WO2019043635A1 - Composés inhibiteurs de l'activité de d-amino acide oxydase - Google Patents

Composés inhibiteurs de l'activité de d-amino acide oxydase Download PDF

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WO2019043635A1
WO2019043635A1 PCT/IB2018/056660 IB2018056660W WO2019043635A1 WO 2019043635 A1 WO2019043635 A1 WO 2019043635A1 IB 2018056660 W IB2018056660 W IB 2018056660W WO 2019043635 A1 WO2019043635 A1 WO 2019043635A1
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pyridin
triazolo
bromo
chloro
mmol
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PCT/IB2018/056660
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English (en)
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Anssi Haikarainen
Muriel Joubert
Benedek KÁROLYI
Heikki KÄSNÄNEN
Mikko PASSINIEMI
Antti POHJAKALLIO
Gábor SZÁNTÓ
Matti VAISMAA
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Richter Gedeon Nyrt.
Orion Corporation
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Publication of WO2019043635A1 publication Critical patent/WO2019043635A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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

Definitions

  • the present invention relates to pharmacologically active triazolopyridinone compounds, or pharmaceutically acceptable esters, salts, hydrates or solvates thereof, as well as to pharmaceutical compositions containing them and to their use as modulators of D-amino acid oxidase (DAAO) activity, D-serine levels, D-serine oxidative products and N- methyl-D-aspartate (NMDA) receptor activity in the nervous system of a mammalian subject.
  • DAAO D-amino acid oxidase
  • NMDA N-methyl-D-aspartate
  • NMDA receptors are ion-channel receptors found at most excitatory synapses of the nervous system. They play an important role in processes underlying learning, memory and neuroplasticity. Activation of the ligand-gated NMDA receptor requires the simultaneous binding of an excitatory amino acid giutamate as well as the binding of a co-agonist, which can either be D-serine or glycine. Additionally, at the resting potential, the channel is blocked by Mg 2+ ions, but sufficient membrane depolarization removes the block allowing Ca 2 as well as Na + and K + ions to flow through the channel pore (Ozawa, S. et al. Prog, NeurobioL, 54 (199%) 581 ).
  • NMDA signaling is pivotal for higher order cognitive functions and imbalance of this system has been proposed to play a role in several cognitive and psychotic symptoms.
  • LTP long term potentiation
  • NMD A receptors While direct activation of NMD A receptors by increasing the extracellular concentration of the excitatory amino acid giutamate possesses risk of neuronal excitotoxicity, an indirect enhancement of the endogenous glutaminergic activity via NMDA receptors may offer a safer approach.
  • DAAO is a flavoenzyme that catalyzes the oxidative deamination of neutral and polar D-amino acids to corresponding imino acids and hydrogen peroxide.
  • DAAO enzyme is located in peroxisomes and is expressed in both the brain and peripheral tissues.
  • D-serine a neurotransmitter involved in MDA receptor activation.
  • D-serine is a more relevant co-agonist for the synaptic NMDA receptors than for the extrasynaptic NMDA receptors, which prefer glycine as a co-agonist (Papouin, T. et al. Cell, 150 (2012) 633).
  • the synaptic NMDA receptors are involved in the glutaminergic neurotransmission and are more likely to mediate neuronal excitotoxicity and cell death. Therefore, elevating the D-serine levels in the synaptic cleft via blockade of the breakdown by DAAO enzyme represents an alternative mechanism to enhance NMDA receptor activity and thus brain glutaminergic neurotransmission.
  • Dysfunction of central nervous system (CNS) glutamatergic signaling has been associated with many psychiatric and neurological disorders.
  • the most studied condition is schizophrenia based on the well-known effects of the NMDA receptor blockers ketamine and phencyclidine, which trigger schizophrenia-like condition in both healthy volunteers and preclinical animal models as well as induce the exacerbation of symptoms in patients with schizophrenia (Lahti, A. C. et al. Newopsychopharmacology, 25 (2001) 455).
  • D-serine levels facilitate the survival and function of mature neurons, which may offer disease modifying potential for DAAO enzyme inhibitors in various neurodegenerative conditions (Sultan, S. et al. Neuron, 88 (2015) 957).
  • NMDA receptors Since the role of NMDA receptors in the modulation of brain dopaminergic systems is well established, the augmentation of NMDA receptor function at the level of basal ganglia and limbic system could be beneficial in treating Parkinson's disease and related motor disorders as well as behavioral syndromes associated with this (Heresco-Levy, U. et al. Mov. Disord, 28 (2013) 419),
  • DAAO enzyme inhibition may also have other than NMDA receptor function enhancing effects.
  • Hydrogen peroxide a product of DAAO enzyme activity, is a well- known neurotoxin, which may induce neurodegeneration and neuropathic pain through oxidative stress. Reduction of spinal hydrogen peroxide levels by inhibiting DAAO enzyme has been confirmed to exert analgesic effects in preclinical pain models, so dampening the activity of the DAAO enzyme may have therapeutic potential in treating neuropathic pain states (Xie, D. et al. Eur. J. M ' ed. Chem,, 117 (2016) 19).
