 Hz, 2H) 2.98-3.14 (m, 2H) 5.84 (q, J=6.47 Hz, 1H) 6.65-6.74 (m, 1H) 6.78-6.89 (m, 2H) 7.29 (d, J=7.40 Hz, 1H) 8.02 (d, J=7.40 Hz, 1H).
    • In Vitro Testing of Compounds of Formula (I-B)
  • The compounds of Formula (I-B) provided in the present invention are positive allosteric modulators of mGluR2. These compounds appear to potentiate glutamate responses by binding to an allosteric site other than the glutamate binding site. The response of mGluR2 to a concentration of glutamate is increased when compounds of Formula (I-B) are present. Compounds of Formula (I-B) are expected to have their effect substantially at mGluR2 by virtue of their ability to enhance the function of the receptor. The effects of positive allosteric modulators tested at mGluR2 using the [35S]GTPγS binding assay method described below and which is suitable for the identification of such compounds, and more particularly the compounds according to Formula (I-B), are shown in Table E.
  • [35S]GTPγS Binding Assay
  • The [35S]GTPγS binding assay is a functional membrane-based assay used to study G-protein coupled receptor (GPCR) function whereby incorporation of a non-hydrolysable form of GTP, [35S]GTPγS (guanosine 5′-triphosphate, labelled with gamma-emitting 35S), is measured. The G-protein a subunit catalyzes the exchange of guanosine 5′-diphosphate (GDP) by guanosine triphosphate (GTP) and on activation of the GPCR by an agonist, [35S]GTPγS, becomes incorporated and cannot be cleaved to continue the exchange cycle (Harper (1998) Current Protocols in Pharmacology 2.6.1-10, John Wiley & Sons, Inc.). The amount of radioactive [35S]GTPγS incorporation is a direct measure of the activity of the G-protein and hence the activity of the agonist can be determined. mGlu2 receptors are shown to be preferentially coupled to Gαi-protein, a preferential coupling for this method, and hence it is widely used to study receptor activation of mGlu2 receptors both in recombinant cell lines and in tissues. Here we describe the use of the [35S]GTPγS binding assay using membranes from cells transfected with the human mGlu2 receptor and adapted from Schaffhauser et al. (Molecular Pharmacology, 2003, 4:798-810) for the detection of the positive allosteric modulation (PAM) properties of the compounds of this invention.
  • Membrane Preparation
  • CHO-cells were cultured to pre-confluence and stimulated with 5 mM butyrate for 24 h. Cells were then collected by scraping in PBS and cell suspension was centrifuged (10 min at 4000 RPM in benchtop centrifuge). Supernatant was discarded and pellet gently resuspended in 50 mM Tris-HCl, pH 7.4 by mixing with a vortex and pipetting up and down. The suspension was centrifuged at 16,000 RPM (Sorvall RC-5C plus rotor SS-34) for 10 minutes and the supernatant discarded. The pellet was homogenized in 5 mM Tris-HCl, pH 7.4 using an ultra-turrax homogenizer and centrifuged again (18,000 RPM, 20 min, 4° C.). The final pellet was resuspended in 50 mM Tris-HCl, pH 7.4 and stored at −80° C. in appropriate aliquots before use. Protein concentration was determined by the Bradford method (Bio-Rad, USA) with bovine serum albumin as standard.
  • [35S]GTPγS Binding Assay
  • Measurement of mGluR2 positive allosteric modulatory activity of test compounds was performed as follows. Test compounds and glutamate were diluted in assay buffer containing 10 mM HEPES acid, 10 mM HEPES salt, pH 7.4, 100 mM NaCl, 3 mM MgCl2 and 10 μM GDP. Human mGlu2 receptor-containing membranes were thawed on ice and diluted in assay buffer supplemented with 14 μg/ml saponin. Membranes were pre-incubated with compound alone or together with a predefined (˜EC20) concentration of glutamate (PAM assay) for 30 min at 30° C. After addition of [35S]GTPγS (f.c. 0.1 nM), assay mixtures were shaken briefly and further incubated to allow [35S]GTPγS incorporation on activation (30 minutes, 30° C.). Final assay mixtures contained 7 μg of membrane protein in 10 mM HEPES acid, 10 mM HEPES salt, pH 7.4, 100 mM NaCl, 3 mM MgCl2, 10 μM GDP and 2 μg/ml saponin. Total reaction volume was 200 μl. Reactions were terminated by rapid filtration through Unifilter-96 GF/B plates (Perkin Elmer, Massachusetts, USA) using a 96-well filtermate universal harvester. Filters were washed 6 times with ice-cold 10 mM NaH2PO4/10 mM Na2HPO4, pH 7.4. Filters were then air-dried, and 40 μl of liquid scintillation cocktail (Microscint-O) was added to each well. Membrane-bound radioactivity was counted in a Microplate Scintillation and Luminescence Counter from Perkin Elmer.
  • Data Analysis
  • The concentration-response curves of representative compounds of the present invention—obtained in the presence of EC20 of mGluR2 agonist glutamate to determine positive allosteric modulation (PAM)—were generated using the Lexis software interface (developed at J&J). Data were calculated as % of the control glutamate response, defined as the maximal response that is generated upon addition of glutamate alone. Sigmoid concentration-response curves plotting these percentages versus the log concentration of the test compound were analyzed using non-linear regression analysis. The concentration producing half-maximal effect is then calculated as EC50. The pEC50 values below were calculated as the −log EC50, when the EC50 is expressed in M. Emax is defined as relative maximal effect (i.e. maximal % effect relative to the control glutamate response).
  • Table E below shows the pharmacological data obtained for compounds of Formula (I-B) and current pharmacological data obtained for compounds of Formulae (I) and (I-A).
  • TABLE E
    Pharmacological data for compounds according to the invention.
    GTPγS- GTPγS-
    hmGluR2 hmGluR2
    Co. No. PAM pEC50 PAM Emax
     1-b 6.59 296
     2-b 6.84 228
     3-b 5.79 187
     6-b 7.39 256
     5-b 6.06 141
     4-b 7.04 329
     7-b 7.31 292
     8-b 7.04 244
     9-b 7.3 260
    10-b 7.47 218
    11-b 8.25 239
    12-b 6.99 178
    16-b 7.54 284
    13-b 7.75 280
    14-b 7.53 281
    15-b 8.16 293
    19-b 6.71 297
    25-b 6.9 233
    24-b 6.42 193
    17-b 7.73 317
    18-b 6.24 213
    22-b 7.61 325
    23-b 5.94 167
    21-b 6.32 102
    20-b 7.07 332
    26-b 6.78 214
    27-b n.c. 51
    30-b 6.9 227
    28-b 7.19 234
    29-b 5.85 77
    31-b 7.05 251
    32-b 5.71 116
    1 7.11 258
    1a 6.95 286
    2 7.82 290
    2a 7.61 484
    3 7.55 212
    4 6.88 260
    5 6.26 231
    6 7.79 263
    6a 7.68 261
    7 8.45 263
    8 6.73 360
    9 6.9 462
    10 7.21 357
    11 6.94 310
    12 8.36 261
    13 6.9 278
     1-a 6.78 314
     2-a 6.84 340
     3-a 6.88 231
     4-a 6.6 269
     5-a n.t.
     6-a 6.34 255
     7-a 6.64 291
     8-a 6.04 157
     9-a 6.59 222
    10-a 6.88 290
    11-a 7.11 249
    12-a 7.03 242
    13-a 6.67 212
    14-a 6.92 259
    15-a 7 253
    16-a 7.12 223
    17-a 6.54 261
    18-a n.t.
    19-a 6.71 240
    20-a 6.91 243
    21-a 6.25 207
    22-a 6.05 259
    23-a 6.58 203
    24-a 6.91 258
    25-a 7.07 261
    26-a 6.5 248
    27-a 6.48 284
    28-a 6.96 297
    29-a 6.97 317
    30-a n.t.
    31-a n.t.
    32-a 6.66 347
    33-a 6.58 362
    n.c. means that the pEC50 could not be calculated
    n.t. means not tested
    pEC50 values were not calculated in cases where the concentration-response curve did not reach a plateau level.
  • All compounds were tested in presence of mGluR2 agonist glutamate at a predetermined EC20 concentration, to determine positive allosteric modulation. pEC50 values were calculated from a concentration-response experiment of at least 8 concentrations.
  • B) Anticonvulsant Studies with mGluR2 Compounds (Orthosteric Agonist and Compounds of Formulae (I)/(I-A)/(I-B)
    • General Preparation of Test Compounds and Solutions
  • Test compounds were administered using an optimal fluid volume to body fluid ratio. Test compounds were administered to mice in a volume of 0.01 mL/g of body weight (White H. S., et al., General Principles: Experimental selection, quantification, and evaluation of antiepileptic drugs, in Antiepileptic Drugs, Fourth Edition, R. H. Levy, R. H. Mattson, and B. S. Meldrum, Editors. 1995, Raven Press, Ltd.: New York, pp. 99-110). For subcutaneous (s.c.) administration, the test compounds were administered into a loose fold of skin along the back of the animal except compound 6-b, which was administered orally (p.o). For each of the tests performed on the test compounds (except on compound 6-b), final compound concentrations were administered as aqueous solution in 20% Hp-β-CD. For compound 6-b, a 40% Hp-β-CD stock solution was first prepared and utilized for formulating compound 6-b at the desired concentrations for testing via the oral route; fmal compound concentrations were administered as suspensions in 20% Hp-β-CD. A 20% Hp-β-CD solution was used for the vehicle groups.
  • For LY-404039, final compound concentrations were administered as a saline solution s.c.
  • For compound CAS 1092453-15-0, final compound concentrations were administered in 10% Hp-β-CD (+NaCl) vehicle following dissolution.
  • Final levetiracetam concentrations were administered in a 0.5% methylcellulose (MC) aqueous solution administered by intraperitoneal (i.p.) injection.
    • Critical Reagents
  • a) Vehicle Solutions
    • 0.5% Methylcellulose (MC)
  • 40% Hydroxypropyl-β-cyclodextrin (Hp-β-CD) stock solution
  • b) Miscellaneous Solutions
  • Tetracaine (0.5% solution w/v) was added dropwise from a plastic dropper bottle onto the eyes of all animals that would subsequently receive electrical stimulation via corneal electrodes.
    • Animals and Animal Husbandry
  • Adult male CF No 1 albino mice (26-35 g) were obtained from Charles River, Portage, Mich. The animals were maintained on an adequate diet (Prolab RMH 3000) and allowed free access to food and water, except during the short time they were removed from their cage for testing Animals newly received in the laboratory were allowed sufficient time to correct for possible food and water restriction incurred during transit before being employed in testing. All mice were housed in plastic cages in specially constructed rooms with controlled humidity, exchange of air and controlled lighting (12 hours on-12 hours off). The animals were housed, fed, and handled in a manner consistent with the recommendations in the National Council Publication, “Guide for the Care and Use of Laboratory Animals”
    • Minimal Motor Impairment (MMI)
  • Acute MMI was assessed by a combination of direct observations of the animal for overt symptoms of the animal's neurological or muscular function. In mice, the rotarod procedure was used to disclose minimal muscular or neurological impairment. When a mouse is placed on a rod that rotates at a speed of 6 rpm, the animal can maintain its equilibrium for long periods of time. The animal was considered toxic if it fell off this rotating rod three times during a 1 min period.
  • Determination of Median Effective and Toxic Doses (ED50 and TD50)
  • In the determination of an ED50 or TD50 for each test compound, the first dose administered is usually the same dose as that used in a successful TPE determination.
  • If the initial dose employed was effective or toxic in more than 50% of animals, the next dose would be one-half that of the initial dose; if the initial dose was effective or toxic in less than 50% of animals, the following dose would be twice that of the initial dose. Third and fourth doses were selected to produce an evenly spaced dose response line. There should be a minimum of 4 points either including or lying between 0 and 100%.
    • TPE Determination
  • Groups of generally four animals each were administered test compounds and each group was tested at one of five time points: 0.25, 0.5, 1, 2, or 4 h post-treatment (White et al. 1995). TPE was determined using the 6 Hz (32 mA) assay. The time (0.25, 0.5, 1, 2, or 4 h post-treatment) at which maximal protection was observed was considered the Time of Peak Effect (TPE).
  • At the TPE determined for this study, or determined previously, compounds were tested in the 6 Hz assay (32 and/or 44 mA), across several doses and comprising doses that elicited little or no protection to full protection.
  • An ED50 and 95% confidence interval (C.I.) were calculated using Probit analysis on a computer program provided in the laboratory (Finney “Probit Analysis” 34d Ed 1971, London: Cambridge University Press).
  • Serum Collection for pK/pD Analysis
  • In various tests, animals were sacrificed following testing, and trunk blood and/or brain tissue (whole brains) was collected for quantification of drug levels Immediately after testing, animals were decapitated and trunk blood was collected into a BD Vacutainer® tube containing K2EDTA and chilled on ice until centrifugation. Following centrifugation (13000-18000 rpm, 5-7 min), the plasma was removed and transferred to a labeled microcentrifuge tube and stored at −80° C. For brain tissue collection, brains were removed immediately following decapitation and flash frozen. The frozen sample was placed in a labeled centrifuge tube and stored at −80° C.
    • 6 Hz Psychomotor Seizure Test in Mice
  • The 6 Hz seizure test is used as a model of pharmacoresistant limbic seizures. The 6 Hz seizure displays a resistance to phenytoin, carbamazepine, lamotrigine, and topiramate (Barton et al. “Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy” Epilepsy Research 2001, Vol. 47, pp. 217-222).
    • Method for 6 Hz Psychomotor Seizure Test
  • Focal seizures were induced in mice via corneal stimulation (6 Hz, 0.2 msec rectangular pulse, 3 sec duration; Barton et al. 2001). Mice were tested at either 32 mA or 44 mA. Prior to stimulation, drops of 0.5% tetracaine were applied to each eye. The seizures that arise from corneal stimulation in this assay are characterized by a minimal clonic phase followed by stereotyped automatistic behaviors including stun, forelimb clonus, twitching of the vibrissae, and Straub-tail. Animals not displaying these behaviors were considered protected.
    • Example 1—Studies with Compounds 1 and 2
  • 1.1. Combination Study with Co. No. 1, Co. No. 2 and Levetiracetam
  • First, each compound was tested individually at a dose that displayed minimal activity in the 6 Hz 44 mA test at each compound's TPE. When the mGluR2 PAM compounds and levetiracetam were administered in combination (same dose and time-point as individual tests) nearly complete protection was observed in the 6 Hz 44 mA test (Table 2). In addition to recording the efficacy and toxicity data for these compounds alone or in combination, both plasma and brain samples were collected from each of the groups for pharmacokinetic/pharmacokinetic analysis. No pharmacokinetic interaction was observed based on compound levels in the plasma and brain samples (data not shown). In summary, compounds 1 and 2 displayed positive pharmacodynamic interaction with levetiracetam in the 6 Hz model that does not appear to be due to pharmacokinetic interaction, and without increasing motor impairment (Tables 2, 2a, 2b). The effect of 1 dose of Compound 2 was also tested on the dose-response of LEV. As shown in Table 3, there was a ˜200-fold shift in the ED50 of LEV compared to when LEV was tested alone. LEV seemed to increase the potency of Co No. 2 slightly (Table 3).
  • 1.2. Isobolographic Analysis of Interactions Between Co. No. 1 and Levetiracetam in the 6 Hz Seizure Model
  • Isobolographic studies were conducted for the combined administration of Co. No. 1 with LEV in the 6 Hz (44 mA) assay. Studies were conducted according to previously described methods (Madsen et al. 2011). Initial ED50 values were determined for both Co. No. 1 and LEV and used to calculate theoretical ED50 (±standard error of the mean, SEM) values for three fixed dose ratio combinations (LEV:Co. No. 1): 1:3, 1:1, and 3:1. Doses used were proportional to calculated ED50 values. For example, the dose ratio used for the 1:1 paradigm was based on 0.5×ED50 for LEV and 0.5×ED50 for Co. No. 1. Similarly, the 1:3 paradigm used 0.25×ED50 for LEV and 0.75×ED50 for Co. No. 1. The 3:1 dose ratio used 0.75×ED50 LEV and 0.25×ED50 for Co. No. 1. Experimental treatment doses (see Table 4) were based on theoretical values and adjusted according to observed effects. Experimentally determined ED50 (±SEM) values for each fixed dose-ratio combination were compared to the theoretical values (t-test) for statistical purposes. The dose ratio was determined to be supra-additive (synergistic) if the experimentally-determined ED50 value was significantly lower than the theoretical ED50. Subsequently, the experimental combined doses were determined for the same paradigms in the 6 Hz seizure test (Table 4 below). The isobolographic study with compound 1 and levetiracetam in the 6 Hz model demonstrates a significant synergistic pharmacodynamic interaction at all dose ratios evaluated and corresponds closely with compound 1 plasma levels. Furthermore, no motor impairment was observed at any of the dose ratios evaluated suggesting that the synergistic pharmacodynamics interaction does not produce increased motor toxicity.
  • 1.3. Mouse Corneal Kindling Model and Studies with Compound 1
  • Mice were kindled electrically with 3 second, 3 mA, 60 Hz stimulus, twice daily using corneal electrodes until a criterion of 5 consecutive Stage 5 seizures as defined by Racine (Racine “Modification of seizure activity by electrical stimulation” II. motor seizure” Electroenceph Clin Neurophysiol 1972, 32, pp. 281-294). After the mice reached a stable kindled state, the test compound or vehicle was administered and, at the previously determined TPE, each animal was given the electrical stimulus indicated above. Following stimulation, the animals were observed for the presence or absence of the seizure activity scored on the Racine scale (0-5) with 5 representing the highest stage rearing and falling. One dose of LEV and two doses of Co. No. 1 were tested individually and in combination against corneal kindled seizures. Combination of compound 1 with levetiracetam in this model suggests a positive pharmacodynamics interaction (Table 5 below).
  • A summary of the data for the compounds tested alone is presented in Table 1 and additional results of studies performed according to example 1 are listed in Tables 2-5 below.
  • TABLE 1
    Summary of the acute anticonvulsant data in the 6 Hz model at 32 mA
    and 44 mA for the mGluR2 PAM compounds 1, 2, 11, 2-a, 25-a, 6-b and
    LY-404039 following s.c. administration (except compound 6-b, which
    was tested p.o.).
    Seizure
    score (dose)
    ED50 (95% CI) mg/kg, s.c. Corneal
    Co. No. TPE (h) 32 mA 44 mA kindling
    11 0.5 4.77 (3.54- 31.5 (15.1-47.3) 2.8
    6.76) (100 mg/kg)
    9.41 (1.53-15.1)
    2 0.25 3.83 (1.62- 5.89 (3.89-8.45) 3.4
    6.71)  (40 mg/kg)
    1 0.5 2.8 (1.3-4.3)  10.2 (3.1-12.4)  3.7
     (20 mg/kg)
    25-a 1 7.7 (2.3-18.4)   1 hr TPE: 25.9 n.t.
    (15.5-33.7)
    0.25 hr TPE: 29.1
    (21.6-39.6)
    2-a 0.5 44.7 (23.4-80.5) 50% protection at 4.4
    20.8 (10.0-31.7) 100 mg/kg (100 mg/kg)
    12.2 (8.4-17.4)    21 (17.9-27.4)
    6-b 0.5 7.2 (4.2-11.8) 16.1 (13.0-20.1) n.t.
    LY-404039 0.5 10.2 (3.62-12.4) n.t. 3.1
    (100 mg/kg)
    TPE means time of peak effect, CI means confidence interval, s.c. means subcutaneous, p.o. means orally, n.t. means not tested. TPE was determined in 32 mA 6 Hz test. Effects are generally observed at doses that do not produce impairment in rotarod test. For compounds 11 and 2-a the individual values of repeat experiments are provided. For compound 25a, both 0.25 and 1 h time points were used for 6 Hz (44 mA) studies.
  • TABLE 1a
    Summary of the 6 Hz 32 mA TPE determination for Co. No. 1
    Dose (mg/kg, s.c.) Time (h) 6 Hz 32 mA Motor impairment
    10 4 0/4 0/0
    2 0/4 0/0
    1 3/4 0/0
    0.5 4/4 0/0
    0.25 4/4 0/0
    5 0.5  8/12 0/0
    0.25  8/12 0/0
    2.5 0.5 5/8 0/0
    0.25 1/8 0/0
    (number of mice protected in 6 Hz or toxic on rotarod/number tested)
  • TABLE 1b
    Dose-response studies for Co. No. 1. The TPE for Co. No. 1 was
    previously determined to be 0.5 h (results shown above in table
    1a). Several doses of Co. No. 1 were administered at this TPE and
    tested in the 6 Hz assay, using both 32 and 44 mA stimulus intensities.
    Dose (mg/kg, #protected/ #rotarod motor
    Test s.c.) #tested impairment/#tested
    6 Hz 32 mA 20 8/8 1/8
    10 7/8 0/8
    5  8/12  0/12
    2.5  7/16  0/16
    0.5 1/8 0/8
    ED50 (95% CI): 2.8 mg/kg (1.3 to 4.3)
    6 Hz 44 mA 20 8/8 1/8
    15 7/8 0/8
    10 4/8 0/8
    2.5 0/8 0/8
    ED50 (95% CI): 10.2 mg/kg (3.1 to 12.4)
  • TABLE 2
    Summary of interaction of Co. No. 1 and Co. No. 2 with Levetiracetam
    (LEV) in the mouse 6 Hz, 44 mA seizure model. Results are listed as
    number of mice exhibiting full protection/total number of mice tested
    in each dosing group (at the specified test compound or combination
    dosage levels).
    # protected/# # motortox/#
    Dose Time (h) tested tested
    LEV 10 mg/kg i.p. 1 1/6 0/6
    Co. No. 2 +   3 mg/kg s.c. 0.25 5/6 0/6
    LEV
    Co. No. 2   3 mg/kg s.c. 0.25 1/6 0/6
    LEV 10 mg/kg i.p. 1 1/8 0/8
    Co. No. 1 + 2.5 mg/kg s.c. 0.5 6/8 0/8
    LEV
    Co. No. 1 2.5 mg/kg s.c. 0.5 0/8 0/8
  • TABLE 2a
    Plasma and brain levels Co. No. 1. in combination study with
    Levetiracetam (LEV).
    Plasma Plasma 6 Hz
    Co. No. 1 LEV (ng/ml) Co. No. 1 (ng/ml) Protection
    6 Hz 44 mA 10 mg/kg 9350 2.5 mg/kg BQL Yes
    8580 244 No
    10900 314 Yes
    10300 382 Yes
    9780 416 Yes
    9780 377 Yes
    13700 2260* No
    10100 607 Yes
    Mean Plasma 10311   657.1 6/8
    Level (390)
    Mean Plasma 1/8 8254 0/8 438
    Levels (non-
    combination)
    Mean plasma level shown in parenthesis ( ) is calculated with a statistical outlier* removed
    BQL means below quantifiable limit.
  • TABLE 2b
    Plasma and brain levels Co. No. 2 in combination study with
    Levetiracetam (LEV). AQL means above quantifiable limit.
    Plasma Brain Plasma 6 Hz
    Co. No. 2 LEV (ng/ml) (ng/ml) Co. No. 2 (ng/ml) Brain (ng/ml) Protection
    6 Hz 44 mA 10 6450 6290 3 1830 1540 Yes
    mg/kg mg/kg
    8200 7990 386 1020 Yes
    3540 4760 4700 1310 Yes
    3850 NA 467 NA No
    7150 6380 AQL 1120 Yes
    (>500)
    3890 3960 2080 1140 Yes
    Mean 5513 5876 1893 1226 ⅚
    Plasma/
    Brain Levels
    Mean ⅙ 8750 5773 1/6 1295 1113
    Plasma/Brain Levels
    (non-combination)
    NA—sample not available for analysis
  • TABLE 3
    6 Hz seizure (44 mA) model ED50 determinations for No. Co. 2 and
    levetiracetam (LEV) alone and in combination. LEV at a dose of 10 mg/kg
    increased the potency of the No. Co. 2 (~5-fold shift in ED50). Co. No. 2
    at a dose of 3 mg/kg increased both the efficacy (to 100% protection)
    and potency of LEV (~200-fold shift in ED50).
    FIG. 1 shows the dose-response for the 6 Hz 44 mA ED50 determinations
    for the Co. No. 2 and LEV alone and in combination.
    ED50 (95% CI) Maximum Effect
    Treatment mg/kg (% Protection)
    Co. No. 2 alone 6.97 100%
    (5.44-8.30)
    Co. No. 2 + 1.35 100%
    LEV (10 mg/kg) (0.8-1.9)
    LEV alone ~200  75%
    LEV + 1.0 100%
    Co. No. 2 (3 mg/kg) (0.23-2.24)
  • TABLE 4
    Results of Co. No. 1 and Levetiracetam in Isobolographic Study.
    Co. No. 1 Rotarod 6 Hz (44 mA)
    LEV (mg/kg combined dose #motortox/ #protected/
    Group (mg/kg i.p.) f s.c.) f (mg/kg) # tested #tested
    1:1 181 0.5 5.1 0.5 93.1 0/8 8/8
    paradigm 90.5 2.6 46.6 0/8 6/8
    45.3 1.3 23.3 0/8 3/8
    22.6 0.6 11.6 0/8 3/8
    ED50 (95% CI; mg/kg): 22.2 (8.4-35.7)
    1:3 45.3 .25 3.8 .75 14.2 0/8 8/8
    paradigm 22.6 1.9 7.1 0/8 4/8
    11.3 1.0 3.6 0/8 2/8
    ED50 (95% CI; mg/kg): 5.9 (3.5-8.7)
    3:1 271.5 .75 2.6 .25 204.3 0/8 8/8
    paradigm 135.8 1.3 102.2 0/8 3/8
    67.9 0.6 51.1 0/8 3/8
    33.9 0.3 25.5 0/8 0/8
    ED50 (95% CI; mg/kg): 86.3 (56.8-131.4)
  • The isobolographic analysis (FIG. 2) demonstrates that the combination of Co. No. 1 and levetiracetam results in a significantly positive synergistic effect.
  • TABLE 5
    Results of Co. No. 1 and Levetiracetam combination study
    in the corneal kindling model in mice.
    # protected/# % Mean Seizure
    Compound(s) tested Protected Score
    Vehicle
    0/10  0% 4.7
    (20% HPBCD@30′, s.c.;
    0.5% MC@60′, i.p.)
    LEV 3 mg/kg 5/13 38% 3.3
    Co. No. 1 30 mg/kg 3/12 25% 4.0
    LEV 3 mg/kg & Co. No. 10/10  100%  0.6
    1 30 mg/kg
    Co. No. 1 20 mg/kg 5/16 31% 3.7
    LEV 3 mg/kg & Co. No. 7/10 70% 1.9
    1 20 mg/kg
    Racine Seizure Score
    0 to 5
    0 = no seizure activity
    5 = maximal seizure activity
    • Example 2—Studies with Compounds 25-a and 2-a
  • 2.1. Combination Study with Co. No. 25-a and Levetiracetam
  • Independent dose-response studies were performed in the 6 Hz 44 mA test for both compounds to determine ED50 values at the TPE of 1 h i.p. for levetiracetam and 1 h s.c. for Co. No. 25-a. The ED50 value for Co. No. 25-a was 25.9 mg/kg and for levetiracetam the value was estimated to be approximately 345 mg/kg. The dose-response for levetiracetam was repeated with co-administration of 10 mg/kg Co. No. 25-a (a dose of Co. No. 25-a that alone did not protect in the 6 Hz 44 mA model). The co-administration of 10 mg/kg Co. No. 25-a produced an ED50 in the levetiracetam dose-response of 4.9 mg/kg (˜70-fold lower compared with levetiracetam alone) and importantly yielded full protection in the 6 Hz 44 mA seizure model. These results are suggestive of a positive pharmacodynamic interaction in the 6 Hz seizure model between Co. No. 25-a and levetiracetam.
  • TABLE 6
    Time -to-Peak Effect Determination for Co. No. 25-a in the 6 Hz (32 mA)
    Assay. Two doses were used in this study, 10 and 20 mg/kg, across several
    time points (0.25-4 h). The compound showed the greatest degree of
    protection in the 6 Hz assay between 0.25 and 1 h, which was more
    evident at 20 mg/kg. Plasma levels of the compound generally
    corresponded to behavioural seizure protection. A TPE of 0.25 h
    was used for 6 Hz (32 mA) studies whereas both the 0.25 and 1 h
    time points were used for 6 Hz (44 mA) studies.
    Dose # rotarod motor Co. No. 25-a mean
    (mg/kg, Time # protected/# impairment/# plasma levels
    s.c.) (h) tested tested (ng/mL)
    10 0.25 2/4 0/4 10,983 (2,477)
    0.5 1/4 0/4 3,330
    1 1/4 1/4 700
    2 0/4 0/4 256
    4 0/4 0/4 40
    20 0.25 4/4 0/4 4,095
    0.5 3/4 1/4 2,800
    1 4/4 1/4 1,765
    2 1/4 0/4 618
    4 1/4 1/4 28
    Mean plasma level shown in parenthesis ( ) is calculated with a statistical outlier removed.
    s.c. means subcutaneous
  • TABLE 7
    Dose-Response Studies for Co. No. 25-a in the
    6 Hz Assay (32 mAa and 44 mAb)
    Dose # rotarod motor Co. No. 25-a mean
    (mg/kg, # protected/ impairment/# plasma levels
    Test s.c.) # tested tested (ng/mL)
    6 Hz 32 mA 20 8/8 0/8 5,570
    15 3/8 0/8 1,201
    10 4/8 0/8 6,113
    5 4/8 0/8 2,558
    1 1/8 0/8 466
    ED50 (95% CI): 7.7 mg/kg (2.3 to 18.4)
    6 Hz 44 mA 40 7/8 0/8 6,263
    30 3/8 0/8 7,220
    20 2/8 0/8 3,368
    10 0/8 0/8 4,345 (1,526)
    5 0/8 1/8 1,428
    ED50 (95% CI): 29.1 mg/kg (21.6 to 39.6)
    aThe time-to-peak effect in the 6 Hz 32 mA assay for Co. No. 25-a was determined to be 0.25 h (see Table 1).
    bThe time-to-peak effect in the 6 Hz 44 mA assay for Co. No. 25-a was similar for 0.25 h and 1 h; results for 1 h confirmed the ED50 (95% CI) 25.9 (15.5-33.7) (see Table 1 and 6).
    Mean plasma level shown in parenthesis ( ) is calculated with a statistical outlier removed.
    CI means confidence interval
  • TABLE 8
    Combination Studies for Co. No. 25-a with Levetiracetam
    (LEV) in the 6 Hz (44 mA) Assay.
    # protected/ # rotarod motor
    Drug Dose (mg/kg, s.c.) # tested impairment/# tested
    LEV 200 2/8 0/8
    400 4/9 0/9
    800 10/12  0/12
    ED50 (95% CI): 345.4 mg/kg (211.0 to 485.3)
    LEV + Co. No. 25-a 200 8/8 1/8
    10 mg/kg
    100 7/8 2/8
    50 5/8 1/8
    10 4/8 0/8
    1 4/8 1/8
    ED50 (95% CI): 4.9 (0.0-14.2)
    Co. No. 25-a (s.c.) 10 mg/kg tested in combination with LEV (i.p.)-Co. No. 25-a 10 mg/kg, not active when administered alone.

    2.2. Combination Study with Co. No. 2-a and Levetiracetam
  • Dose-response studies were performed in the 6 Hz 32 mA and 44 mA tests (table 9 below) and in the combination test with levetiracetam (effect of Co. No. 2-a on the dose-response of LEV in tables 10a and effect of LEV on the dose-response of Co. No. 2-a in table 10b below) in the same manner as described for the studies with Co. No. 25-a and levetiracetam above.
  • TABLE 9
    Dose-Response Studies for Co. No. 2-a in the 6 Hz Assay (32 mA and
    44 mA; 0.5 h TPE). A time-to-peak effect of 0.5 h was determined in
    the 32 mA 6 Hz test (s.c.) and used for 6 Hz (32 mA and 44 mA) studies.
    #protected/# # rotarod motor
    Test Dose (mg/kg, s.c.) tested impairment/# tested
    6 Hz 40 8/8 2/8
    32 mA 20 6/8 3/8
    10 4/8 0/8
    5 0/8 0/8
    2.5 0/8 1/8
    ED50 (95% CI): 12.2 mg/kg (8.4 to 17.4)
    6 Hz 40 8/8 4/8
    44 mA 20 3/8 0/8
    3/8 0/8
    15 2/8 1/8
    10 0/8 1/8
    0/8 0/8
    ED50 (95% CI): 21.0 mg/kg (17.9 to 27.4)
    TD50: >40 mg/kg a
    a40 mg/kg-6 out of 16 total (32 mA and 44 mA combined) with impairment. Dose selected for combination studies with LEV in 6 Hz (44 mA): Co. No. 2-a 10 mg/kg.
  • TABLE 10a
    Combination Studies for Co. No. 2-a with Levetiracetam
    (LEV) in the 6 Hz (44 mA) Assay. Combination of 10 mg/kg
    Co. No. 2-a with varying doses of levetiracetam.
    # rotarod
    motor
    Dose # protected/ impairment/
    Drug (mg/kg) # tested # tested
    LEV 200 2/8 0/8
    400 4/9 0/9
    800 10/12  0/12
    LEV ED50 (95% CI): 345.4 mg/kg (211.0 to 485.3)
    LEV + Co. 200 6/8 1/8
    No. 2-a 100 6/8 0/8
    10 mg/kg a 50 6/8 0/8
    25 8/8 0/8
    12.5 5/8 0/8
    6.25 4/8 0/8
    3.125 3/8 1/8
    1.5625 0/8 0/8
    LEV ED50 (95% CI): 9.6 mg/kg (1.7-21.9)
    aCo. No. 2-a (s.c.) 10 mg/kg tested in combination with LEV (i.p.);
    Co. No. 2-a 10 mg/kg, not active when administered alone. Additional LEV (low-dose) control groups were tested at 25 and 6.25 mg/kg (1/8 and 0/6 protected, respectively). Vehicle-treated mice (0.5% methylcellulose i.p. (1 h)/20% HPBCD s.c. (0.5 h)) showed no protection (0/8 protected).
  • TABLE 10b
    Combination Studies for Co. No. 2-a with Levetiracetam
    (LEV) in the 6 Hz (44 mA) Assay. Combination of 350 mg/kg
    levetiracetam with varying doses of Co. No. 2-a.
    # rotarod
    motor
    Dose # protected/ impairment/
    Drug (mg/kg) # tested # tested
    LEV (alone)a 350 3/8 0/8
    LEV 350 20 8/8 2/8
    mg/kg + 10 7/8 1/8
    Co. No. 2-ab 5 7/8 1/8
    2.5 5/8 0/8
    1.25 4/8 0/8
    previous Co. No. 2-a ED50 (95% CI): 21.0 mg/kg
    (17.9 to 27.4) LEV combination Co. No. 2-a ED50
    (95% CI): 1.5 mg/kg (0.1-2.7) ~14-fold shift in potency
    aLEV ED50 (presented separately) previously determined in 6 Hz (44 mA): 345 mg/kg.
    bCo. No. 2-a (s.c.) 10 mg/kg tested in combination with LEV (i.p.);
    Co. No. 2-a 10 mg/kg, not active when administered alone. Additional LEV (low-dose) control groups were tested at 25 and 6.25 mg/kg (1/8 and 0/6 protected, respectively). Vehicle-treated mice (0.5% methylcellulose i.p. (1 h)/20% HPBCD s.c. (0.5 h) showed no protection (0/8 protected).
  • At a dose of 10 mg/kg s.c., Co. No. 2-a increases the potency of LEV, leading to an approximate 35-fold shift in the ED50. This suggests a positive pharmacodynamic relationship (Table 10a). At a dose of 350 mg/kg i.p., LEV increases the potency of Co. No. 2-a, leading to an approximate 14-fold shift in the ED50. This suggests a positive pharmacodynamics relationship (Table 10b).
    • Example 3—Studies with Compound 6-b
  • 3.1. Combination Study with Co. No. 6-b and Levetiracetam
  • Independent dose-response studies were performed in the 6 Hz 44 mA test for both compounds to determine ED50 values at the TPE of 1 h i.p. for levetiracetam and 0.5 h p.o. for Co. No. 6-b. The ED50 value for Co. No. 6-b was 16.1 mg/kg and for levetiracetam the value was estimated to be approximately 345 mg/kg. The dose-response for levetiracetam was repeated with co-administration of 10 mg/kg Co. No. 6-b (a dose of Co. No. 6-b that alone did not protect in the 6 Hz 44 mA model). The co-administration of 10 mg/kg Co. No. 6-b produced an ED50 in the levetiracetam dose-response of 2.4 mg/kg (˜100-fold lower compared with levetiracetam alone) and importantly yielded full protection in the 6 Hz 44 mA seizure model. These results are suggestive of a positive pharmacodynamic interaction in the 6 Hz seizure model between Co. No. 6-b and levetiracetam.
  • The results of the studies performed with compound 6-b are listed in Tables 11-13 below.
  • TABLE 11
    Time-to-Peak Effect Determination for Co. No.
    6-b (p.o.) in the 6 HZ (32 mA) Assay.
    # rotarod
    motor
    Dose # protected/ impairment/
    (mg/kg, p.o.) Time (h) # tested # tested
    10 0.25 1/4 0/4
    0.5 3/4 0/4
    1 0/4 0/4
    2 1/4 0/4
    4 0/4 0/4
    20 0.25 4/4 0/4
    0.5 3/4 0/4
    1 4/4 0/4
    2 0/4 0/4
    4 1/4 0/4
    TPE determined to be 0.5 h.
  • TABLE 12
    Dose-Response Study for Co. No. 6-b in the
    6 Hz Assay (32 mA and 44 mA; 0.5 h TPE).
    # rotarod
    motor
    Dose # protected/ impairment/
    Test (mg/kg, p.o.) # tested # tested
    6 Hz 20 7/8 0/8
    32 mA 10 6/8 0/8
    5 2/8 0/8
    2.5 1/8 0/8
    ED50 (95% CI): 7.2 mg/kg (4.2 to 11.8)
    6 Hz 40 8/8 0/8
    44 mA 20 6/8 0/8
    15 4/8 0/8
    10 0/8 0/8
    ED50 (95% CI): 16.1 mg/kg (13.0 to 20.1)
  • TABLE 13
    Combination Studies for Co. No. 6-b
    with LEV in the 6 Hz Assay (44 mA).
    # rotarod
    motor
    Dose # protected/ impairment/
    Drug (mg/kg) # tested # tested
    LEV 200 2/8 0/8
    400 4/9 0/9
    800 10/12  0/12
    ED50 (95% CI): 345.4 mg/kg (211.0 to 4853)
    LEV + Co. 200 8/8 0/8
    No. 6-b
    10 mg/kg
    100 8/8 0/8
    50 5/8 0/8
    10 5/8 0/8
    1 5/8 0/8
    ED50 (95% CI): 2.4 (0.0-6.4)
    Co. No. 6-b (p.o.) 10 mg/kg tested in combination with LEV (i.p.)
    Co. No. 6-b 10 mg/kg, not active when administered alone
    • Example 4—Studies with Compound LY404039
  • 3.1. Combination Study with LY404039 and Levetiracetam
  • LY-404039 was tested alone and in combination with levetiracetam according to the procedures already described hereinabove. The results of the studies performed with LY-404039 are listed in tables 14-15.
  • TABLE 14
    Dose-Response Studies for LY404039 in the 6 Hz Assay
    (32 mA and 44 mA). A time-to-peak effect of 0.5 h
    was determined in the 32 mA 6 Hz test (s.c.)
    and used for 6 Hz (32 mA and 44 mA) studies.
    # rotarod
    motor
    Dose # protected/ impairment/
    Test (mg/kg, s.c.) # tested # tested
    6 Hz 40 8/8 1/8
    32 mA 20 6/8 1/8
    10 5/8 0/8
     5  1/16  1/16
    ED50 (95% CI): 10.9 mg/kg (7.8 to 15.9)
    6 Hz 40 7/8 2/8
    44 mA 20 7/8 1/8
    10 3/8 1/8
     5  0/16  0/16
    ED50 (95% CI): 14.1 mg/kg (10.0 to 20.6)
    TD50: >40 mg/kg a
    a40 mg/kg-3 out of 16 total (32 mA and 44 mA combined) with impairment.
    Note:
    no activity observed following vehicle administration in 32 or 44 mA.
  • Dose selected for combination studies with LEV in 6 Hz (44 mA): LY404039 5 mg/kg.
  • TABLE 15
    Combination Studies for LY404039 with
    Levetiracetam (LEV) in the 6 Hz (44 mA) Assay.
    # rotarod
    motor
    Dose # protected/ impairment/
    Drug (mg/kg) # tested # tested
    LEV a 200 2/8 0/8
    400 4/9 0/9
    800 10/12  0/12
    LEV ED50 (95% CI): 345.4 mg/kg (211.0 to 485.3)
    LEV + 200 8/8 0/8
    LY404039  50 6/8 1/8
    5 mg/kg b  20 6/8 2/8
     5 2/8 1/8
    LEV ED50 (95% CI): 12.8 mg/kg (2 5-25.2)
    aLEV alone shown previously, confirmation doses performed in combination with Co. No. 2-a (see previous table above).
    bLY404039 (s.c.) 5 mg/kg tested in combination with LEV (i.p.);
    LY404039 5 mg/kg was not active when administered alone. Additional LEV (low-dose) control groups were tested at 25 and 6.25 mg/kg (1/8 and 0/6 protected, respectively). Vehicle-treated mice (10% sterile water-NaCl;
    s.c., 0.5 h TPE and 0.5% MC, i.p., 1 h TPE) showed no protection or rotarod impairment.
  • At a dose of 5 mg/kg LY404039 increases the potency of LEV, leading to an approximate 27-fold shift in the ED50. This suggests a positive pharmacodynamic relationship.
    • Example 4—Studies with Compound CAS 1092453-15-0 4.1. Combination Study with 2,3-dihydro-7-methyl-5-[3-(1-piperazinylmethyl)-1,2,4-oxadiazol-5-yl]-2-[[4-(trifluoromethoxy)phenyl]methyl]-1H-isoindol-1-one [CAS 1092453-15-0] (Described in WO 2008150233, WO 2011084098) and Levetiracetam
  • Figure US20220143141A1-20220512-C00177
  • CAS 1092453-15-0 was tested alone and in combination with levetiracetam according to the procedures already described hereinabove. The results of example 5 are listed in tables 16-17.
  • TABLE 16
    Dose-Response Studies for CAS
    1092453-15-0 in the 6 Hz Assay (32 mA).
    # rotarod
    motor
    Dose # protected/ impairment/
    (mg/kg, s.c.) Time (h) # tested # tested
    20 0.25 1/4 0/4
    0.5 0/4 0/4
    1 1/4 0/4
    2 0/4 0/4
    4 0/4 0/4
    40 0.25 1/4 0/4
    0.5 1/4 0/4
    1 1/4 0/4
    2 0/4 0/4
    4 0/4 0/4
    80 0.25 0/4 0/4
    0.5 0/4 0/4
    1 1/4 1/4
  • Low activity was observed at doses and time points tested. Greatest activity at 0.25-1 h in tested doses. Combination studies were performed using 20 mg/kg, s.c, 1 h TPE in the 6 Hz (44 mA) assay.
  • TABLE 17
    Combination Studies for CAS 1092453-15-0
    with Levetiracetam (LEV) in the 6 Hz (44 mA) Assay.
    # rotarod
    LEV motor
    Dose # protected/ impairment/
    Drug (mg/kg) # tested # tested
    LEV a 200 2/8 0/8
    400 4/9 0/9
    800 10/12  0/12
    LEV ED50 (95% CI): 345.4 mg/kg (211.0 to 485.3)
    [CAS 1092453-15-0] 0/8 0/8
    (20 mg/kg, alone)
    LEV + 400 4/8 0/8
    [CAS 1092453-15-0] 200 5/8 0/8
    20 mg/kg b  50 3/8 0/8
     20 2/8 0/8
     5 1/8 1/8
    LEV ED50 (95% CI): 238.9 mg/kg (41.6-above highest dose tested)
    aAdditional LEV (low-dose) control groups were tested at 25 and 6.25 mg/kg (1/8 and 0/6 protected, respectively).
    b[CAS 1092453-15-0] 20 mg/kg (s.c.; 1 h TPE) tested in combination with LEV (i.p.; 1 h TPE); [CAS 1092453-15-0] 20 mg/kg displayed low activity when administered alone (6 Hz, 32 mA), and it was not tested in 6 Hz (44 mA). This compound displayed an in vitro EC50 = 562 nM (Emax = 197%) when tested in the GTPγS assay described hereinbefore and no occupancy was observed in ex vivo experiments in rats.
    Note:
    Vehicle-treated animals (10% HPβCD-NaCl, s.c., 1 h and 0.5% MC, i.p., 1 h) showed no protection or motor impairment, N = 8.
  • The current data set indicates that mGlu2 PAM or agonist molecules have anticonvulsant activity in the 6 Hz animal model. Tested mGlu2 PAMs with EC50 potencies 150 nM (as determined in the [35S]GTPγS assay), appropriate PK parameters and brain penetration, showed activity in both the 32 and 44 mA 6 Hz paradigm. Furthermore, all the tested molecules showed synergistic effects with LEV. In contrast, molecule CAS 1092453-15-0, which was only weakly active (ECK, 562 nM) in vitro, did not show activity in either of the 6 Hz tests, and also did not display synergy with LEV.
  • Importantly, the data indicate that, under conditions of comparable PK characteristics and appropriate brain penetration, the most potent mGlu2 PAMs, based on in vitro EC50 values, also appeared most potent in vivo, suggesting that in vitro and in vivo potency can be linked. Moreover, synergistic effects with LEV were consistently seen with mGlu2 PAM doses similar to the ED50 obtained in the 32 mA model or at least 2-fold lower as the ED50 determined in the 44 mA paradigm (i.e. a dose inactive in the 44 mA test when the molecules were tested alone).
  • Also for LY404039, the mGlu2/3 agonist, activity in both 6 Hz tests was seen and synergy was seen at a dose 3-fold lower than the ED50 determined in the 44 mA model, which was inactive when tested alone.
  • Based on the available preclinical data in the 6 Hz 44 mA model, it seems that combining a potent SV2A ligand and a potent mGlu2 PAM, leads to a decrease in the median effective dose or ED50 of the SV2A ligand, such as LEV, between 35 and 100-fold.
  • Thus, while not wishing to be bound by theory, it is suggested that positive allosteric modulator of metabotropic glutamatergic receptor subtype 2 (mGluR2 PAM) compounds, in particular mGluR2 PAM compounds having an EC50 potency of 1.50 nM (as determined in the [35S]GTPγS assay), wherein EC50 is the concentration producing half-maximal effect in a concentration-response curve obtained in the presence of EC20 of glutamate, and appropriate PK parameters and brain penetration, result in a synergistic combination with an SV2A ligand, in particular levetiracetam, at non-effective doses of one or both of compound (a) and compound (b) of the combination of the invention.
  • Thus, in a further embodiment, the positive allosteric modulator of metabotropic glutamatergic receptor subtype 2 (mGluR2 PAM) compound of the combination of the invention as defined herein is selected from an mGluR2 PAM compound having an EC50 potency of ≤150 nM (as determined in the [35S]GTPγS assay), wherein EC50 is the concentration producing half-maximal effect in a concentration-response curve obtained in the presence of EC20 of glutamate.
    • PROPHETIC EXAMPLES
  • A) Dominant-Submissive Relations (DSR) in Rat In Vivo Assay
  • The DSR assay is divided into two models: Reduction of Dominant Behavior Model (RDBM) of mania and Reduction of Submissive Behavior Model (RSBM) of depression. The RDBM, wherein the dominant animals are treated with test compound, is predictive of the ability of the test compound to treat mania. The RSBM, wherein the submissive animals are treated with test compound, is predictive of the ability of the test compound to treat depression.
  • Male Sprague Dawley rats (140 to 160 g) from Charles River Laboratories Wilmington, Mass. are used in this assay. Shipments of rats are received at two-week intervals. Each shipment will go through five-day quarantine, one-week acclimation period and one-week selection process, followed by five-weeks of drug or vehicle treatment to those pairs selected.
  • Rats will be housed four per cage. Access to food will be restricted to one hour per day after testing on Monday through Thursday. After testing on Friday, rats will have free access to food until being fasted again on Sunday. At no time will the rats be deprived of water. The food deprivation periods used will have little effect on weight gain as the average weight of rats will be about 300 g by the end of the study. At the conclusion of experiment rats will be sacrificed by decapitation, the trunk blood and brains will be collected for in vitro experiments and drug concentration measurements.
  • The basic testing apparatus consisted of two chambers connected with a tunnel only large enough to allow one rat to pass through at a time. On the floor, at the mid-point of the tunnel will be a container of sweetened milk. This basic apparatus will be replicated, so that a total of four pairs of rats can be video tracked simultaneously. The camera can distinguish rats marked by different colors. Thus, the rats' heads will be colored for the purpose of video tracking, red in one cage and yellow in the other cage. Only one animal at a time can have comfortable access to the feeder, but both animals can drink milk during the five-minute daily session. During the five-minute daily sessions, time spent in the feeder zone by each rat will be recorded by the video tracking software and saved into a text file.
  • The test will begin with a random assignment of rats into pairs. Each member of a pair will be placed in an opposite chamber of the testing apparatus. The time spent in the feeder zone by each animal will be recorded. During the first week (five days) of testing the animals habituate to the new environment. Dominance will be assigned to the animal with the highest score during the second week of testing if three criteria are achieved. First, there must be a significant difference (two-tailed t-test, P<0.05) between the average daily drinking scores of both animals. Second, the dominant animal score must be at least 25% greater than the submissive animal's score. Finally, there must be no “reversals” during the pair selection week where the putative submissive rat out-scored its dominant partner on isolated occasions. Ideally there will be minimal reversals during the acclimation week as well. Only animal pairs that achieve these criteria will be continued in the study.
  • Significant differences between time spent on the feeder by dominant and submissive rats will be determined by ANOVA using GraphPad Prism software (GraphPad Software, Inc. San Diego, Calif.) followed by a two-tailed t-test (P<0.05). Comparisons will be made between treatment groups using normalized dominance level values in paired animals. The dominance level is a value that measures social relation between paired subjects. Dominance level (DL)=FTD−FTS where FTD is the feeder time of dominant rats and FTS is the feeder time of submissive rats. The normalization will be conducted according to the formula:
  • Dominance ⁢ ⁢ Level ⁢ ⁢ ( week ⁢ ⁢ n ⁢ ⁢ in ⁢ ⁢ % ) = ( Dominance ⁢ ⁢ Level ⁢ ⁢ ( week ⁢ ⁢ n ) ) / ( Dominance ⁢ ⁢ Level ⁢ ⁢ ( week ⁢ ⁢ 2 )
  • The statistical significance of the difference in dominance level between the control group (pairs of rats where both dominant and submissive animals will be treated with vehicle) and the treatment group (submissive rats will be treated with drug and dominant rats with vehicle) will be determined by ANOVA, followed by a t-test. The activity onset time value at 50% of response (AOT-50) and the minimum and maximum response to drug will be calculated based on the reduction of the dominance level value using non-linear regression analysis (GraphPad Software, Inc., San Diego, Calif.). The normalized DL values will be used for this calculation, where DL values for treatment weeks will be normalized as a percent of the second week (pretreatment) value of that pair according the above formula. In these settings the minimum of the response (DL) determines drug positive activity, corresponding to efficacy, since DL values will be reduced if the response to a drug is positive. In the case of the negative response to a drug (worsening of symptoms) DL values will be increased. If the drug does not have such activity the maximum of the response will not exceed 100%. Any maximal DL value significantly higher than control value (about 100%) indicates drug negative activity.
  • Levetiracetam and mGluR2 PAM/agonist compound (e.g. compounds 2, 2-a, 25-a, 6-b or LY-404039) will be evaluated in the rat RDBM according to the procedure described in more detail below.
  • Groups of dominant rats will be treated p.o. QD with levetiracetam 10 mg/kg and mGluR2 PAM/agonist compound at various concentrations from approximately 0.05 mg/kg (n≥3), at 0.5 mg/kg (n≥3), at 2.5 mg/kg (n≥3), at 5.0 mg/kg (n≥3) and at 50.0 mg/kg (n≥3). A vehicle control group of dominant rats will be treated with 0.5% methylcellulose (n≥3) and a second control group of dominant rats will be treated i.p. QD with sodium valproate at 30 mg/kg (n≥6 from 2 studies of n≥3 each).
  • All treatments will be administered approximately 1 hour prior to testing. All treatments will be started on Saturday after the second testing week (selection week). The levetiracetam and mGluR2 PAM/agonist compound will be administered orally (p.o.).
  • When dominant animals are treated with levetiracetam 10 mg/kg and mGluR2 PAM/agonist compound the difference between dominant and submissive rats will be lost after the first or second week of treatment depending on the dosage. Similarly, when dominant animals are treated with sodium valproate, the difference between dominant and submissive rats will also be lost after first week of treatment. The permissiveness of the dominant rats treated with levetiracetam and mGluR2 PAM/agonist compound or sodium valproate may be observed to increase. Thus the treated dominant rats will permit their submissive partners to increase their time on the feeder.
  • To compare different drug and dose effects the data will be normalized to the initial control week values. The strongest effect of levetiracetam and mGluR2 PAM/agonist compound combination will be observed where there is a significant difference in dominance level (DL) values between vehicle and combination treated rats starting in the second week and continuing through the treatment duration of 5 weeks. In comparison, animals (30 mg/kg) that will be treated with sodium valproate will consistently show a decreased dominance level after the second week of treatment with the effect increasing in the following weeks.
  • To estimate activity onset time (AOT), daily average values for feeder time of dominant and submissive animal pairs will be plotted and significant differences between these two groups will be calculated using the two-tail t-test.
  • To compare activity onset time (AOT) between different treatments the activity onset time will be estimated from the non-linear regression fit. The non-linear regression model will fit for each drug, combination and dose normalized daily DL values.
  • Effects of levetiracetam and mGluR2 PAM/agonist compound in the RDBM are expected to be dose dependent.
  • In this assay, the combination of levetiracetam and mGlu2 PAM/agonist compounds is expected to reduce dominant behavior indicating that the combination is active as an anti-manic.
  • B) Oral Tablets
  • As a specific embodiment of an oral composition, 100 mg of a mGluR2 PAM/agonist compound is formulated with sufficiently finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gel capsule.
  • While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.