  • Non-limiting examples of disorders that may be treated with compounds inhibiting the DAAO enzyme include cognition-related disorders, neurodegenerative disorders and disorders associated with neuropathic pain.
  • DAAO enzyme inhibitors are useful for treating symptoms or condition associated with MDA receptor hypofunction such as schizophrenia, schizophreniform disorder, schizoaffective disorder and other psychotic disorders (e.g., psychotic disorder, psychosis), dementia and other cognitive disorders, anxiety disorders (e.g., generalized anxiety disorder, panic disorder), mood disorders (e.g., depressive disorders, major depressive disorders, bipolar disorders including bipolar I and II, bipolar mania, bipolar depression, apathy), posttraumatic stress disorder, eating disorders, addiction, sleep disorders, disorders usually first diagnosed in infancy, childhood or adolescence (e.g., attention-deficit disorder, autism spectrum disorders, disruptive behavior disorders), pain (e.g., neuropathic pain, inflammatory pain), neurodegenerative disorders (e.g., Parkinson' s disease, Alzheimer' s disease, Hunt
  • Known inhibitors of DAAO include benzoic acid, fused heterocycies (US 2010/0029737, WO 2008/089453/WO 2010/017418, WO 201 1/017634), furopyrroles (WO 2009/020814), 1,2,4-triazines (WO 2014/025993), 3-aminopyrazolines (WO 2007/093829), dihydroxy aromatic heterocycies (WO 2013/073577), hydroxyquinolinones (WO 2010/058314), pyridazinones (WO 2013/027000,
  • WO 2014/096757 pyridinones (WO 2013/004996), pyrimidinones (WO 2013/004995), pyrrolopyridines (WO 2010/005528), selenophenes and selenazoles (WO 2009/148564), quinazolinones and pyridopyrimidinones (CN 106749045 A), benzo[d]isothiazolones (Terry-Lorenzo, R. T. et al . J. Biomol. Screen., 20 (2015) 1218) and benzisoxazoles (WO 2005/066143, WO 2005/089753).
  • WO 2006/138695 discloses triazolopyridinone derivatives as cannabinoid receptor 1 (CB-1 ) antagonists.
  • WO 2012/003392 discloses triazolopyridinone derivatives as ion channel modulators for the treatment of cardiovascular diseases.
  • WO 2012/150829 discloses triazolopyridinone derivatives as glycogen synthase kinase-3 (GSK-3) inhibitors.
  • GSK-3 glycogen synthase kinase-3
  • WO 2013/074390 discloses triazolopyridinone derivatives which are useful as therapeutic agents for the treatment of CNS disorders associated with phosphodiesterase 10 (PDE10).
  • WO 2017/0463 8 discloses triazolopyridinone derivatives useful in treating, ameloriating or preventing viral diseases. 6-Bromo-8-fluoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one has been disclosed in US
  • the present invention relates to compounds of formula (I),
  • Ri and 13 ⁇ 4 are independently H, halogen, Q-ealkyl, haloCi-ealkyl, hydroxyCi-e.alkyl, C 3-5 Cycloalkyl, Cj-ealkoxy or cyano;
  • Rj is fluoro, chloro, bromo, C ⁇ alkyl, difluoromethyl or trif!uoromethyl;
  • the compound is not 6-bromo-8-fluoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 6-chloro- 7-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 7-(trifluoromethyl)-[l,2,4]triazolo[4,3- a]pyridin-3(2H)-one, 7-bromo-8-methoxy-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 8- fluoro-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 6-fluoro-[l,2,4]triazolo[4,3-a]pyridin- 3(2H) ⁇ one, 7-bromo-8-iodo-[l,2,4]triazolo[4,3-a]pyridin-3(2
  • the present invention provides a compound of formula (II),
  • Rj and R 2 are independently H, halogen, C h lky!, haloC 1 -6 alkyl, hydroxyCi ⁇ alkyl, C 3-5 Cycloalkyl, C 3 -5 CycloalkylC 1 ⁇ alkyl, C ⁇ alkoxy or cyano;
  • R 3 is fluoro, chloro, bromo, C h alky!, difluoromethyl, trifluoromethyl or cyano;
  • the present invention provides the use of a compound of formula (II), as defined above, for the manufacture of a medicament for the treatment or prevention of a disease associated with D-amino acid oxidase.
  • the present invention provides a method for the treatment or prevention of a disease associated with D-amino acid oxidase comprising administering to a mammal in need of such treatment or prevention an effective amount of at least one compound of formula (II), as defined above.
  • the compounds of formula (I), as defined above can be administered in combination with other compounds used for the treatment or prevention of a disease associated with D-amino acid oxidase.
  • the present invention provides a process for the manufacture of the compounds of formula (I).
  • the DAAO inhibitors provided by the present invention possess enhanced brain permeability.