Claims (22)

1-21. (canceled)
22. A method for treating epilepsy comprising administering to a patient in need thereof:
(a) a synaptic vesicle protein 2A (“SV2A”) ligand; and
Figure US20220143141A1-20220512-C00178
or a pharmaceutically acceptable salt thereof,
wherein the SV2A ligand and Compound 2a or the pharmaceutically acceptable salt thereof are administered in amounts that are therapeutically effective together, and
wherein the SV2A ligand and Compound 2a or the pharmaceutically acceptable salt thereof are administered together in a single dosage form or in separate dosage forms.
23. The method of claim 22, wherein the SV2A ligand and a free base of Compound 2a are administered.
24. The method of claim 22, wherein one or both of the SV2A and Compound 2a or the pharmaceutically acceptable salt thereof is in a non-effective dosage.
25. The method of claim 22, wherein the SV2A ligand is selected from the group consisting of levetiracetam, brivaracetam, and seletracetam.
26. The method of claim 25, wherein the SV2A ligand is levetiracetam or brivaracetam.
27. The method of claim 26, wherein the SV2A ligand is levetiracetam.
28. The method of claim 26, wherein the SV2A ligand is brivaracetam.
29. The method of claim 22, wherein the SV2A ligand and Compound 2a or the pharmaceutically acceptable salt thereof are administered in separate dosage forms.
30. The method of claim 29, wherein the separate dosage forms comprise:
(i) a first dosage form comprising the SV2A ligand, and at least one pharmaceutically acceptable excipient; and
(ii) a second dosage form comprising Compound 2a or the pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
31. The method of claim 30, wherein the first dosage form and the second dosage form are administered sequentially or simultaneously.
32. The method of claim 31, wherein the first dosage form and the second dosage form are administered sequentially.
33. The method of claim 31, wherein the first dosage form and the second dosage form are administered simultaneously.
34. The method of claim 22, wherein the SV2A ligand and Compound 2 or the pharmaceutically acceptable salt thereof are administered together in a single dosage form.
35. The method of claim 22, wherein the SV2A ligand and Compound 2a or the pharmaceutically acceptable salt thereof are orally administered.
36. The method of claim 34, wherein the single dosage form is an injectable solution or suspension.
37. The method of claim 30, wherein at least one of the first dosage form and the second dosage form is an injectable solution or suspension.
38. The method of claim 22, wherein the single dosage form or the separate dosage forms are part of a kit.
39. The method of claim 22, wherein the epilepsy is focal onset seizures.
40. The method of claim 22, wherein the epilepsy is myoclonic seizures.
41. The method of claim 22, wherein the epilepsy is primary generalized tonic-clonic seizures.
42. The method of claim 22, wherein the epilepsy is treatment resistant epilepsy.
US17/643,751 2014-01-21 2021-12-10 Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use Pending US20220143141A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US17/643,751 US20220143141A1 (en) 2014-01-21 2021-12-10 Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use

Applications Claiming Priority (14)

Application Number Priority Date Filing Date Title
US201461929795P 2014-01-21 2014-01-21
EP14153887.6 2014-02-04
EP14153880.1 2014-02-04
EP14153887 2014-02-04
EP14153880 2014-02-04
EP14183324 2014-09-03
EP14183324.4 2014-09-03
EP14187429.7 2014-10-02
EP14187429 2014-10-02
US201462091668P 2014-12-15 2014-12-15
PCT/EP2015/051029 WO2015110435A1 (en) 2014-01-21 2015-01-20 Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US201615112818A 2016-07-20 2016-07-20
US16/720,750 US11369606B2 (en) 2014-01-21 2019-12-19 Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US17/643,751 US20220143141A1 (en) 2014-01-21 2021-12-10 Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US16/720,750 Continuation US11369606B2 (en) 2014-01-21 2019-12-19 Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use

Publications (1)

Publication Number Publication Date
US20220143141A1 true US20220143141A1 (en) 2022-05-12

Family

ID=53680862

Family Applications (4)

Application Number Title Priority Date Filing Date
US15/112,818 Active US10537573B2 (en) 2014-01-21 2015-01-20 Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US16/720,475 Active US11103506B2 (en) 2014-01-21 2019-12-19 Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US17/446,387 Active US12048696B2 (en) 2014-01-21 2021-08-30 Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US17/643,751 Pending US20220143141A1 (en) 2014-01-21 2021-12-10 Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use

Family Applications Before (3)

Application Number Title Priority Date Filing Date
US15/112,818 Active US10537573B2 (en) 2014-01-21 2015-01-20 Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US16/720,475 Active US11103506B2 (en) 2014-01-21 2019-12-19 Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US17/446,387 Active US12048696B2 (en) 2014-01-21 2021-08-30 Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use

Country Status (21)

Country Link
US (4) US10537573B2 (en)
EP (4) EP3431106B1 (en)
JP (1) JP6629740B2 (en)
KR (8) KR20220038826A (en)
CN (3) CN109999025A (en)
AU (7) AU2015208233B2 (en)
BR (2) BR122020008947B1 (en)
CA (1) CA2933394C (en)
CY (2) CY1122696T1 (en)
DK (1) DK3431106T3 (en)
EA (4) EA033889B1 (en)
MX (2) MX2016009471A (en)
MY (2) MY182627A (en)
PH (1) PH12016501213B1 (en)
PL (2) PL3096790T3 (en)
RS (2) RS59302B1 (en)
SG (1) SG11201605742TA (en)
SI (2) SI3431106T1 (en)
TW (5) TWI823160B (en)
UA (2) UA127921C2 (en)
WO (1) WO2015110435A1 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK3486242T3 (en) 2016-08-31 2022-01-10 Jiangsu Hengrui Medicine Co OXOPICOLINIDE DERIVATIVE, METHOD OF MANUFACTURE THEREOF AND PHARMACEUTICAL APPLICATION
US11596596B2 (en) 2016-10-14 2023-03-07 CNS Biosciences, Inc. Treating neuropathic pain in spinal cord injured individuals

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103462886A (en) * 2013-09-13 2013-12-25 四川鼎诺泰宸科技有限公司 Stable levetiracetam injection