  • the present invention relates to compounds of formul
  • Ri and R 2 are independently H, halogen, Ci_ 6 alkyl, haloC ⁇ alkyl, hydroxyC ⁇ alkyl, C3.5eyeloa.kyi, C 3 -scy cloalkylC ⁇ or cyano:
  • R-3 is fluoro, chloro, bromo, C ⁇ alkyl, difluoromethyl or trifluoromethyl;
  • the compound is not 6-bromo-8-fiuoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 6-chloro- 7-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 7-(trifiuoromethyl)-[l ,2,4]triazolo[4,3- a]pyridin-3(2H)-one, 7-bromo-8-methoxy-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 8- fluoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 6-fluoro-[ 1 ,2,4] triazolo[4,3 -a]pyridin- 3(2H)-one, 7-bromo-8-iodo-[l,2,4]triazolo[4,3--
  • the present invention relates to compounds of formula (I), wherein Ri and R 2 are independently H, halogen, Ci-eaikyl, haloCi-galkyl,
  • R 3 is fluoro, chloro, bromo, C h alky 1, difluoromethyi or trifluorom ethyl;
  • R 3 is fluoro, chloro, bromo, C h alky 1 or trifluoromethyl, i and R 2 are not simultaneously H;
  • the compound is not 8-bromo-7-iodo-[l.,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 8-chloro- 7-iodo-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 6-bromo-8-fluoro-[l,2,4]triazolo[4,3- a]pyridin-3(2H)-one, 6-bromo-8-methyl-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one, 6-chloro- 7-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H -one, 8-chloro-6-(trifiuoromethyl)- [ 1 ,2,4]triazolo[4,3-a]pyridin-3 (2H)-one, 8-bromo-6-methyl-[ 1 ,2,4]
  • Ri are independently H, halogen, hydroxyC
  • R is fluoro, chloro, bromo, difluoromethyi or trifluoromethyl.
  • the present invention relates to compounds of formula (I), wherein Ri and R 2 are independently H, halogen, methyl, trifluoromethyl, hydroxy methyl, cyclopropyl, methoxy or cyano;
  • R 3 is fluoro, chloro, bromo, methyl, difluoromethyl or trifluoromethyl.
  • the present invention relates to compounds of formula (I), wherein Ri and R 2 are independently H, halogen, or cyano; R 3 is fluoro, chloro, bromo, or trifluoromethyl.
  • the present invention relates to compounds of formula (I), wherein Rj and R 2 are independently H, halogen, haloCi-ealkyl or hydroxyCi-6aikyi;
  • j is fluoro, chloro, bromo, C h alky! or trifluoromethyl.
  • the present invention relates to compounds of formula (I), wherein Ri and R 2 are independently H, halogen or haloC 4 .6alk.yl;
  • R is chloro, bromo or C 1 -6 alkyl.
  • the present invention relates to compounds of formula (IV),
  • Rj is H or halogen
  • R 2 is H, halogen, haloCi-ealkyl, hydroxyCi-ealkyl or cyano;
  • R 3 is fluoro, chloro, bromo, Ci- 6 alkyl, difluoromethyl or trifluoromethyl;
  • R 2 is halogen or cyano
  • R is chloro or C h alky!.
  • the present invention relates to compounds of formula (IV
  • Ri is H or halogen
  • R 2 is H, halogen, C ⁇ alkyl, haloC ⁇ alkyl or hydroxyCi-ealkyi;
  • R 3 is fluoro, chloro, bromo, Ci-ealkyl, difluoromethyi or trifluoromethyl.
  • the present invention relates to compounds of formula (IV), wherein
  • Ri is halogen or Ci-ealkyl
  • R 3 is fluoro, chloro, bromo or trifluoromethyl.
  • the present invention relates to compounds of formula (I) selected from the group of:
  • halo or halogen, as used herein as such or as part of another group, refers to fluoro, chloro, bromo or iodo.
  • Ci -6 alkyl refers to a branched or straight chain saturated hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, i-propyl and t-butyl.
  • haloCi-ealkyl refers to at least one halogen, as defined above, bonded to the parent molecular moiety through an "Ci-calkyl” group, as defined above.
  • the halogens can be identical or different and the halogens can be attached to different carbon atoms or several halogens can be attached to the same carbon atom.
  • groups include, but are not limited to, difluoromethyl, trifluoromethyi and 2-chioroethyl.
  • hydroxyCi-ealkyl refers to a hydroxy group bonded to the parent molecular moiety through an "C ⁇ alkyl” group, as defined above, including, but not limited to, hydroxymethyi, 2-hydroxyethyl and 3-hydroxypropyl.
  • Cs-scycloaikyl refers to cyclopropyl, cyclobutyl or cyciopentyl.
  • CVscyeloalkyl group as defined above, bonded to the parent molecular moiety through an group, as defined above, including, but not limited to, cyclopropylmethyl, cyclobutylmethyl and 2- cyclopropylethyl.
  • the term as used herein refers to an C h alky! group, as defined above, bonded to the parent molecular moiety through an oxygen atom including, but not limited to, methoxy, ethoxy, n-propoxy, i-propoxy and t-butoxy.
  • pharmaceutically acceptable describes an ingredient that is useful in preparing a pharmaceutical composition, is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes those acceptable for veterinary use as well as human pharmaceutical use.