Family Cites Families (498)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2976146A (en) 1958-11-28 1961-03-21 Eastman Kodak Co Novel cyan-forming couplers
GB1039113A (en) 1964-08-06 1966-08-17 Ucb Sa New n-substituted lactams
GB1309692A (en) 1970-02-13 1973-03-14 Ucb Sa N-substituted lactams
BE790440A (en) 1971-10-23 1973-04-24 Bayer Ag
JPS524071B2 (en) 1972-01-20 1977-02-01
JPS538707B2 (en) 1974-02-05 1978-03-31
US3906953A (en) 1974-05-23 1975-09-23 American Optical Corp Endoscopic surgical laser system
SU509578A1 (en) 1974-09-19 1976-04-05 Стерлитамакский Химический Завод The method of producing propylenediamine
IE43079B1 (en) 1975-03-20 1980-12-17 Ici Ltd Quinolone derivatives
GB1502312A (en) 1975-03-20 1978-03-01 Ici Ltd Quinolone derivatives
FR2311776A1 (en) 1975-05-23 1976-12-17 Sogeras 2,4-DIAMINO-5-CHLORO-6 PYRIMIDINES AND PROCESS FOR THEIR PREPARATION
JPS5346133Y2 (en) 1975-06-24 1978-11-04
JPS524071A (en) 1975-06-30 1977-01-12 Matsushita Electric Works Ltd Buffer device for electomagnetic contactor
GB1570494A (en) 1975-11-28 1980-07-02 Ici Ltd Thienopyrimidine derivatives and their use as pesticides
JPS5382783A (en) 1976-12-29 1978-07-21 Yamanouchi Pharmaceut Co Ltd Novel pyridone derivs and process for their preparation
US4196207A (en) 1977-05-23 1980-04-01 Ici Australia Limited Process for controlling eradicating or preventing infestations of animals by Ixodid ticks
DE2750288A1 (en) 1977-11-10 1979-05-17 Thomae Gmbh Dr K NEW 9- (OMEGA-HETEROARYLAMINO-ALKYLAMINO) -ERYTHROMYCINE, THEIR SALTS, METHOD FOR THE PRODUCTION THEREOF AND THE MEDICINAL PRODUCTS CONTAINING THEM
JPS5676589A (en) 1979-11-28 1981-06-24 Tokyo Shibaura Electric Co Wiring pattern
JPS5718381A (en) 1980-07-08 1982-01-30 Mitsubishi Electric Corp Printed circuit board
JPS6057300B2 (en) 1980-09-11 1985-12-14 株式会社東芝 Energy transfer device between superconducting coils
US4432979A (en) 1981-10-26 1984-02-21 William H. Rorer, Inc. Pyridone compounds
EP0082023A3 (en) 1981-12-16 1983-07-20 Sankyo Company Limited Thienopyrimidine derivatives, their preparation and their medical use
US4358453A (en) 1982-01-08 1982-11-09 Schering Corporation 1,2,4-Triazolo[4,3-a]pyridines
US4520025A (en) 1982-07-21 1985-05-28 William H. Rorer, Inc. Bicyclic nitrogen heterocyclic ethers and thioethers, and their pharmaceutical uses
JPS60159184A (en) 1984-01-27 1985-08-20 Agency Of Ind Science & Technol Anode for electrolyzing water
DE3406329A1 (en) 1984-02-22 1985-08-22 Merck Patent Gmbh, 6100 Darmstadt PYRIDONE
GB8412357D0 (en) 1984-05-15 1984-06-20 Ucb Sa Pharmaceutical composition
GB8412358D0 (en) 1984-05-15 1984-06-20 Ucb Sa Pharmaceutical composition
US4550166A (en) 1984-05-21 1985-10-29 American Cyanamid Company (Pyridinyl)-1,2,4-triazolo[4,3-a]pyridines
JPS6110557U (en) 1984-06-25 1986-01-22 株式会社日立製作所 Column connection adapter
JPH0219439Y2 (en) 1985-07-08 1990-05-29
JPS6211797U (en) 1985-07-08 1987-01-24
JPS6211798A (en) 1985-07-09 1987-01-20 Tokyo Gas Co Ltd Method of increasing heat of liquefied natural gas
DE3717561A1 (en) 1987-05-25 1988-12-08 Thomae Gmbh Dr K INDOL, ISOCHINOLINE AND BENZAZEPINE DERIVATIVES, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF
US5175157A (en) 1985-11-27 1992-12-29 Boehringer Ingelheim Gmbh Cyclic amine derivatives, pharmaceutical compositions containing these compounds and methods for preparing them
JPH081861Y2 (en) 1986-06-13 1996-01-24 カシオ計算機株式会社 Printing device cartridge structure
JPS6211797A (en) 1986-07-24 1987-01-20 Idemitsu Petrochem Co Ltd Thermal decomposition pipe for hydrocarbon
US4866074A (en) 1987-05-08 1989-09-12 Rorer Pharmaceutical Corporation Naphtheridinone- and pyridooxazinone-pyridone compounds, cardiotonic compositions including same, and their uses
EP0308020A3 (en) 1987-09-18 1990-12-05 Merck & Co. Inc. 5-(aryl and heteroaryl)-6-(aryl and heteroaryl)-1,2-dihydro-2-oxo 3-pyridinecarboxylic acids and derivatives thereof
US5260293A (en) 1988-01-30 1993-11-09 Merck Sharp & Dohme Limited Pyrazines, pyrimidines and pyridazines useful in the treatment of senile dementia
GB8804448D0 (en) 1988-02-25 1988-03-23 Smithkline Beckman Intercredit Compounds
JP2614081B2 (en) 1988-05-27 1997-05-28 大塚化学株式会社 Method for producing optically active β-lactam derivative
JPH02124871A (en) 1988-07-27 1990-05-14 Dainippon Pharmaceut Co Ltd 1-substituted heterocyclic carboxylic acid amide derivative
DE68923527D1 (en) 1988-10-20 1995-08-24 Sandoz Ag Fiber reactive azo dyes.
GB8827389D0 (en) 1988-11-23 1988-12-29 Ucb Sa Process for preparation of(s)alpha-ethyl-2-oxo-1-pyrrolidineacetamide
US5032602A (en) 1988-12-14 1991-07-16 Bayer Aktiengesellschaft Inhibiting HMG-CoA reductase with novel substituted 2-pyridones and pyrid-2-thiones
HU206337B (en) 1988-12-29 1992-10-28 Mitsui Petrochemical Ind Process for producing pyrimidine derivatives and pharmaceutical compositions
JPH02277044A (en) 1989-04-19 1990-11-13 Fuji Photo Film Co Ltd Silver halide photographic sensitive material
US5236917A (en) 1989-05-04 1993-08-17 Sterling Winthrop Inc. Saccharin derivatives useful as proteolytic enzyme inhibitors and compositions and method of use thereof
US5280026A (en) 1989-05-30 1994-01-18 Smithkline Beecham Intercredit B.V. Thienopyrimidines
AU622330B2 (en) 1989-06-23 1992-04-02 Takeda Chemical Industries Ltd. Condensed heterocyclic compounds having a nitrogen atom in the bridgehead for use as fungicides
US4978663A (en) 1989-08-16 1990-12-18 Hoechst-Roussel Pharmaceuticals Inc. 5-(1-aminocyclohexyl)-2(1H)-pyridinone compounds which have pharmaceutical utility
GB8926560D0 (en) 1989-11-24 1990-01-17 Zambeletti Spa L Pharmaceuticals
IL96432A0 (en) 1989-11-30 1991-08-16 Schering Ag Pesticidal compositions containing pyridine derivatives and novel pyridine derivatives
DE3940480A1 (en) 1989-12-07 1991-06-13 Bayer Ag CHROMOGENIC ENAMINE COMPOUNDS, THEIR PRODUCTION AND USE AS A COLOR IMAGE
AU6979091A (en) 1989-12-22 1991-07-24 Upjohn Company, The Pyridinones useful as antiatherosclerotic agents
FR2657610A1 (en) 1990-01-29 1991-08-02 Rhone Poulenc Agrochimie TRIAZOLOPYRIDINES HERBICIDES.
GB9104238D0 (en) 1990-03-16 1991-04-17 Ici Pharma 3-tetrazolylthiomethyl cephalosporin antibiotics
DE4008726A1 (en) 1990-03-19 1991-09-26 Basf Ag Thieno-(2,3-D)pyrimidine derivs. - are plant growth regulators, herbicides and pesticides, esp. insecticides
AU651337B2 (en) 1990-03-30 1994-07-21 Dowelanco Thienopyrimidine derivatives
JP2503317Y2 (en) 1990-05-25 1996-06-26 日本電気株式会社 Air conditioner
RU1796625C (en) 1990-06-27 1993-02-23 Киевский Государственный Университет Им.Т.Г.Шевченко 3-amino-7-nitro-4-(2,3,4-trimethoxyphenyl)-2-phenyl-1(2h) isoquinolone having analeptic effect
DE69131268T2 (en) 1990-09-21 1999-12-30 Rohm And Haas Co., Philadelphia Dihydropyridazinone and pyridazinone as fungicides
KR920008026A (en) 1990-10-24 1992-05-27 오노 화아마슈티칼 캄파니 리미팃드 Isoquinolinone derivatives or nontoxic acid addition salts thereof or hydrates thereof, methods for preparing the same, and pharmaceutical compositions comprising the same
WO1992018115A1 (en) 1991-04-18 1992-10-29 Dr Lo Zambeletti S.P.A. Use of heterocyclic compounds for the treatment of inflammatory pain
DE4122240A1 (en) 1991-07-05 1993-01-07 Boehringer Mannheim Gmbh DIBENZ (B, E) AZEPINE DERIVATIVES AND MEDICAMENTS CONTAINING THEREOF
DE4129340A1 (en) 1991-09-04 1993-03-11 Merck Patent Gmbh 1,2-dihydro-2-OXOPYRIDINE
US5332750A (en) 1991-09-04 1994-07-26 Merck Patent Gesellschaft Mit Beschrankter Haftung 1,2-dihydro-2-oxopyridines
DE4131924A1 (en) 1991-09-25 1993-07-08 Hoechst Ag SUBSTITUTED 4-ALKOXYPYRIMIDINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A PEST CONTROL
US5204198A (en) 1991-10-28 1993-04-20 Eastman Kodak Company Photoelectrographic elements utilizing nonionic sulfonic acid photogenerators
US5416099A (en) 1991-10-29 1995-05-16 Merck & Co., Inc. Fibrinogen receptor antagonists
DE4221583A1 (en) 1991-11-12 1993-05-13 Bayer Ag SUBSTITUTED BIPHENYLPYRIDONE
JP2878531B2 (en) 1991-12-16 1999-04-05 富士写真フイルム株式会社 Silver halide photographic material
US5378720A (en) 1991-12-19 1995-01-03 Sterling Winthrop Inc. Saccharin derivative proteolytic enzyme inhibitors
AU668694B2 (en) 1991-12-19 1996-05-16 Sanofi-Synthelabo Saccharin derivative proteolytic enzyme inhibitors
TW219935B (en) 1991-12-25 1994-02-01 Mitsubishi Chemicals Co Ltd
GB9200293D0 (en) 1992-01-08 1992-02-26 Wyeth John & Brother Ltd Piperazine derivatives
GB9201694D0 (en) 1992-01-27 1992-03-11 Smithkline Beecham Intercredit Compounds
JP3042156B2 (en) 1992-02-20 2000-05-15 田辺製薬株式会社 Naphthalene derivative, its production method and its synthetic intermediate
DE4206045A1 (en) 1992-02-27 1993-09-02 Bayer Ag SULFONYLBENZYL SUBSTITUTED PYRIDONE
US5922773A (en) 1992-12-04 1999-07-13 The Children's Medical Center Corp. Glaucoma treatment
AU660132B2 (en) 1992-12-21 1995-06-08 Bayer Aktiengesellschaft Substituted 4-phenyl-pyridones and 4-phenyl-2-alkoxypyridine
SE9300657D0 (en) 1993-02-26 1993-02-26 Astra Ab NEW COMPOUNDS
US5814645A (en) 1993-03-24 1998-09-29 Bayer Aktiengesellschaft Arylor hetaryl substituted nitrogen heterocycles and their use as pesticides
DE4316077A1 (en) 1993-05-13 1994-11-17 Bayer Ag Substituted mono- and bihydridylmethylpyridones
WO1994029273A1 (en) 1993-06-09 1994-12-22 Smithkline Beecham Corporation Bicyclic fibrinogen antagonists
DE4326758A1 (en) 1993-08-10 1995-02-16 Basf Ag [1,3,4] triazolo [1,5-a] pyridines
DE69433401T2 (en) 1993-08-19 2004-09-16 Janssen Pharmaceutica N.V. VASCELINATING DIHYDROBENZOPYRAN DERIVATIVES
KR100345046B1 (en) 1993-08-19 2002-12-05 얀센 파마슈티카 엔.브이. Vasoconstrictive Substituted Aryloxyalkyl Diamines
WO1995006032A1 (en) 1993-08-20 1995-03-02 Banyu Pharmaceutical Co., Ltd. Tyrosine kinase inhibitor
JP3701984B2 (en) 1993-08-31 2005-10-05 サントリー株式会社 Labeled cyclopropane derivative and process for producing the same
US5424435A (en) 1993-10-18 1995-06-13 Olin Corporation 1-hydroxy-6-substituted-2-pyridones
US5500420A (en) 1993-12-20 1996-03-19 Cornell Research Foundation, Inc. Metabotropic glutamate receptor agonists in the treatment of cerebral ischemia
US5679683A (en) 1994-01-25 1997-10-21 Warner-Lambert Company Tricyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
US5763489A (en) 1994-03-10 1998-06-09 Fujisawa Pharmaceutical Co., Ltd. Naphthalene derivatives as prostaglandin I2 agonsists
ES2079323B1 (en) 1994-06-21 1996-10-16 Vita Invest Sa DERIVATIVES OF INDOL USEFUL FOR THE TREATMENT OF THE MIGRAINE, COMPOSITION AND CORRESPONDING USE.
GB9416554D0 (en) 1994-08-19 1994-10-12 Ciba Geigy Ag Glutamate receptor
WO1996005828A1 (en) 1994-08-24 1996-02-29 Eli Lilly And Company Pyrrolidinyl di-carboxylic acid derivatives as metabotropic glutamate receptor antagonists
US6017697A (en) 1994-11-14 2000-01-25 Eli Lilly And Company Excitatory amino acid receptor protein and related nucleic acid compounds
US5473077A (en) 1994-11-14 1995-12-05 Eli Lilly And Company Pyrrolidinyl di-carboxylic acid derivatives as metabotropic glutamate receptor agonists
US5512576A (en) 1994-12-02 1996-04-30 Sterling Winthrop Inc. 2-substituted 1,2,5,-thiadiazolidin-3-one 1,1-dioxides and compositions and method of use thereof
US5789426A (en) 1995-01-20 1998-08-04 Cornell Research Foundation, Inc. Method for the treatment of fibroproliferative disorders by application of inhibitors of protein hydroxylation
US5869486A (en) 1995-02-24 1999-02-09 Ono Pharmaceutical Co., Ltd. Fused pyrimidines and pyriazines as pharmaceutical compounds
DE19507522C2 (en) 1995-03-03 2003-05-28 Basf Ag Process for the preparation of 3,4-dihydroisoquinoline compounds and 3,4-dihydroisoquinolinium salts
TW324008B (en) 1995-03-13 1998-01-01 Ishihara Sangyo Kaisha Pyridone sulfonylurea compound, its production process and weed killer containing such compound
DE19510965A1 (en) 1995-03-24 1996-09-26 Asta Medica Ag New pyrido / 3,2-e / pyrazinone with anti-asthmatic activity and process for their preparation
CN1131210C (en) 1995-04-27 2003-12-17 三菱制药株式会社 Heterocyclic amide compounds and medicinal use of the same
JPH08325248A (en) 1995-05-26 1996-12-10 Chugoku Kayaku Kk New reagent for synthesizing tetrazole compound and production of tetrazole compound using the same
US5849587A (en) 1995-06-09 1998-12-15 Cornell Research Foundation, Inc. Method of inhibiting viral replication in eukaryotic cells and of inducing apoptosis of virally-infected cells
US5659033A (en) 1995-09-13 1997-08-19 Neurogen Corporation N-aminoalkylfluorenecarboxamides; a new class of dopamine receptor subtype specific ligands
ES2142089T3 (en) 1995-09-15 2000-04-01 Sanofi Synthelabo DERIVATIVES OF QUINOLEIN-2 (1H) -ONE, ITS PREPARATION AND ITS APPLICATION IN THERAPEUTICS.
US6130217A (en) 1995-09-20 2000-10-10 Pfizer Inc Compounds enhancing antitumor activity of other cytotoxic agents
JPH1045750A (en) 1995-09-20 1998-02-17 Takeda Chem Ind Ltd Azole compound, its production and use
AR004010A1 (en) 1995-10-11 1998-09-30 Glaxo Group Ltd HETERO CYCLIC COMPOUNDS
PL326695A1 (en) * 1995-11-16 1998-10-26 Lilly Co Eli Derivatives of stimulating aminoacids
ES2260156T3 (en) 1995-12-08 2006-11-01 Janssen Pharmaceutica N.V. DERIVATIVES OF (IMIDAZOL-5-IL) METHYL-2-QUINOLINONE AS INHIBITORS OF PROTEIN FARNESIL-TRANSFERASA.
EP0880501A1 (en) 1996-02-02 1998-12-02 Zeneca Limited Heterocyclic compounds useful as pharmaceutical agents
GB9602166D0 (en) 1996-02-02 1996-04-03 Zeneca Ltd Aminoheterocyclic derivatives
GB9602294D0 (en) 1996-02-05 1996-04-03 Zeneca Ltd Heterocyclic compounds
US6084084A (en) 1996-02-21 2000-07-04 Nps Pharmaceuticals, Inc. Human metabotropic glutamate receptor
US5710274A (en) 1996-02-28 1998-01-20 Neurogen Corporation N-aminoalkyldibenzofurancarboxamides; new dopamine receptor subtype specific ligands
US5756518A (en) 1996-04-02 1998-05-26 Kowa Co., Ltd. Phenylene derivatives
JPH1029979A (en) 1996-04-12 1998-02-03 Ajinomoto Co Inc New pyridine derivative
WO1997046532A1 (en) 1996-06-03 1997-12-11 Boehringer Ingelheim Pharmaceuticals, Inc. 2-benzyl-4-sulfonyl-4h-isoquinolin-1,3-diones and their use as anti-inflammatory agents
WO1998006724A1 (en) 1996-08-09 1998-02-19 Yamanouchi Pharmaceutical Co., Ltd. Metabotropic glutamate receptor agonists
DE19632423A1 (en) 1996-08-12 1998-02-19 Merck Patent Gmbh Thienopyrimidines
TR199900303T2 (en) 1996-08-14 1999-06-21 Zeneca Limited Substituted pyrimidine derivatives and their pharmaceutical use.
AU4270297A (en) 1996-09-16 1998-04-02 Du Pont Pharmaceuticals Company Pyrazinones and triazinones and their derivatives thereof
DE19638486A1 (en) 1996-09-20 1998-03-26 Basf Ag Hetaroyl derivatives
DE19638484A1 (en) 1996-09-20 1998-03-26 Basf Ag Hetaroyl derivatives
DE19644228A1 (en) 1996-10-24 1998-04-30 Merck Patent Gmbh Thienopyrimidines
US6284794B1 (en) 1996-11-05 2001-09-04 Head Explorer Aps Method for treating tension-type headache with inhibitors of nitric oxide and nitric oxide synthase
HUP0001140A3 (en) 1996-12-05 2002-05-28 Amgen Inc Thousand Oaks Substituted pyrimidinone and pyridone compounds and methods of use
HU224918B1 (en) 1997-01-24 2006-04-28 Conpharma As Gemcitabine derivatives, process for their preparation and pharmaceutical compositions containing them
US5855654A (en) 1997-01-30 1999-01-05 Rohm And Haas Company Pyridazinones as marine antifouling agents
FR2759366B1 (en) 1997-02-11 1999-04-16 Centre Nat Rech Scient COMPOUNDS CONSTITUTING IN PARTICULAR CENTRAL NERVOUS SYSTEM RECEPTOR EFFECTORS SENSITIVE TO AMINO NEURO-EXCITER ACIDS, THEIR PREPARATION AND THEIR BIOLOGICAL APPLICATIONS
US6262068B1 (en) 1997-02-21 2001-07-17 Bristol-Myers Squibb Company Lactam derivatives as antiarrhythmic agents
AU6230098A (en) 1997-02-27 1998-09-18 Tanabe Seiyaku Co., Ltd. Isoquinolinone derivatives, process for preparing the same, and their use as phosphodiesterase inhibitors
ES2131463B1 (en) 1997-04-08 2000-03-01 Lilly Sa DERIVATIVES OF CYCLOPROPYLGLYCIN WITH PHARMACEUTICAL PROPERTIES.
GB9708945D0 (en) 1997-05-01 1997-06-25 Merck Sharp & Dohme Therapeutic agents
DE19728996A1 (en) 1997-07-07 1999-01-14 Basf Ag Triazole compounds and their use
ATE214704T1 (en) 1997-07-18 2002-04-15 Hoffmann La Roche 5H-THIAZOLO(3,2-A)PYRIMIDINE DERIVATIVES
EP1000015A1 (en) 1997-07-18 2000-05-17 Georgetown University Bicyclic metabotropic glutamate receptor ligands
CA2295295A1 (en) 1997-07-31 1999-02-11 Celgene Corporation Substituted alkanohydroxamic acids and method of reducing tnf.alpha. levels
EP1003505B1 (en) 1997-08-14 2004-03-24 F. Hoffmann-La Roche Ag Heterocyclic vinylethers against neurological disorders
US6358975B1 (en) 1997-08-15 2002-03-19 Johns Hopkins University Method of using selective parp inhibitors to prevent or treat neurotoxicity
US6121278A (en) 1997-09-03 2000-09-19 Guilford Pharmaceuticals, Inc. Di-n-heterocyclic compounds, methods, and compositions for inhibiting parp activity
WO1999011622A1 (en) 1997-09-03 1999-03-11 Guilford Pharmaceuticals Inc. Amino-substituted compounds, methods, and compositions for inhibiting parp activity
US20020028813A1 (en) 1997-09-03 2002-03-07 Paul F. Jackson Thioalkyl compounds, methods, and compositions for inhibiting parp activity
US6635642B1 (en) 1997-09-03 2003-10-21 Guilford Pharmaceuticals Inc. PARP inhibitors, pharmaceutical compositions comprising same, and methods of using same
US20020022636A1 (en) 1997-09-03 2002-02-21 Jia-He Li Oxo-substituted compounds, process of making, and compositions and methods for inhibiting parp activity
US6197785B1 (en) 1997-09-03 2001-03-06 Guilford Pharmaceuticals Inc. Alkoxy-substituted compounds, methods, and compositions for inhibiting PARP activity
AU9740998A (en) 1997-09-08 1999-03-29 F. Hoffmann-La Roche Ag Piperidine derivatives against malaria
DE69815008T2 (en) 1997-09-19 2004-04-01 Ssp Co., Ltd. Alpha-substituted phenylpropionic acid derivatives and medicaments containing them
WO2000012089A1 (en) 1998-08-31 2000-03-09 Merck & Co., Inc. Novel angiogenesis inhibitors
US6465484B1 (en) 1997-09-26 2002-10-15 Merck & Co., Inc. Angiogenesis inhibitors
EP1017682A4 (en) 1997-09-26 2000-11-08 Merck & Co Inc Novel angiogenesis inhibitors
US6162804A (en) 1997-09-26 2000-12-19 Merck & Co., Inc. Tyrosine kinase inhibitors
AU9781098A (en) 1997-10-02 1999-04-27 Merck & Co., Inc. Inhibitors of prenyl-protein transferase
BR9814820A (en) 1997-10-14 2000-10-03 Welfide Corp Piperazine compounds and their medical use
WO1999021992A2 (en) 1997-10-23 1999-05-06 Ganimed Pharmaceuticals Gmbh Nucleic acid molecules encoding a glutamate receptor
WO1999031062A1 (en) 1997-12-17 1999-06-24 Shionogi & Co., Ltd. Novel pyridine compounds
AU1719499A (en) 1997-12-18 1999-07-05 Boehringer Ingelheim Pharmaceuticals, Inc. Pyridones as src family sh2 domain inhibitors
US6013672A (en) 1997-12-18 2000-01-11 Uab Research Foundation Agonists of metabotropic glutamate receptors and uses thereof
DK1042293T3 (en) 1997-12-19 2008-07-14 Amgen Inc Substituted pyridine and pyridazine compounds and their pharmaceutical use
FR2772763B1 (en) 1997-12-24 2004-01-23 Sod Conseils Rech Applic NOVEL TETRACYCLIC CAMPTOTHECIN ANALOGS, PROCESSES FOR THEIR PREPARATION, THEIR USE AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
IT1298155B1 (en) 1998-01-19 1999-12-20 Moreno Paolini PYRIDID 3-OXIDE COMPOUNDS FOR THE TREATMENT OF MUSCLE-SKELETAL PATHOLOGIES, IN PARTICULAR FOR THE TREATMENT OF
US6664250B2 (en) 1998-01-20 2003-12-16 Bristol-Myers Squibb Co. Lactam derivatives as antiarrhythmic agents
ES2191412T3 (en) 1998-01-28 2003-09-01 Taisho Pharmaceutical Co Ltd DERIVATIVES OF AMINO ACIDS CONTAINING FLUOR.
CA2321153A1 (en) 1998-02-17 1999-08-19 Timothy D. Cushing Anti-viral pyrimidine derivatives
TR200002671T2 (en) 1998-03-17 2000-12-21 Pfizer Products Inc. Bicyclo (2.2.1) Heptane and related compounds
BR9909487A (en) 1998-04-08 2000-12-12 Novartis Ag N-pyridonyl herbicides
WO1999053956A1 (en) 1998-04-16 1999-10-28 Yamanouchi Pharmaceutical Co., Ltd. Remedies for obesity
EP0955301A3 (en) 1998-04-27 2001-04-18 Pfizer Products Inc. 7-aza-bicyclo[2.2.1]-heptane derivatives, their preparation and use according to their affinity for neuronal nicotinic acetylcholine receptors
DE19822198C2 (en) 1998-05-16 2003-02-13 Wella Ag Agents containing oxonol dyes and process for producing semi-permanent dyeings on hair
CA2333770A1 (en) 1998-06-04 1999-12-09 Abbott Laboratories Cell adhesion-inhibiting antinflammatory compounds
DE19826671A1 (en) 1998-06-16 1999-12-23 Hoechst Schering Agrevo Gmbh 1,3-oxazoline and 1,3-thiazoline derivatives, processes for their preparation and their use as pesticides
FR2781218B1 (en) 1998-07-15 2001-09-07 Lafon Labor PHARMACEUTICAL COMPOSITIONS COMPRISING 2-QUINOLONES
JP2000072751A (en) 1998-08-26 2000-03-07 Tanabe Seiyaku Co Ltd Isoquinolinone derivative
JP2000072731A (en) 1998-08-31 2000-03-07 Taisho Pharmaceut Co Ltd 4-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivative and pharmaceutical composition
PT1110943E (en) 1998-08-31 2004-08-31 Taisho Pharmaceutical Co Ltd DERIVATIVES 6-FLUOROBICYCLO- 3,1.0 | HEXANE
CH694053A5 (en) 1998-09-03 2004-06-30 Hoffmann La Roche Ver method for the production of 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid derivatives.
US6284759B1 (en) 1998-09-30 2001-09-04 Neurogen Corporation 2-piperazinoalkylaminobenzo-azole derivatives: dopamine receptor subtype specific ligands
SE9803518D0 (en) 1998-10-15 1998-10-15 Astra Pharma Prod Novel compounds
PE20001236A1 (en) 1998-11-13 2000-11-10 Lilly Co Eli EXCITING AMINO ACID RECEIVER MODULATORS
US6133271A (en) 1998-11-19 2000-10-17 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure thienopyrimidine derivatives
US5948911A (en) 1998-11-20 1999-09-07 Cell Pathways, Inc. Method for inhibiting neoplastic cells and related conditions by exposure to thienopyrimidine derivatives
EP1006112A1 (en) 1998-12-01 2000-06-07 Cerebrus Pharmaceuticals Limited 3-Hydroxy-2(1H)-pyridinone or 3-hydroxy-4(1H)-pyridinone derivatives useful as reactive oxygen species (ROS) scavengers
PT1133474E (en) 1998-12-04 2007-04-30 Bristol Myers Squibb Co 3-substituted-4-arylquinolin-2-one derivatives as potassium channel modulators
US6245759B1 (en) 1999-03-11 2001-06-12 Merck & Co., Inc. Tyrosine kinase inhibitors
TW564247B (en) 1999-04-08 2003-12-01 Akzo Nobel Nv Bicyclic heteraromatic compound
GB9908175D0 (en) 1999-04-09 1999-06-02 Lilly Co Eli Method of treating neurological disorders
US6972296B2 (en) 1999-05-07 2005-12-06 Encysive Pharmaceuticals Inc. Carboxylic acid derivatives that inhibit the binding of integrins to their receptors
US6723711B2 (en) 1999-05-07 2004-04-20 Texas Biotechnology Corporation Propanoic acid derivatives that inhibit the binding of integrins to their receptors
EP1183238A1 (en) 1999-05-17 2002-03-06 Eli Lilly And Company Metabotropic glutamate receptor antagonists
CN1789246A (en) 1999-06-02 2006-06-21 Nps药物有限公司 Metabotropic glutamate receptor antagonists and their use for treating central nervous system diseases
CA2390948A1 (en) 1999-06-03 2000-12-14 Abbott Laboratories Cell adhesion-inhibiting antiinflammatory compounds
EP1189873A1 (en) 1999-06-03 2002-03-27 Lilly, S.A. Excitatory amino acid receptor modulators
JP4783967B2 (en) 1999-07-21 2011-09-28 大正製薬株式会社 Pharmaceuticals containing fluorine-containing amino acid derivatives as active ingredients
EP1210338A2 (en) 1999-08-05 2002-06-05 IGT Pharma Inc. 1,4-diazepine derivatives for the treatment of diseases related to the central nervous system
US6660753B2 (en) 1999-08-19 2003-12-09 Nps Pharmaceuticals, Inc. Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
US7040838B2 (en) 1999-08-27 2006-05-09 Kristar Enterprises, Inc. High capacity catch basin filtration system with adjustable deflector ring
RU2259360C2 (en) 1999-10-15 2005-08-27 Ф.Хоффманн-Ля Рош Аг Derivatives of benzodiazepine and medicinal agent comprising thereof
DK1224175T3 (en) 1999-10-15 2004-07-12 Hoffmann La Roche Benzodiazepine derivatives as metabotropic glutamate receptor antagonists
RS50380B (en) 1999-10-19 2009-11-10 Merck & Co.Inc., Tyrosine kinase inhibitors
EP1230225A2 (en) 1999-11-01 2002-08-14 Eli Lilly And Company Pharmaceutically active 4-substituted pyrimidine derivatives
GB2355982A (en) 1999-11-03 2001-05-09 Lilly Co Eli Heterocyclic amino acids
WO2001039779A1 (en) * 1999-12-01 2001-06-07 Ucb, S.A. A pyrrolidineacetamide derivative alone or in combination for treatment of cns disorders
WO2001046190A1 (en) 1999-12-22 2001-06-28 Kyorin Pharmaceutical Co., Ltd. Tricyclic compounds and addition salts thereof
CN1395575A (en) 2000-01-20 2003-02-05 卫材株式会社 Novel piperidine compounds and drugs containing the same
GB0002100D0 (en) 2000-01-28 2000-03-22 Novartis Ag Organic compounds
US6800651B2 (en) 2000-02-03 2004-10-05 Eli Lilly And Company Potentiators of glutamate receptors
GB0004297D0 (en) 2000-02-23 2000-04-12 Ucb Sa 2-oxo-1 pyrrolidine derivatives process for preparing them and their uses
BR0108611A (en) 2000-02-25 2003-05-06 Hoffmann La Roche Adenosine Receptor Modulators
FR2806171B1 (en) 2000-03-10 2002-06-14 France Telecom CONTROLLABLE LITTLE PHOTON SOURCE
DE10012373A1 (en) 2000-03-14 2001-09-20 Dresden Arzneimittel Treating erectile dysfunction using new or known imidazo(1,5-a)pyrido(3,2-e)pyrazinone derivatives, as cGMP-selective phosphodiesterase V inhibitors free of cardiovascular side-effects
GB0007108D0 (en) 2000-03-23 2000-05-17 Novartis Ag Organic compounds
EP1268432A1 (en) 2000-03-24 2003-01-02 Millenium Pharmaceuticals, Inc. ISOQUINOLONE INHIBITORS OF FACTOR Xa
GB0007193D0 (en) 2000-03-25 2000-05-17 Univ Manchester Treatment of movrmrnt disorders
US20020094787A1 (en) 2000-04-07 2002-07-18 Avnet Mark S. Method and apparatus for transmitting information from point-to-point
DK1277754T3 (en) 2000-04-27 2005-11-14 Astellas Pharma Inc imidazopyridine
US6403588B1 (en) 2000-04-27 2002-06-11 Yamanouchi Pharmaceutical Co., Ltd. Imidazopyridine derivatives
EP1288199A4 (en) 2000-04-28 2005-10-12 Shionogi & Co Mmp-12 inhibitors
KR100551925B1 (en) 2000-04-28 2006-02-16 니혼노야쿠가부시키가이샤 Process for the preparation of 2-halobenzoic acids
NZ522674A (en) 2000-05-11 2004-10-29 Kenneth Curry Novel spiro[2.4]heptane amino carboxy compounds and derivatives thereof
US20020009713A1 (en) 2000-05-11 2002-01-24 Miller Freda D. Methods for identifying modulators of neuronal growth
JP2004507457A (en) 2000-05-11 2004-03-11 協和醗酵工業株式会社 2-piperidone compound
US7081481B2 (en) 2000-05-31 2006-07-25 Eli Lilly And Company Excitatory amino acid receptor modulators
KR100850728B1 (en) 2000-06-12 2008-08-06 에자이 알앤드디 매니지먼트 가부시키가이샤 1,2-dihydropyridine compounds, process for preparation of the same and use thereof
US6962976B2 (en) 2000-06-27 2005-11-08 Centre National De La Recherche Scientifique-Cnrs Human TREK2, a stretch- and arachidonic acid-sensitive K+ channel activated by inhalational anesthetics and niluzole
JP2002012533A (en) 2000-06-27 2002-01-15 Kao Corp Hair dye composition
JP2002003401A (en) 2000-06-27 2002-01-09 Japan Science & Technology Corp Brain-derived neurotrophic factor inducer
CA2411059A1 (en) 2000-06-28 2002-12-06 Taisho Pharmaceutical Co., Ltd. Novel dicarboxylic acid derivatives
DE10031390A1 (en) 2000-07-03 2002-01-17 Knoll Ag Pyrimidine derivatives and their use for the prophylaxis and therapy of cerebral ischemia
US20020041880A1 (en) 2000-07-05 2002-04-11 Defeo-Jones Deborah Method of treating cancer
JP2002069057A (en) 2000-07-07 2002-03-08 Kyowa Hakko Kogyo Co Ltd Piperidine derivative
JP2002040252A (en) 2000-07-27 2002-02-06 Shiseido Co Ltd Optical sheet containing cholesteric liquid crystal layer, information recording body using the same, method for recording information and method for discriminating information
DE10038019A1 (en) 2000-08-04 2002-02-14 Bayer Ag Substituted triazolopyride (az) ine
CN1446202A (en) 2000-08-11 2003-10-01 卫材株式会社 2-aminopyridine compounds and use thereof as drugs
CA2421120C (en) 2000-09-11 2008-07-15 Chiron Corporation Quinolinone derivatives as tyrosine kinase inhibitors
AU2002213422A1 (en) 2000-09-13 2002-03-26 Georgetown University Synthesis of 2-hydroxymethylglutamic acid and congeners thereof
JP2002105085A (en) 2000-09-28 2002-04-10 Yamanouchi Pharmaceut Co Ltd New imidazothiazole derivative
IL155163A0 (en) 2000-10-02 2003-10-31 Janssen Pharmaceutica Nv Metabotropic glutamate receptor antagonists
DE10058663A1 (en) 2000-11-25 2002-05-29 Merck Patent Gmbh Use of thienopyrimidines
WO2002051849A1 (en) 2000-12-26 2002-07-04 Daiichi Pharmaceutical Co., Ltd. Cdk4 inhibitors
JP4137636B2 (en) 2000-12-28 2008-08-20 塩野義製薬株式会社 Pyridone derivatives having cannabinoid type 2 receptor affinity
JP2002308882A (en) 2001-02-08 2002-10-23 Yamanouchi Pharmaceut Co Ltd Thienopyrimidine derivative
US20030130264A1 (en) 2001-02-16 2003-07-10 Tularik Inc. Methods of using pyrimidine-based antiviral agents
CA2439263C (en) 2001-03-02 2012-10-23 Frank Becker Three hybrid assay system
AU2002308354A1 (en) 2001-03-08 2002-09-24 Ilfa Industrieelektronik Und Leiterplattenfertigung Aller Art Gmbh Multilayer printed circuit board
US6596731B2 (en) 2001-03-27 2003-07-22 Hoffmann-La Roche Inc. Substituted imidazo[1,2-A] pyridine derivatives
WO2002079498A1 (en) 2001-04-02 2002-10-10 Merck & Co., Inc. In vivo methods of determining activity of receptor-type kinase inhibitors
RU2270197C2 (en) 2001-04-12 2006-02-20 Ф.Хоффманн-Ля Рош Аг DERIVATIVES OF DIHYDROBENZO[b][1,4]DIAZEPINE-2-ONE AS I mGluR2 ANTAGONISTS
AU2002312788B2 (en) 2001-04-12 2005-11-10 F. Hoffmann-La Roche Ag Dihydro-benzo [b] [1, 4] diazepin-2-one derivatives as mGluR2 antagonists II
SE0101579D0 (en) 2001-05-04 2001-05-04 Astrazeneca Ab New compounds
CZ20033053A3 (en) 2001-05-14 2004-05-12 Bristol@Myersásquibbápharmaácompany Substituted pyrazinones, pyridines and pyrimidines as corticotropin releasing factor ligands
WO2002094264A1 (en) 2001-05-23 2002-11-28 Tularik Inc. Ccr4 antagonists
CA2448306A1 (en) 2001-05-30 2002-12-05 Alteon Inc. Method for treating fibrotic diseases or other indications
CA2448317A1 (en) 2001-05-30 2002-12-05 Alteon Inc. Method for treating glaucoma v
WO2002098869A2 (en) 2001-06-05 2002-12-12 Boehringer Ingelheim Pharmaceuticals, Inc. 1,4-disubstituted benzo-fused cycloalkyl urea compounds
EP1408042A4 (en) 2001-06-14 2005-02-02 Banyu Pharma Co Ltd Novel isoxazolopyridone derivatives and use thereof