  • salt means nontoxic base addition salts of the compounds of the invention which are generally prepared by reacting the acid with a suitable organic or inorganic base.
  • hydrate means non-covalent combinations between water and solute.
  • solvate means non-covalent combinations between solvent and solute.
  • Solvents include, but are not limited to, ethanol, 2-propanol, acetonitrile and tetrahydrofuran.
  • the present invention relates to a compound of formula (II),
  • Ri and R 2 are independently H, halogen, Ci-eaikyl, haloCi-galkyl,
  • R3 is fluoro, chloro, bromo, C h alky!, difluoromethyl, trifiuorom ethyl or cyano;
  • the present invention relates to the use of a compound of formula (II), as defined above, for the manufacture of a medicament for the treatment or prevention of a disease associated with D-amino acid oxidase.
  • the present invention relates to a method for the treatment or prevention of a disease associated with D-amino acid oxidase comprising administering to a mammal in need of such treatment or prevention an effective amount of at least one compound of formula (II), as defined above.
  • the disease associated with D-amino acid oxidase is selected from the group of: schizophrenia, schizophreniform disorder, schizoaffective disorder and other psychotic disorders (e.g., psychotic disorder, psychosis), dementia and other cognitive disorders, anxiety disorders (e.g., generalized anxiety disorder, panic disorder), mood disorders (e.g., depressive disorders, major depressive disorders, bipolar disorders including bipolar I and II, bipolar mania, bipolar depression, apathy), posttraumatic stress disorder, eating disorders, addiction, sleep disorders, disorders usually first diagnosed in infancy.
  • schizophrenia schizophreniform disorder, schizoaffective disorder and other psychotic disorders
  • schizoaffective disorder and other psychotic disorders e.g., psychotic disorder, psychosis
  • dementia and other cognitive disorders e.g., anxiety disorders (e.g., generalized anxiety disorder, panic disorder), mood disorders (e.g., depressive disorders, major depressive disorders, bipolar disorders including bipolar I and II, bipolar mania
  • childhood or adolescence e.g., attention-deficit disorder, autism spectrum disorders and disruptive behavior disorders
  • pain e.g., neuropathic pain, inflammatory pain
  • neurodegenerative disorders e.g., Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis
  • motor defective syndromes including ' NMD A receptor hypofunction in cerebellum as well as other movement disorders.
  • the disease associated with D-amino acid oxidase is selected from the group of: schizophrenia, schizophreniform disorder, schizoaffective disorder, cognitive disorders and pain.
  • the invention therefore, further relates to combination therapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention is administered with another therapeutic agent or agents and/or with serine, for the treatment of one or more of the conditions previously indicated.
  • therapeutic agents may be selected from: antidepressants, antipsychotics, anxiolytics, anticonvulsants, mood stabilizers, 5 ⁇ ⁇ ligands, mGluR2 agonists, alpha 7 nicotinic agonists, chemokine receptor CCR1 inhibitors, delta opioid agonists and compounds used in the treatment of Alzheimer's disease, Parkinson's disease, migraine, stroke, neuropathic pain or nociceptive pain.
  • the present invention provides a process for the manufacture of the compounds of formula (I) according to the following reaction route:
  • Step a can be carried out using 1-10 equivalents of hydrazine hydrate at elevated rature in solvents, eg, methanol, ethanol, isopropanol or dioxane.
  • solvents eg, methanol, ethanol, isopropanol or dioxane.
  • Step b can be carried out using 1-1.5 equivalents of carbonyl-transfer reagent, e.g., phosgene, triphosgene or carbonyl diimidazole in different solvents, e.g., THF, acetonitrile or dioxane.
  • carbonyl-transfer reagent e.g., phosgene, triphosgene or carbonyl diimidazole
  • solvents e.g., THF, acetonitrile or dioxane.
  • Step c can be carried out using palladium catalyst, e.g., tris(dibenzylideneacetone)dipalladium(0) or palladium(II) acetate, suitable ligand, e.g., 1, 1 '- bis(diphenylphosphino)ferrocene, base, e.g., cesium carbonate or potassium carbonate, and di-tert-butyl hvdrazodiformate in aprotic solvent e.g., 1 ,2-dichloroethane, chlorobenzene and toluene.
  • palladium catalyst e.g., tris(dibenzylideneacetone)dipalladium(0) or palladium(II) acetate
  • suitable ligand e.g., 1, 1 '- bis(diphenylphosphino)ferrocene
  • base e.g., cesium carbonate or potassium carbonate
  • Step d can be carried out using 2-20 equivalents of HC1 in ether-type solvent e.g., ether or dioxane typically in room temperature but sometimes in elevated temperatures.
  • Step e can be carried out using 2-5 equivalents of alkyi-, e.g., methyl hydrazinecarboxylate or semicarbazide at elevated temperature in alcohol, e.g., methanol, ethanoi or isopropyl alcohol.
  • Step / can be carried out by nitrating the amino group with the use of 1,5-3 equivalents of nitric acid in sulphuric acid.
  • Step g and h can be carried out together using 1-5 equivalents of chemical reducing agents, e.g., Zn/ammonium chloride in THF/water/MeOH mixture or tin(II) chloride in acidic conditions, followed by the reaction of 1-2 equivalents of triphosgene in the same solvent system, without the isolation of intermediate.