EP1397142A4 (en) 2001-06-19 2004-11-03 Bristol Myers Squibb Co Pyrimidine inhibitors of phosphodiesterase (pde) 7
JP2003012653A (en) 2001-06-28 2003-01-15 Yamanouchi Pharmaceut Co Ltd Quinazoline derivative
AU2002321878A1 (en) 2001-08-02 2003-02-17 Neurocrine Biosciences, Inc. Pyridinone and pyridazinone derivatives as gonadotropin-releasing hormone receptor antagonists
EP1425284A2 (en) 2001-09-11 2004-06-09 Smithkline Beecham Corporation Furo- and thienopyrimidine derivatives as angiogenesis inhibitors
JP4459619B2 (en) 2001-10-02 2010-04-28 グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー Compound
TWI330183B (en) 2001-10-22 2010-09-11 Eisai R&D Man Co Ltd
TW200406466A (en) 2001-11-13 2004-05-01 Ciba Sc Holding Ag Compositions comprising at least one oxonol dye and at least one metal complex
US6921762B2 (en) 2001-11-16 2005-07-26 Amgen Inc. Substituted indolizine-like compounds and methods of use
GB0129260D0 (en) 2001-12-06 2002-01-23 Eisai London Res Lab Ltd Pharmaceutical compositions and their uses
AU2002351732A1 (en) 2001-12-14 2003-06-30 Novo Nordisk A/S Compositions decreasing activity of hormone-sensitive lipase
ES2421511T3 (en) 2001-12-21 2013-09-03 X Ceptor Therapeutics Inc LXR modulators
PL208123B1 (en) 2001-12-27 2011-03-31 Taisho Pharmaceutical Co Ltd 6-fluorobicyclo[3.1.0]hexane derivatives
DE10164139A1 (en) 2001-12-27 2003-07-10 Bayer Ag 2-heteroaryl carboxamides
JP2005170790A (en) 2002-01-09 2005-06-30 Ajinomoto Co Inc N-alkylsulfonyl-substituted amide derivative
JP2005515254A (en) 2002-01-17 2005-05-26 スミスクライン ビーチャム コーポレーション Cycloalkylketoamide derivatives useful as cathepsin K inhibitors
WO2003062392A2 (en) 2002-01-18 2003-07-31 Ceretek Llc Methods of treating conditions associated with an edg receptor
US20050113283A1 (en) 2002-01-18 2005-05-26 David Solow-Cordero Methods of treating conditions associated with an EDG-4 receptor
WO2003064428A1 (en) 2002-01-29 2003-08-07 H. Lundbeck A/S Furano- and thienopyrimidines as neurokinase inhibitors
US6949542B2 (en) 2002-02-06 2005-09-27 Hoffman-La Roche Inc. Dihydro-benzo[b][1,4]diazepin-2-one derivatives
KR20040101220A (en) 2002-02-07 2004-12-02 더 유니버시티 오브 마이애미 Schwann cell bridge implants and phosphodiesterase inhibitors to stimulate cns nerve regeneration
US20040116489A1 (en) 2002-02-12 2004-06-17 Massey Steven Marc Synthetic excitatory amino acids
AU2003211931A1 (en) 2002-02-13 2003-09-04 Takeda Chemical Industries, Ltd. Jnk inhibitor
CN100486576C (en) 2002-02-14 2009-05-13 法玛西雅公司 Substituted pyridinones as modulators of P38MAP kinase
AU2003205558A1 (en) 2002-02-19 2003-09-09 H. Lundbeck A/S Thioibotenic acid and derivatives thereof
US6833380B2 (en) 2002-03-07 2004-12-21 Warner-Lambert Company, Llc Compounds that modulate PPAR activity and methods of preparation
EP1487794A1 (en) 2002-03-14 2004-12-22 Bayer Aktiengesellschaft Monocyclic aroylpyridinones as antiinflammatory agents
JP2005531520A (en) 2002-03-28 2005-10-20 メルク　エンド　カムパニー　インコーポレーテッド Substituted 2,3-diphenylpyridines
CA2479109C (en) 2002-03-29 2011-08-02 Janssen Pharmaceutica N.V. Radiolabelled quinoline and quinolinone derivatives and their use as metabotropic glutamate receptor ligands
EP1492595A1 (en) 2002-04-03 2005-01-05 Eli Lilly And Company Therapy for psychoses combining an atypical antipsychotic and an mglu2/3 receptor agonist
US6864261B2 (en) 2002-05-02 2005-03-08 Euro-Celtique S.A. Therapeutic agents useful for treating pain
CA2483084A1 (en) 2002-05-02 2003-11-13 Merck & Co., Inc. Tyrosine kinase inhibitors
CA2485166A1 (en) 2002-05-21 2003-12-04 Amgen Inc. Substituted pyrimidinone and pyridinone compounds
EA011231B1 (en) 2002-06-11 2009-02-27 Эли Лилли Энд Компани Prodrug of excitatory amino acid and use thereof
ATE345132T1 (en) 2002-06-13 2006-12-15 Vertex Pharma 2-UREIDO-6-HETEROARYL-3H-BENZOIMIDAZOLE-4- CARBOXYLIC ACID DERIVATIVES AND RELATED COMPOUNDS AS GYRASE AND/OR TOPOISOMERASE IV INHIBITORS FOR THE TREATMENT OF BACTERIAL INFECTIONS
MY141867A (en) 2002-06-20 2010-07-16 Vertex Pharma Substituted pyrimidines useful as protein kinase inhibitors
GB0214268D0 (en) 2002-06-20 2002-07-31 Celltech R&D Ltd Chemical compounds
WO2004004720A1 (en) 2002-07-03 2004-01-15 Astex Technology Limited 3-`(hetero) arylmethoxy ! pyridines and their analogues as p38 map kinase inhibitors
US7262194B2 (en) 2002-07-26 2007-08-28 Euro-Celtique S.A. Therapeutic agents useful for treating pain
US20040138238A1 (en) 2002-08-08 2004-07-15 Dhanoa Dale S. Substituted aminopyrimidine compounds as neurokinin antagonists
GB0218630D0 (en) 2002-08-10 2002-09-18 Tanabe Seiyaku Co Novel compounds
GB0218800D0 (en) 2002-08-13 2002-09-18 Celltech R&D Ltd Chemical compounds
WO2004017950A2 (en) 2002-08-22 2004-03-04 Piramed Limited Phosphadidylinositol 3,5-biphosphate inhibitors as anti-viral agents
CA2495756A1 (en) 2002-08-26 2004-03-04 Merck & Co., Inc. Acetophenone potentiators of metabotropic glutamate receptors
CA2496577A1 (en) 2002-08-28 2004-03-11 Intermune, Inc. Combination therapy for treatment of fibrotic disorders
MY139563A (en) 2002-09-04 2009-10-30 Bristol Myers Squibb Co Heterocyclic aromatic compounds useful as growth hormone secretagogues
BR0314192A (en) 2002-09-10 2005-07-26 Novartis Ag Mglu receptor antagonists for treating disorders associated with mglu receptors including addiction and depression.
CA2497356A1 (en) 2002-09-11 2004-03-25 Merck & Co., Inc. Nucleic acid sequences encoding novel point mutations on mglur2 and mglur3
ATE331716T1 (en) 2002-09-19 2006-07-15 Boehringer Ingelheim Ca Ltd NON-NUCLEOSIDIC INHIBITORS OF REVERSE TRANSCRIPTASE
JP2006505532A (en) 2002-09-19 2006-02-16 ベーリンガー インゲルハイム （カナダ） リミテッド Non-nucleoside reverse transcriptase inhibitors
US20040058997A1 (en) 2002-09-24 2004-03-25 David Gordon Daniel Method for treatment of disorders of personal attachment and deficient social interaction
AR044743A1 (en) 2002-09-26 2005-10-05 Nihon Nohyaku Co Ltd HERBICIDE, METHOD OF USE, DERIVED FROM REPLACED TIENOPIRIMIDINE, INTERMEDIATE COMPOUNDS, AND PROCEDURES USED TO PRODUCE THEM,
US7067658B2 (en) 2002-09-30 2006-06-27 Bristol-Myers Squibb Company Pyridino and pyrimidino pyrazinones
US7998163B2 (en) 2002-10-03 2011-08-16 Boston Scientific Scimed, Inc. Expandable retrieval device
WO2004038033A1 (en) 2002-10-23 2004-05-06 Daiichi Pure Chemicals Co., Ltd. Defructosylation method
US20040138204A1 (en) 2002-10-30 2004-07-15 Harrington James Frederick Compositions and methods for pain reduction
US7902203B2 (en) 2002-11-01 2011-03-08 Abbott Laboratories, Inc. Anti-infective agents
CA2504385C (en) 2002-11-01 2012-12-18 Abbott Laboratories Thiadiazine compounds and uses thereof
US6930117B2 (en) 2002-11-09 2005-08-16 The Procter & Gamble Company N-alkyl-4-methyleneamino-3-hydroxy-2-pyridones
EA013811B1 (en) 2002-11-21 2010-08-30 Новартис Вэксинес Энд Дайэгностикс, Инк. 2,4,6-trisubstituted pyrimidines as phosphotidylinositol (pi) 3-kinase inhibitors and their use in the treatment of cancer
WO2004054979A1 (en) 2002-12-18 2004-07-01 Takeda Pharmaceutical Company Limited Jnk inhibitors
US7173058B2 (en) 2002-12-30 2007-02-06 Celgene Corporation Fluoroalkoxy-substituted 1,3-dihydro-isoindolyl compounds and their pharmaceutical uses
GEP20084540B (en) 2003-01-14 2008-11-25 Arena Pharm Inc 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prpphylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
ITMI20030151A1 (en) 2003-01-30 2004-07-31 Recordati Ind Chimica E Farma Ceutica S P A USE OF SELECTIVE MGLU5 RECEPTOR ANTAGONISTS FOR THE TREATMENT OF NEUROMUSCULAR DYSFUNCTIONS OF THE LOWER URINARY TRACT.
ES2311795T3 (en) 2003-02-04 2009-02-16 F. Hoffmann-La Roche Ag MALONAMIDE DERIVATIVES AS GAMMA-SECRETASA INHIBITORS.
DE10306250A1 (en) 2003-02-14 2004-09-09 Aventis Pharma Deutschland Gmbh Substituted N-aryl heterocycles, processes for their preparation and their use as pharmaceuticals
EA200501348A1 (en) 2003-02-24 2006-02-24 Арена Фармасьютикалз Инк. SUBSTITUTED ARYL AND HETEROYARILE DERIVATIVES USED AS MODULATORS OF GLUTE METABOLISM METABOLISM AND FOR PREVENTION AND TREATMENT OF RELATED DISORDERS
EP1601358B1 (en) 2003-03-03 2007-12-19 F. Hoffmann-La Roche Ag 2,5-substituted tetrahydroisoquinolines for use as 5-ht6 modulators
ITFI20030058A1 (en) 2003-03-06 2004-09-07 Univ Firenze PHARMACEUTICAL FORMULATIONS CONTAINING THIAZOLIDINEDIONI
DE10311065A1 (en) 2003-03-13 2004-09-23 Abbott Gmbh & Co. Kg New 1-(cyclic amino-alkyl)-pyrimidin-2(1H)-one derivatives, are selective dopamine D3 receptor ligands useful for treating CNS disorders, especially schizophrenia or depression
TW200508197A (en) 2003-03-31 2005-03-01 Ucb Sa Indolone-acetamide derivatives, processes for preparing them and their uses
WO2004092123A2 (en) 2003-04-10 2004-10-28 Microbia, Inc. Inhibitors of fungal invasion
DE602004012083T2 (en) 2003-04-15 2009-04-23 Astrazeneca Ab New compounds that serve as enhancers of glutamate receptors
JP2004339080A (en) 2003-05-13 2004-12-02 Tokyo Institute Of Technology Hypertension therapeutic agent containing pyrazole derivative
MXPA05012281A (en) 2003-05-14 2006-05-19 Torreypines Therapeutics Inc Compouds and uses thereof in modulating amyloid beta.
WO2005040337A2 (en) 2003-05-20 2005-05-06 The Regents Of The University Of California METHODS FOR BINDING AGENTS TO β-AMYLOID PLAQUES
GB0315950D0 (en) 2003-06-11 2003-08-13 Xention Discovery Ltd Compounds
CA2572324A1 (en) 2003-07-02 2005-01-13 Warner-Lambert Company Llc Combination of an allosteric inhibitor of matrix metalloproteinase-13 and a ligand to an alpha-2-delta receptor
CA2532203A1 (en) 2003-07-14 2005-01-27 Decode Genetics Ehf. Method of diagnosis and treatment for asthma based on haplotype association
AU2004268820B2 (en) 2003-08-29 2011-07-21 Cancer Research Technology Ltd Pyrimidothiophene compounds
GB0320300D0 (en) 2003-08-29 2003-10-01 Cancer Rec Tech Ltd Pyrimidothiophene compounds
GB0322016D0 (en) 2003-09-19 2003-10-22 Merck Sharp & Dohme New compounds
MXPA06006026A (en) 2003-12-02 2006-08-23 Ucb Sa Imidazole derivatives, processes for preparing them and their uses.
UA85576C2 (en) 2004-02-18 2009-02-10 Астразенека Аб Tetrazole compounds and their use as metabotropic glutamate receptor antagonits
DE102004009039A1 (en) 2004-02-23 2005-09-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8- [3-Amino-piperidin-1-yl] xanthines, their preparation and use as pharmaceuticals
US7306631B2 (en) 2004-03-30 2007-12-11 The Procter & Gamble Company Keratin dyeing compounds, keratin dyeing compositions containing them, and use thereof
CN1968954A (en) 2004-04-12 2007-05-23 三共株式会社 Thienopyridine derivative
US7459562B2 (en) 2004-04-23 2008-12-02 Bristol-Myers Squibb Company Monocyclic heterocycles as kinase inhibitors
JP4866352B2 (en) 2004-06-11 2012-02-01 ユセベ ファルマ ソシエテ アノニム Method for producing 2-oxo-1-pyrrolidine derivative
GB0413605D0 (en) 2004-06-17 2004-07-21 Addex Pharmaceuticals Sa Novel compounds
US8063004B2 (en) 2004-07-22 2011-11-22 Malcera, L.L.C. Chemical composition of matter for the liquefaction and dissolution of asphaltene and paraffin sludges into petroleum crude oils and refined products at ambient temperatures and method of use
EP1773792A1 (en) 2004-07-30 2007-04-18 Merck & Co., Inc. Indanone potentiators of metabotropic glutamate receptors
EP1773774A4 (en) 2004-07-30 2009-12-30 Merck & Co Inc Heterocyclic acetophenone potentiators of metabotropic glutamate receptors
WO2006015737A1 (en) 2004-08-02 2006-02-16 Schwarz Pharma Ag Indolizine carboxamides and the aza and diaza derivatives thereof
WO2006024970A1 (en) 2004-08-11 2006-03-09 Koninklijke Philips Electronics, N.V. Ultrasonic diagnosis of ischemic cardiodisease
TW200613272A (en) 2004-08-13 2006-05-01 Astrazeneca Ab Isoindolone compounds and their use as metabotropic glutamate receptor potentiators
EP1781655A2 (en) 2004-08-18 2007-05-09 Pharmacia & Upjohn Company LLC Triazolopyridine compounds useful for the treatment of inflammation
DE102004044884A1 (en) 2004-09-14 2006-05-24 Grünenthal GmbH Substituted bicyclic imidazo-3-yl-amine compounds
GB0420722D0 (en) 2004-09-17 2004-10-20 Addex Pharmaceuticals Sa Novel allosteric modulators
GB0420719D0 (en) 2004-09-17 2004-10-20 Addex Pharmaceuticals Sa Novel allosteric modulators
CN101068577A (en) 2004-10-07 2007-11-07 皇家飞利浦电子股份有限公司 Use of the staudinger ligation in imaging and therapy end kits for imaging and therapy
AU2005299797A1 (en) 2004-10-25 2006-05-04 Merck & Co., Inc. Heterocyclic indanone potentiators of metabotropic glutamate receptors
NZ554399A (en) 2004-11-22 2010-10-29 Lilly Co Eli Potentiators of glutamate receptors
US7434262B2 (en) 2004-12-08 2008-10-07 At&T Intellectual Property I, L.P. Methods and systems that selectively resurrect blocked communications between devices
DE102004061288A1 (en) 2004-12-14 2006-06-29 Schering Ag New 3-amino-pyrazolo(3,4b)pyridine derivatives are protein tyrosine kinases inhibitors useful e.g. for treating hyperproliferation of body cells, neurodegenerative disease, blood vessel disease and angiogenic disease
CA2591003A1 (en) 2004-12-27 2006-07-06 Astrazeneca Ab Pyrazolone compounds as metabotropic glutamate receptor agonists for the treatment of neurological and psychiatric disorders
US7456289B2 (en) 2004-12-31 2008-11-25 National Health Research Institutes Anti-tumor compounds
WO2006091496A2 (en) 2005-02-24 2006-08-31 Merck & Co., Inc. Benzazole potentiators of metabotropic glutamate receptors
JP4801724B2 (en) 2005-03-23 2011-10-26 エフ．ホフマン−ラ ロシュ アーゲー Acetylenyl-pyrazolo-pyrimidine derivatives as mGluR2 antagonists
US20090030017A1 (en) 2005-04-08 2009-01-29 Eisai R & D Management Co., Ltd Therapeutic agent for dyskinesia
CA2610695A1 (en) 2005-06-01 2006-12-07 Ucb Pharma, S.A. 2-oxo-1-pyrrolidine derivatives and their therapeutic use on the central nervous system
US7572807B2 (en) 2005-06-09 2009-08-11 Bristol-Myers Squibb Company Heteroaryl 11-beta-hydroxysteroid dehydrogenase type I inhibitors
US7579360B2 (en) 2005-06-09 2009-08-25 Bristol-Myers Squibb Company Triazolopyridine 11-beta hydroxysteroid dehydrogenase type I inhibitors
WO2006137350A1 (en) 2005-06-22 2006-12-28 Kissei Pharmaceutical Co., Ltd. Novel furopyridine derivative, pharmaceutical composition comprising the derivative, and use of the derivative or composition
RU2008101923A (en) 2005-08-05 2009-09-10 Астразенека Аб (Se) TRICYCLIC BENZIMIDAZOLE AND THEIR APPLICATION AS MODULATORS OF METABOTROPIC GLUTAMATE RECEPTOR
WO2007021309A1 (en) 2005-08-12 2007-02-22 Astrazeneca Ab Substituted isoindolones and their use as metabotropic glutamate receptor potentiators
WO2007027669A1 (en) 2005-08-29 2007-03-08 Cps Biofuels, Inc. Improved biodiesel fuel, additives, and lubbricants
EP1764099A3 (en) 2005-09-17 2007-05-09 Speedel Experimenta AG Diaminoalcohol derivatives for the treatment of Alzheimer, malaria, HIV
PL1948654T3 (en) 2005-09-17 2009-12-31 Novartis Ag 5-amino-4-hydroxy-7- (imidazo [1,2-a] pyridin-6- ylmethyl)-8-methyl-nonamide derivatives and related compounds as renin inhibitors for the treatment of hypertension