  • chemical reducing agents e.g., Zn/ammonium chloride in THF/water/MeOH mixture or tin(II) chloride in acidic conditions
  • triphosgene 1-2 equivalents of triphosgene in the same solvent system
  • esters of hydroxy groups may be prepared by known methods using pharmaceutically acceptable carboxylic acids that are conventional in the field of pharmaceuticals.
  • Representative examples of pharmaceutically acceptable esters of hydroxy groups include, but are not limited to, esters formed with acetic acid and propionic acid.
  • Pharmaceutically acceptable salts such as metal salts and acid addition salts, with organic acids or inorganic acids are well known in the field of pharmaceuticals.
  • pharmaceutically acceptable metal salts include, but are not limited to, lithium, sodium, potassium, calcium, magnesium, aluminum and zinc salts.
  • pharmaceutically acceptable acid addition salts include, but are not limited to, chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, methane sulfonates, formates, tartrates, maieates, citrates, benzoates, salicylates and ascorbates.
  • the present disclosure includes within its scope all the possible isotopicaily labeled forms of the compounds.
  • the compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, intraarticular, intrathecal, intraperitoneal, direct intraventricular, intracerebroventicular, intramedullary injection, intracisternai injection or infusion, subcutaneous injection or implant), by inhalation spray, eye drops, or nasal, vaginal, rectal, sublingual and topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable excipients appropriate for each route of administration.
  • parenteral e.g., intramuscular, intraperitoneal, intravenous, intraarticular, intrathecal, intraperitoneal, direct intraventricular, intracerebroventicular, intramedullary injection, intracisternai injection or infusion, subcutaneous injection or implant
  • parenteral e.g., intramuscular, intraperitoneal, intravenous, intraarticular, intrathecal, intraperitoneal
  • compositions containing the active ingredient according to the present invention usually contain 0.01 to 500 mg of active ingredient in a single dosage unit, it is, of course possible that the amount of the active ingredient in some compositions exceeds the upper or lower limits defined above.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • This dosage level and regimen may be adjusted to provide the optimal therapeutic response. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition and the host undergoing therapy. As a further aspect of the invention there is provided the pharmaceutical manufacture of medicaments containing the compounds of formula (I) or pharmaceutically acceptable esters, salts, hydrates and solvates thereof.
  • compositions of the present invention may be formulated as different pharmaceutical dosage forms, such as but not limited to, solid oral dosage forms like tablets (e.g., buccal, sublingual, effervescents, chewable, orodispersible, freeze dried), capsules, lozenges, pastilles, pills, orodispersible films, granules, powders; liquid oral dosage forms, such as but not limited to, solutions, emulsions, suspensions, syrups, elixires, oral drops; parenteral dosage forms, such as but not limited to, intravenous injections, intramuscular injections, subcutaneous injections; other dosage form , such as but not limited to, eye drops, semi-solid eye preparations, transdermal dosage forms, suppositories, rectal capsules, rectal solutions, emulsions and suspensions, etc.
  • solid oral dosage forms like tablets (e.g., buccal, sublingual, effervescents, chewable, orodispersible, freeze dried), capsules, lozenges,
  • compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, emulsifying, suspending, entrapping, freeze-drying, extrusion, laminating, film-casting, granulating, grinding, encapsulating, dragee-making or tabletting processes.
  • compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more physiologically acceptable excipients. Any of the well-known techniques and excipients may be used as suitable and as understood in the art.
  • Suitable excipients for the preparation of the dosage forms may be selected from the following categories, such as but not limited to, tablet and capsule fillers, tablet and capsule binders, release modifying agents, disintegrants, glidants, lubricants, sweetening agents, taste-masking agents, flavoring agents, coating agents, surfactants, antioxidants, buffering agents, complexing agents, emulsifying agents, lyophilization aids, microencapsulating agents, ointment bases, penetration enhancers, solubilizing agents, solvents, suppository bases, suspending agents.
  • tablet and capsule fillers tablet and capsule binders
  • release modifying agents such as but not limited to, tablet and capsule fillers, tablet and capsule binders, release modifying agents, disintegrants, glidants, lubricants, sweetening agents, taste-masking agents, flavoring agents, coating agents, surfactants, antioxidants, buffering agents, complexing agents, emulsifying agents, lyophilization aids, microencapsulating agents
  • the invention relates to the use of specific excipients which are able to improve the solubility, dissolution, penetration, absorption or bioavailability of the active ingredient(s), such as but not limited to, hydrophilic polymers, hot melt extrusion excipients, surfactants, buffering agents, complexing agents, emulsifying agents, lyophilization aids, superdisintegrants, microencapsulating agents, penetration enhancers, solubilizing agents, co-solvents, suspending agents.
  • hydrophilic polymers such as but not limited to, hydrophilic polymers, hot melt extrusion excipients, surfactants, buffering agents, complexing agents, emulsifying agents, lyophilization aids, superdisintegrants, microencapsulating agents, penetration enhancers, solubilizing agents, co-solvents, suspending agents.