US8492428B2 (en) 2005-09-20 2013-07-23 Mayo Foundation For Medical Education And Research Small-molecule botulinum toxin inhibitors
CN101273040B (en) 2005-09-27 2011-11-09 弗·哈夫曼-拉罗切有限公司 Oxadiazolyl pyrazolo-pyrimidines as MGLUR2 antagonists
ATE446294T1 (en) 2005-11-15 2009-11-15 Array Biopharma Inc N4-PHENYL-QUINAZOLINE-4-AMINE DERIVATIVES AND RELATED COMPOUNDS AS ERBB TYPE I RECEPTOR TYROSINE KINASE INHIBITORS FOR THE TREATMENT OF HYPERPROLIFERATIVE DISEASES
AU2006322349A1 (en) 2005-12-07 2007-06-14 Ucb Pharma, S.A. Xanthine derivatives, processes for preparing them and their uses
TW200732313A (en) 2005-12-15 2007-09-01 Astrazeneca Ab Oxazolidinone compounds and their use as metabotropic glutamate receptor potentiators
US8338621B2 (en) 2005-12-21 2012-12-25 Ucb S.A. Process for the preparation of 2-oxo-1-pyrrolidine derivatives
TW200804281A (en) 2006-02-16 2008-01-16 Astrazeneca Ab New metabotropic glutamate receptor-potentiating isoindolones
EP1993539A4 (en) 2006-03-02 2010-05-19 Glaxosmithkline Llc Thiazolones for use as pi3 kinase inhibitors
TWI417095B (en) 2006-03-15 2013-12-01 Janssen Pharmaceuticals Inc 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mglur2-receptors
GB0606774D0 (en) 2006-04-03 2006-05-10 Novartis Ag Organic compounds
GB0608263D0 (en) 2006-04-26 2006-06-07 Glaxo Group Ltd Compounds
WO2007135529A2 (en) 2006-05-23 2007-11-29 Pfizer Products Inc. Azabenzimidazolyl compounds as mglur2 potentiators
WO2007135527A2 (en) 2006-05-23 2007-11-29 Pfizer Products Inc. Benzimidazolyl compounds
JP5443981B2 (en) * 2006-06-15 2014-03-19 ウーツェーベー ファルマ ゲーエムベーハー Pharmaceutical composition having a synergistic anticonvulsant effect
ES2384400T3 (en) 2006-06-19 2012-07-04 Toray Industries, Inc. Therapeutic or prophylactic agent for multiple sclerosis
WO2008006540A1 (en) 2006-07-12 2008-01-17 Syngenta Participations Ag Triazolopyridine derivatives as herbicides
PE20121506A1 (en) 2006-07-14 2012-11-26 Amgen Inc TRIAZOLOPYRIDINE COMPOUNDS AS C-MET INHIBITORS
US8217177B2 (en) 2006-07-14 2012-07-10 Amgen Inc. Fused heterocyclic derivatives and methods of use
US8198448B2 (en) 2006-07-14 2012-06-12 Amgen Inc. Fused heterocyclic derivatives and methods of use
WO2008012623A1 (en) 2006-07-25 2008-01-31 Pfizer Products Inc. Benzimidazolyl compounds as potentiators of mglur2 subtype of glutamate receptor
WO2008012622A2 (en) 2006-07-25 2008-01-31 Pfizer Products Inc. Azabenzimidazolyl compounds as potentiators of mglur2 subtype of glutamate receptor
JP2010503656A (en) 2006-09-13 2010-02-04 アストラゼネカ アクチボラグ Spiro-oxazolidinone compounds and their use as metabotropic glutamate receptor potentiators
ATE542818T1 (en) 2006-10-11 2012-02-15 Amgen Inc IMIDAZO AND TRIAZOLOPYRIDINE COMPOUNDS AND METHOD OF USE THEREOF
WO2008057855A2 (en) 2006-11-01 2008-05-15 Bristol-Myers Squibb Company Heterocyclic compounds as modulators of glucocorticoid receptor, ap-i, and/or np-kappa-b activity
TW200831085A (en) 2006-12-13 2008-08-01 Merck & Co Inc Non-nucleoside reverse transcriptase inhibitors
CA2672172C (en) 2006-12-22 2016-05-03 Astex Therapeutics Limited Bicyclic heterocyclic compounds as fgfr inhibitors
JP5442449B2 (en) 2006-12-22 2014-03-12 アステックス、セラピューティックス、リミテッド New compounds
CN101605792A (en) 2007-02-09 2009-12-16 阿斯利康(瑞典)有限公司 Aza-isoindolones and they purposes as close metabotropic glutamate receptor potentiators-613
ES2320955B1 (en) 2007-03-02 2010-03-16 Laboratorios Almirall S.A. NEW DERIVATIVES OF 3 - ((1,2,4) TRIAZOLO (4,3-A) PIRIDIN-7-IL) BENZAMIDA.
ES2377165T3 (en) 2007-03-07 2012-03-23 Janssen Pharmaceutica N.V. N-alkylated phenoxy-substituted thiazolidinedione as alpha estrogen receptor modulators
AR065622A1 (en) 2007-03-07 2009-06-17 Ortho Mcneil Janssen Pharm DERIVATIVES OF 3-CIANO -4- (4-PHENYL- PIPERIDIN -1- IL) PIRIDIN -2- ONA
TW200845978A (en) 2007-03-07 2008-12-01 Janssen Pharmaceutica Nv 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
GB0704407D0 (en) 2007-03-07 2007-04-18 Glaxo Group Ltd Compounds
TW200900065A (en) 2007-03-07 2009-01-01 Janssen Pharmaceutica Nv 3-cyano-4-(4-pyridinyloxy-phenyl)-pyridin-2-one derivatives
US7846953B2 (en) 2007-03-07 2010-12-07 Janssen Pharmaceutica, Nv Substituted phenoxy thiazolidinediones as estrogen related receptor-α modulators
MX2009009520A (en) 2007-03-07 2009-11-18 Janssen Pharmaceutica Nv Substituted phenoxy aminothiazolones as estrogen related receptor-alpha modulators.
KR101547573B1 (en) 2007-03-09 2015-08-26 사노피 Substituted dihydro and tetrahydro oxazolopyrimidinones preparation and use thereof
WO2008124085A2 (en) 2007-04-03 2008-10-16 Exelixis, Inc. Methods of using combinations of mek and jak-2 inhibitors
WO2008130853A1 (en) 2007-04-17 2008-10-30 Astrazeneca Ab Hydrazides and their use as metabotropic glutamate receptor potentiators - 681
EP2152262A2 (en) 2007-04-27 2010-02-17 UCB Pharma, S.A. New heterocyclic derivatives useful for the treatment of cns disorders
CA2686651C (en) 2007-05-25 2015-11-24 Abbott Gmbh & Co. Kg Heterocyclic compounds as positive modulators of metabotropic glutamate receptor 2 (mglu2 receptor)
TWI417100B (en) 2007-06-07 2013-12-01 Astrazeneca Ab Oxadiazole derivatives and their use as metabotropic glutamate receptor potentiators-842
TW200911255A (en) 2007-06-07 2009-03-16 Astrazeneca Ab Metabotropic glutamate receptor oxadiazole ligands and their use as potentiators-841
WO2009004430A1 (en) 2007-06-29 2009-01-08 Pfizer Inc. N-benzyl oxazolidinones and related heterocycleic compounds as potentiators of glutamate receptors
ES2356032T3 (en) * 2007-09-14 2011-04-04 Ortho-Mcneil-Janssen Pharmaceuticals, Inc. 4-PHENYL-3,4,5,6-TETRAHIDRO-2H, 1'H- [1,4 '] BIPIRIDINIL-2'-ONAS 1,3'-DISUSTITUTED.
AU2008297877C1 (en) 2007-09-14 2013-11-07 Addex Pharma S.A. 1,3-disubstituted-4-phenyl-1 H-pyridin-2-ones
NZ584152A (en) 2007-09-14 2011-11-25 Ortho Mcneil Janssen Pharm 1,3-disubstituted 4-(aryl-x-phenyl)-1h-pyridin-2-ones
US20100324049A1 (en) 2007-09-27 2010-12-23 Makoto Ando Diaryl ketimine derivative having antagonism against melanin-concentrating hormone receptor
US8119658B2 (en) 2007-10-01 2012-02-21 Bristol-Myers Squibb Company Triazolopyridine 11-beta hydroxysteroid dehydrogenase type I inhibitors
CA2704436C (en) 2007-11-14 2016-01-05 Ortho-Mcneil-Janssen Pharmaceuticals, Inc. Imidazo[1,2-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors
EP2244576A4 (en) 2008-01-24 2011-06-08 Merck Sharp & Dohme 3,5-substituted-1,3-oxazolidin-2-one derivatives
JP5309162B2 (en) 2008-03-06 2013-10-09 サノフイ Substituted dihydro, trihydro and tetrahydrocycloalkyl oxazolopyrimidinones, their preparation and use
DE102008001056A1 (en) 2008-04-08 2009-10-15 Robert Bosch Gmbh Deflection device for a beam of an electromagnetic wave
JP2011520890A (en) 2008-05-15 2011-07-21 メルク・シャープ・エンド・ドーム・コーポレイション Oxazolobenzimidazole derivatives
WO2009140166A2 (en) 2008-05-15 2009-11-19 Merck & Co., Inc. Oxazolobenzimidazole derivatives
SA109300358B1 (en) 2008-06-06 2012-11-03 استرازينيكا ايه بي Isoindolone Metabotropic Glutamate receptor Potentiators
TW201006801A (en) 2008-07-18 2010-02-16 Lilly Co Eli Imidazole carboxamides
UY32049A (en) 2008-08-14 2010-03-26 Takeda Pharmaceutical CMET INHIBITORS
WO2010022081A1 (en) 2008-08-19 2010-02-25 Array Biopharma Inc. Triazolopyridine compounds as pim kinase inhibitors
TWI496779B (en) 2008-08-19 2015-08-21 Array Biopharma Inc Triazolopyridine compounds as pim kinase inhibitors
JP5547194B2 (en) 2008-09-02 2014-07-09 ジャンセン ファーマシューティカルズ， インコーポレイテッド． 3-Azabicyclo [3.1.0] hexyl derivatives as modulators of metabotropic glutamate receptors
RU2517181C2 (en) 2008-10-16 2014-05-27 Орто-Макнейл-Янссен Фармасьютикалз, Инк. Indole and benzomorpholine derivatives as modulator of metabotropic glutamate receptors
CN102232074B (en) 2008-11-28 2014-12-03 奥梅-杨森制药有限公司 Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors
AT507619B1 (en) 2008-12-05 2011-11-15 Oesterreichisches Forschungs Und Pruefzentrum Arsenal Ges M B H PROCESS FOR APPROXIMATING THE TIMELY OF TRAFFIC DATA
WO2010089303A1 (en) 2009-02-04 2010-08-12 Boehringer Ingelheim International Gmbh CYCLIC INHIBITORS OF 11 β-HYDROXYSTEROID DEHYDROGENASE 1
WO2010089372A1 (en) * 2009-02-09 2010-08-12 Ucb Pharma, S.A. Pharmaceutical compositions comprising brivaracetam
WO2010114726A1 (en) 2009-03-31 2010-10-07 Merck Sharp & Dohme Corp. Aminobenzotriazole derivatives
EP2417135A1 (en) 2009-04-07 2012-02-15 Schering Corporation Substituted triazolopyridines and analogs thereof
MY153913A (en) 2009-05-12 2015-04-15 Janssen Pharmaceuticals Inc 7-aryl-1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors
MY161325A (en) 2009-05-12 2017-04-14 Janssen Pharmaceuticals Inc 1, 2, 4-triazolo[4,3-a]pyridine derivatives and their use for the treatment or prevention of neurological and psychiatric disorders
BRPI1010831A2 (en) 2009-05-12 2016-04-05 Addex Pharmaceuticals Sa 1,2,4-triazolo [4,3-a] pyridine derivatives and their as positive allosteric modulators of mglur2 receptors
WO2010141360A1 (en) 2009-06-05 2010-12-09 Merck Sharp & Dohme Corp. Biaryl benzotriazole derivatives
LT2464645T (en) 2009-07-27 2017-10-25 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8975286B2 (en) 2009-08-20 2015-03-10 Merck Sharp & Dohme Corp. Ether benzotriazole derivatives
CN102002040A (en) 2009-09-01 2011-04-06 上海药明康德新药开发有限公司 Synthesis method of triazol pyridine ring compound
WO2011034741A1 (en) 2009-09-15 2011-03-24 Merck Sharp & Dohme Corp. Imidazopyridin-2-one derivatives
AR078172A1 (en) 2009-09-15 2011-10-19 Sanofi Aventis PHENOXIMETHYL DIHIDRO OXAZOLOPIRIMIDINONES REPLACED AND USE OF THE SAME AS MODULATORS OF METABOTROPIC RECEPTORS OF MGLUR
AR078171A1 (en) 2009-09-15 2011-10-19 Sanofi Aventis DIHYDROBENZOCICLOALQUILOXIMETIL-OXAZOLOPIRIMIDINONES REPLACED, PREPARATION AND USE OF THE SAME
AR078173A1 (en) 2009-09-15 2011-10-19 Sanofi Aventis BIFENYLOXIMETHYL DIHIDRO OXAZOLOPIRIMIDINONES REPLACED, ITS PREPARATION AND USE
JP5204071B2 (en) 2009-09-25 2013-06-05 パナソニック株式会社 Electric razor
CA2778194C (en) 2009-10-23 2016-07-12 Ucb Pharma, S.A. 2-oxo-1-pyrrolidinyl imidazothiadiazole derivatives
WO2011051490A2 (en) 2009-11-02 2011-05-05 N.V. Organon Heterocyclic derivatives
BR112012014235A2 (en) 2009-12-18 2016-06-14 Janssen Pharmaceutica Nv Bicyclic thiazoles as allosteric mglur5 receptor modulators
AR079343A1 (en) * 2009-12-21 2012-01-18 Lilly Co Eli ACID COMPOUND 2-AMINO-4- (4H-1,2,4-TRIAZOL-3-ILSULFANIL) BICYCLE [3.1.0] HEXANO-2,6-DICARBOXILICO, PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AND ITS USE TO PREPARE A MEDICINAL PRODUCT USEFUL TO TREAT A PSYCHIATRIC DISORDER
EP2542083B1 (en) 2010-03-04 2015-05-06 Merck Sharp & Dohme Corp. Positive allosteric modulators of mglur2
WO2011116356A2 (en) 2010-03-19 2011-09-22 Sanford-Burnham Medical Research Institute Positive allosteric modulators of group ii mglurs
US8735397B2 (en) * 2010-03-29 2014-05-27 Vanderbilt University Method for treating schizophrenia and related diseases
US8314120B2 (en) 2010-03-30 2012-11-20 Abbott Gmbh & Co. Kg Small molecule potentiators of metabotropic glutamate receptors
US8664214B2 (en) 2010-03-30 2014-03-04 AbbVie Deutschland GmbH & Co. KG Small molecule potentiators of metabotropic glutamate receptors I
US20130035332A1 (en) 2010-04-29 2013-02-07 Layton Mark E Substituted 1,3-Benzothiazol-2(3H)-Ones and [1,3]Thiazolo[5,4-B]Pyridin-2(IH)-Ones as Positive Allosteric Modulators of MGLUR2
KR20130094179A (en) 2010-04-30 2013-08-23 아스트라제네카 아베 Polymorphs of a metabotropic glutamate receptor positive allosteric modulator
US8765784B2 (en) 2010-06-09 2014-07-01 Merck Sharp & Dohme Corp. Positive allosteric modulators of MGLUR2
CN101893589B (en) 2010-06-29 2012-10-17 中国人民解放军第三0二医院 Sterility test method and totally closed bacteria collection ampoule incubator used thereby
CN105541849B (en) 2010-08-12 2018-03-23 勃林格殷格翰国际有限公司 The ketone derivatives of the dihydro-pyrazolo of 6 cycloalkyl 1,5 [3,4 d] pyrimidine 4 and its purposes as PDE9A inhibitor
US8993779B2 (en) 2010-08-12 2015-03-31 Merck Sharp & Dohme Corp. Positive allosteric modulators of MGLUR2
US8785481B2 (en) 2010-09-29 2014-07-22 Merck Sharp & Dohme Corp. Ether benzotriazole derivatives
WO2012062751A1 (en) 2010-11-08 2012-05-18 Janssen Pharmaceuticals, Inc. 1,2,4-TRIAZOLO[4,3-a]PYRIDINE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
ES2552879T3 (en) 2010-11-08 2015-12-02 Janssen Pharmaceuticals, Inc. 1,2,4-Triazolo [4,3-a] pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
CA2815120A1 (en) 2010-11-08 2012-05-18 Jose Ignacio Andres-Gil Radiolabelled mglur2 pet ligands
ES2552455T3 (en) 2010-11-08 2015-11-30 Janssen Pharmaceuticals, Inc. 1,2,4-Triazolo [4,3-a] pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
JP2014505108A (en) 2011-02-09 2014-02-27 ザ・ジョンズ・ホプキンス・ユニバーシティー Methods and compositions for improving cognitive function
HUE026889T2 (en) 2011-04-18 2016-07-28 Ucb Biopharma Sprl 2-oxo-1-imidazolidinyl imidazothiadiazole derivatives
WO2012143116A1 (en) 2011-04-18 2012-10-26 Ucb Pharma, S.A. 4-oxo-1-imidazolidinyl imidazothiadiazole derivatives
US20140088151A1 (en) 2011-05-03 2014-03-27 Douglas C. Beshore Alhydroxymethyl biaryl benzotriazole derivatives
EP2705024B1 (en) 2011-05-03 2015-12-16 Merck Sharp & Dohme Corp. Alkyne benzotriazole derivatives
US9139576B2 (en) 2011-05-03 2015-09-22 Merck Sharp & Dohme Corp. Aminomethyl biaryl benzotriazole derivatives
US8765767B2 (en) 2012-03-16 2014-07-01 Bristol-Myers Squibb Company Positive allosteric modulators of mGluR2
US20130289019A1 (en) 2012-04-26 2013-10-31 Amazing Grace, Inc. Methods of treating behaviorial and/or mental disorders
JP6211797B2 (en) 2012-05-14 2017-10-11 パナソニック株式会社 Deodorizing device with deodorant and refrigerator with deodorizing device
WO2013192306A1 (en) 2012-06-21 2013-12-27 Bristol-Myers Squibb Company Positive allosteric modulators of mglur2
WO2014078377A1 (en) 2012-11-14 2014-05-22 Agenebio, Inc. Methods and compositions for treating schizophrenia
JP6440625B2 (en) * 2012-11-14 2018-12-19 ザ・ジョンズ・ホプキンス・ユニバーシティー Methods and compositions for treating schizophrenia
EP2968237A4 (en) 2013-03-15 2016-08-31 Univ Johns Hopkins Methods and compositions for improving cognitive function
US9191739B2 (en) 2013-03-25 2015-11-17 Bose Corporation Active reduction of harmonic noise from multiple rotating devices
JP6211798B2 (en) 2013-05-17 2017-10-11 富士機械製造株式会社 Foreign matter inspection method and foreign matter inspection apparatus on substrate
JO3368B1 (en) 2013-06-04 2019-03-13 Janssen Pharmaceutica Nv 6,7-DIHYDROPYRAZOLO[1,5-a]PYRAZIN-4(5H)-ONE COMPOUNDS AND THEIR USE AS NEGATIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
JO3367B1 (en) 2013-09-06 2019-03-13 Janssen Pharmaceutica Nv 1,2,4-TRIAZOLO[4,3-a]PYRIDINE COMPOUNDS AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
JOP20150179B1 (en) 2014-08-01 2021-08-17 Janssen Pharmaceutica Nv 6,7-DIHYDROPYRAZOLO[1,5-a]PYRAZIN-4(5H)-ONE COMPOUNDS AND THEIR USE AS NEGATIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
JP6678672B2 (en) 2014-12-11 2020-04-08 ヤンセン ファーマシューティカ エヌ．ベー． 1,2,4-Triazolo [4,3-a] pyridine compounds and their use as positive allosteric modulators of the MGLUR2 receptor