  • hydrophilic polymers such as but not limited to, hydrophilic polymers, hot melt extrusion excipients, surfactants, buffering agents, complexing
  • the compounds of formula (I) can be prepared according to the general knowledge of one skilled in the art and/or using methods set forth in the following Example sections. Solvents, temperatures, pressures and other reaction conditions can readily be selected by one of ordinary skill in the art. Starting materials are commercially available and/or readily prepared by one skilled in the art.
  • room temperature denotes a temperature in the range from 20 °C to 25 °C.
  • nitramide (1 eq) product from the general procedure A was dissolved in THF/MeOH/H 2 0 and NH 4 C1 (5-6 eq) was added. The mixture was cooled to 0 °C in an ice bath. Powdered zinc (5-6 eq) was added and the mixture was allowed to react for 0.5 - 1.5 hour. The mixture was filtered through a pad of celite and recooled to 0 °C. Triphosgene (1.3 - 1.6 eq) was added and the reaction mixture was stirred at 0 °C. After typically 1-2 hours but sometimes overnight of reaction time, the mixture was evaporated to dryness and 1 M HC1 solution was added. Crude triazolone was filtered off and dried in vacuum.
  • Step 1 7Y-(4,5-dichloropyridin-2-yl)nitramide
  • Step 2 6, 7-Dichloro-[ 1 ,2,4]triazolo[4, 3 -a]pyridin-3 (2H)-one
  • Step 1 N-(5-bromo-4-fluoropyridin-2-yl)nitramid
  • Step 2 iV-(5-chloro-4-fluoropyridin-2-yl)nitramide
  • Step 3 6-Chloro-7-fluoro-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one
  • Step 1 iV-(4-bromo-5-chloropyridin-2-yl)nitramide
  • Example 7 6-(Difluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one Step 1 : 6-Iodo-2-(4-methoxybenzyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one
  • Step 2 2-(4-Methoxybenzyl)-3 -oxo-2,3-dihydro-[ 1 ,2,4]tri azolo[4,3 -ajpyridi ne-6- carbaldehyde
  • Step 4 6-(Difluoromethyl)-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one
  • Step 1 6-Chloro-7-(trifluoromethyl)-[ 1 ,2,4]triazolo[4,3-a]pyridin-3(2H)-one
  • Step 1 5-Bromo-2-hydrazinyl-4-(trifluoromethyl)pyridine
  • Step 1 N-(4,5-dibromopyridin-2-yl)nitramide
  • Step I N-(4-chloro-5-methylpyridin-2-yl)nitramide
  • Step 2 7-Chloro-6-methyl-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one
  • Step 1 4-Chloro-3-fluoropyridin-2-amine
  • Step 3 iV-(5-bromo-4-chloro-3-fluoropyridin-2-yl)nitramide
  • Step 4 6-Bromo-7-chloro-8-f!uoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one
  • the title compound was synthesised according to general procedure B from N-(5-bromo-4-chloro-3-fluoropyridin-2-yl)nitramide (0.10 g, 0.37 mmol), NH 4 CI (0, 10 g, 1.85 mmol), Zn dust (0.12 g, 1.85 mmol) and triphosgene (0.17 g, 0.56 mmol) in THF (5 ml), MeOH (1 ml) and H 2 0 (1 ml). After completion of the reaction, the mixture was extracted with EtOAc, Organic layer was extracted with 1 M aqueous NaOH solution. The basic water layer was then acidified with 1M HC1 solution and extracted with EtOAc.
  • Step 5 7-Fluoro-6-methyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one
  • Step 2 4-Bromo-2-hydrazinyl-5-methylpyridine 1 -oxide
  • the title compound was synthesised according to general procedure B from impure N-(4-fluoro-5-methylpyridin-2-yl)nitramide (80 mg, ⁇ 0.39 mmol), NH 4 CI (0. 1 1 g, 1.97 mmol), Zn dust (0.13 g, 1.97 mmol) and triphosgene (0.18 g, 0.59 mmol) in THF (3 ml), MeOH (0.75 ml) and H 2 0 (0.75 ml).
  • the crude product was purified by FC (C 18) yielding 5 n g of 6-(difluoromethyl)-7-methyl-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one.
  • Step 1 4,5-Dichloro-3-fluoropyridin-2-amine
  • Step 3 6,7-Dichloro-8-fluoro-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one
  • the title compound was synthesised according to general procedure B from A r -(4,5 ⁇ dichloro-3 ⁇ fluoropyridin-2-yl)mtraniide (0.1 1 g, 0.49 mmol), NH 4 C1 (0.13 g, 2.43 mmol), Zn dust (0.16 g, 2.43 mmol) and triphosgene (0.22 g, 0.73 mmol) in THF (4 ml), MeOH (1 ml) and H 2 0 (1 ml).
  • the crude product was purified by FC (CI 8) yielding 4 mg of 6,7-dichk)ro-8-fluoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one.