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103462886A (en) * 2013-09-13 2013-12-25 四川鼎诺泰宸科技有限公司 Stable levetiracetam injection

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CN103462886- English (Year: 2013) *

Also Published As

Publication number Publication date
EP3424535A1 (en) 2019-01-09
RS59302B1 (en) 2019-10-31
SI3431106T1 (en) 2021-03-31
MY182627A (en) 2021-01-27
TW202206067A (en) 2022-02-16
EA201691467A1 (en) 2016-12-30
CN106061504A (en) 2016-10-26
US20200138813A1 (en) 2020-05-07
EA201891617A2 (en) 2018-12-28
AU2020286271B2 (en) 2022-11-10
KR102502485B1 (en) 2023-02-21
EA201891617A3 (en) 2019-04-30
PL3096790T3 (en) 2020-01-31
RS61334B1 (en) 2021-02-26
KR102414246B1 (en) 2022-06-27
TW201940168A (en) 2019-10-16
BR112016016390B1 (en) 2023-04-11
AU2015208233A1 (en) 2016-06-16
SI3096790T1 (en) 2019-11-29
US20160367554A1 (en) 2016-12-22
AU2022246400A1 (en) 2022-11-03
AU2021200512A1 (en) 2021-02-25
EA202192128A1 (en) 2022-02-28
EP3827830A1 (en) 2021-06-02
AU2019208181A1 (en) 2019-08-08
PL3431106T3 (en) 2021-06-28
KR20220038826A (en) 2022-03-29
KR20220084436A (en) 2022-06-21
BR122020008947B1 (en) 2023-04-11
KR102461134B1 (en) 2022-10-28
SG11201605742TA (en) 2016-08-30
AU2021200512B2 (en) 2023-01-19
TW202335671A (en) 2023-09-16
UA127921C2 (en) 2024-02-14
BR112016016390A2 (en) 2017-08-08
CN106061504B (en) 2019-09-06
KR20160108359A (en) 2016-09-19
US10537573B2 (en) 2020-01-21
EP3096790B1 (en) 2019-07-10
KR20220039824A (en) 2022-03-29
CY1122696T1 (en) 2021-03-12
TWI823160B (en) 2023-11-21
US12048696B2 (en) 2024-07-30
TW201620513A (en) 2016-06-16
EA033889B1 (en) 2019-12-05
MX2020011811A (en) 2020-12-07
US11103506B2 (en) 2021-08-31
AU2019208181B2 (en) 2021-02-11
PH12016501213A1 (en) 2016-08-22
JP2017503825A (en) 2017-02-02
US20220047593A1 (en) 2022-02-17
EP3096790A1 (en) 2016-11-30
MX2016009471A (en) 2016-10-13
PH12016501213B1 (en) 2016-08-22
TWI674095B (en) 2019-10-11
EA202192105A2 (en) 2021-11-30
TW201940196A (en) 2019-10-16
KR20200037877A (en) 2020-04-09
AU2015208233B2 (en) 2019-08-29
CN109999033B (en) 2022-12-23
TWI747005B (en) 2021-11-21
JP6629740B2 (en) 2020-01-15
CY1124207T1 (en) 2021-10-29
CA2933394C (en) 2024-02-20
AU2019208178A1 (en) 2019-08-08
CN109999033A (en) 2019-07-12
BR112016016390A8 (en) 2020-06-09
WO2015110435A1 (en) 2015-07-30
AU2020286269B2 (en) 2023-03-23
MY203464A (en) 2024-06-28
KR20220051273A (en) 2022-04-26
CN109999025A (en) 2019-07-12
KR20200130502A (en) 2020-11-18
EP3431106B1 (en) 2020-12-30
KR20220049612A (en) 2022-04-21
AU2020286271A1 (en) 2021-01-21
CA2933394A1 (en) 2015-07-30
TWI745716B (en) 2021-11-11
DK3431106T3 (en) 2021-03-15
AU2020286269A1 (en) 2021-01-21
UA128346C2 (en) 2024-06-19
EA202192105A3 (en) 2022-02-28
EP3431106A1 (en) 2019-01-23

Similar Documents

Publication Publication Date Title
US20220143141A1 (en) Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US11369606B2 (en) Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
NZ753453B2 (en) Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
EA045021B1 (en) COMBINATIONS CONTAINING POSITIVE ALLOSTERIC MODULATORS OF METABOTROPIC GLUTAMATERGIC RECEPTOR SUBTYPE 2 AND THEIR APPLICATION
NZ753451B2 (en) Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use

Legal Events

Date Code Title Description
STPP Information on status: patent application and granting procedure in general

Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: NOTICE OF ALLOWANCE MAILED -- APPLICATION RECEIVED IN OFFICE OF PUBLICATIONS

STPP Information on status: patent application and granting procedure in general

Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION

STPP Information on status: patent application and granting procedure in general

Free format text: NOTICE OF ALLOWANCE MAILED -- APPLICATION RECEIVED IN OFFICE OF PUBLICATIONS