  • Step 1 tert-Butyl (4-fluoro-5-iodopyridin-2-yl)carbamate
  • Step 3 fert-Butyl (5-(difluoromethyl)-4-fluoropyridin-2-yl)carbamate
  • Step 5 N-(5-(difluoromethyl)-4-fluoropyridin-2-yl)nitramide
  • Step 6 6-(Difluoromethyl)-7-fluoro-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one
  • the title compound was synthesised according to general procedure B from N-(5-(difluoromethyl)-4-fluoropyridin-2-yl)nitramide (0.14 g, 0.68 mmol), NH 4 C1 (0. 18 g, 3.38 mmol ), Zn dust (0.22 g, 3.38 mmol) and triphosgene (0.30 g, 1.01 mmol) in THF (5 ml), MeOH (1.2 ml) and H 2 0 (1.2 ml). The crude product was extracted from acidic aqueous phase with EtOAc (no precipitate). The combined organic extracts were washed with brine, dried with 3 ⁇ 48 ⁇ 4 , filtered and evaporated.
  • Step 1 iV-(4,5-difluoropyridin-2-yl)nitramide
  • Step 1 (2-Chloro-5-(trifluoromethyl)pyridin-4-yl)methan-i/ 2 -ol
  • the title compound was synthesised according to general procedure D from 2-hydrazinyl-4- (methyl-t3 ⁇ 4)-5-(trifluoromethyl)pyridine (0.53 g, 2.73 mmol) and CDI (0.53 g, 3.28 mmol) in THF (15 ml) with 1 hour reaction time.
  • the crude product was purified by FC (CI 8) yielding 0.32 g of 7-(methyl-i3 ⁇ 4)-6-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)- one.
  • Step 1 2-Chloro-4-(difluoromethyl)-5-(trifluoromethyl)pyridine
  • Step 2 4-(Difluoromethyl)-2-hydrazinyl-5-(trifluoromethyl)pyridine
  • the title compound was synthesised according to general procedure C from 2-chloro-4-(difluoromethyl)-5-(trifluoromethyl)pyridine (0.11 g, 0.48 mmol), hydrazine hydrate (0, 18 ml, 3,80 mmol) and IPA (1 ml) at 100 °C with 1 hour reaction time.
  • the reaction mixture was evaporated to dryness, EtOAc was added and the solution was washed with H 2 0 and brine, dried with Na 2 S0 4 , filtered and evaporated to dryness yielding 0.10 g of 4-(difluoromethyl)-2-hydrazinyl-5-(trifluoromethyl)pyridine.
  • Step 3 7-(Oifluoromethyl)-6-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one
  • Step 1 5-bromo-3-chloro-2-hydrazinylpyridine
  • Step 1 2-hydrazinyl-4,5-bi s(trifluoromethyl)pyridine
  • Step 2 7-methyl-6-(trifluoromethyl)-[ 1 ,2,4]triazolo[4,3-a]pyridin-3(2H)-one
  • Step 1 5-bromo-2-chloro-4-cyclopropylpyridine
  • Step 3 5-bromo-4-cyclopropyl-2-hydrazinylpyridine hydrochloride
  • Step 4 6-bromo-7-cyclopropyl-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one
  • Step 2 tert-butyl 2-(5-chloro-4-cyclopropylpyridin-2-yl)hydrazine- 1 -carboxylate
  • reaction mixture was diluted with DCM (25 mL) and washed with water (10 ml) dried (Na 2 S0 4 ), filtered and concentrated under reduced pressure.
  • the resulting crude material was purified by column chromatography (silica gel) to get 350 mg of tert-butyl 2-(5-chloro-4-cyclopropylpyridin-2- yl)hydrazine-l-carboxylate.
  • Step 4 6-chloro-7-cyclopropyl-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one
  • Step 2 tert-butyl 2-(4-(difluoromethyl)pyridin-2-yl)hydrazine-l-carboxylate
  • Step 4 7-(difluoromethyl)-[l ,2,4]triazolo[4,3-a]pyridin-3(2H)-one
  • Step 1 4-chloro-5-fluoro-2-hydrazineylpyridine
  • Example 35 6-flsioro-7-(irifleoroii5ethyl)-[1 ,2,4]triazolo[4,3-a]pyr5di8i ⁇ 3(2H)-oiie Step 1 : di-tert-butyl l-(5-fluoro-4-(trifluoromethyl)pyridin-2-yl)hydrazine-l,2'
  • Step 3 6-fluoro-7-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one
  • Step 1 N-(4-Chloro-5-cyanopyridin-2-yl)nitramide
  • Example 38 7 ⁇ M thyI ⁇ 3 ⁇ oxo-2 -dihydro-[l,2,4]triazoIo[4 ⁇ a]pyridiiK > -6 ⁇ carboH8triS Step 1 : iV-(5-cyano-4-methylpyridin-2-yl)nitramide
  • Step 1 4-Cyano-3-methylpyridine 1 -oxide
  • Step 3 2-((4-methoxybenzyl) amino)-5-methylisonicotinonitrile
  • Step 1 4-Chloro-2-hydrazinyl-5-(trifluoromethyl)pyridine
  • N,iV-Carbonyldiimidazole (72 mg, 0.45 mmol) was added to a solution of 4-chloro-2- hydrazinyl-5-(trifluoromethyl)pyridine (70 mg, 0.33 mmol) in THF (2.5 mL) at rt.
  • the reaction mixture was stirred at rt for 2 hours.
  • aq. 1 M HCi solution was added.
  • the precipitate formed was filtered off, washed with water and dried under vacuum at 40°C.
  • the crude material was dissolved in 1 mL of 1 M NaOH solution. The water solution was washed twice with EtOAc and then acidified (pH 2-3) with 6 M HCI solution.
  • Step 1 N-[4-Bromo-5-(trifluoromethyl)pyridin-2-yl]nitramide
  • N-[4-Bromo-5-(trifluoromethyl)pyridin-2-yl]nitramide was prepared according to General procedure A with 4-bromo-5-(trifluoromethyl)pyridin-2-amine (600 mg, 1.49 mmol) in cone. H 2 SO 4 (2 mL) and a mixture of 65% HNO 3 (0.29 mL, 4.23 mmol) and cone. H 2 SO 4 (0.26 mL), Yield 542 mg.
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ : 8.75 (s, 1 H), 8.24 (s, 1H).
  • Step 3 DiBoc-protected 4-fluoro-5-(trifluoromethyl)pyridin-2-amine
  • Step 5 N-[4-Fluoro-5-(trifluoromethyl)pyridin-2-yl]nitramide
  • N-[4-Fluoro-5-(trifluoromethyl)pyridin-2-yl]nitramide was prepared according to General procedure A using 4-fluoro-5-(trifluoromethyl)pyridin-2-amine (100 nig, 0.56 mmol) in 5 cone.
  • H 2 S0 4 (0.38 mL) and a mixture of 65% HN0 3 (0.066 mL, 0.96 mmol) and cone.
  • Step 6 7-Fluoro-6-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one
  • Step 1 5-bromo-2-chloro-4-methoxypyridine
  • Step 2 6-bromo-7-methoxy-[ 1 ,2,4]triazolo[4,3 -a]pyridin-3 (2H)-one
  • Step 1 (2-Chloro-5-(trifluoromethyl)pyridin-4-yl)methanol
  • Active ingredient(s) 0,01 - 50%
  • Liquid vehicle 10 99.9%
  • Buffering agent quantum satisfies
  • Active ingredient(s) 0.01 - 50%
  • Buffering agent quantum satisfies
  • Active ingredient(s) 0,01 - 50%
  • Active ingredient(s) 0,01 - 50%
  • Buffering agent quantum satisfies
  • the compounds of formula (I) show valuable pharmacological properties, namely they exhibit DAAO inhibiting activity and possess enhanced brain permeability. Said properties are demonstrated with the pharmacological tests presented below.
  • the DAAO inhibiting activity of compounds was determined by using D-kynurenine as substrate for DAAO.
  • DAAO transforms D-kynurenine into D-kynurenic acid and production of the latter can be detected by fluorescence spectroscopy.
  • the changes in fluorescence were monitored in a Novostar (BMG) fluorescence plate reader (excitation/emission wavelength: 344/405 nm).
  • Recombinant human DAAO enzyme was supplied by Novoprotein (Summit, NJ, USA), D-kynurenine was supplied by Sigma- Aldrich.
  • Caco-2 cells were seeded at a density of ⁇ 500,000 cells/1.12 cm 2 on basement membrane matrix covered Transwell R polycarbonate filters (0.45 ⁇ pore size; 1.12 cm 2 surface area; Costar). The cultures were grown at 37 °C in an atmosphere of 5% C0 2 and 95% relative humidity and used for permeability assays on days between 19-21.
  • test compound dosing solution was added to the donor side of individual Transwells and transport buffer without test compound was added to the receiver side.
  • the 12-well plate was placed in a shaking water bath (120-140 rpm) with saturating humidity at 37°C. The plates were incubated up to 40 minutes. The concentration of the test compound present in the donor and receiver side was analysed using HPLC-UV.
  • Permeability screening was performed under iso-pH condition (pH 7.4 a -7.4B).
  • Vr apparent permeability in cm/sec
  • a to B Vr 1.5 mL
  • B to A Vr 0.5 mL
  • Co the initial concentration of the test drug in the donor chamber
  • dC/dt is the linear slope of the drug concentration in the receiver chamber with time.
  • the permeability directional ratio (PDR) for B to A (basolateral to apical) and A to B (apical to basolateral) transport is defined by the following equation: Where P app B to A and P apP A to B represent the apparent permeability of test compound from the basal to apical, and apical to basal side of the cellular monolayer, respectively. Data are presented in Table 2.
  • Liquid chromatography-tandem mass spectrometric (UHPLC -MS/MS) methods were used for the determination of the compounds in rat plasma and brain tissue.
  • the tissue samples were weighed, homogenized with cold phosphate buffer pH 7.2 ( :4, w/w), and the homogenates were stored at -70 °C prior to analysis.
  • the stock solutions of compounds were prepared in acetonitrile and diluted with distilled water: acetonitrile mixture (50:50) to obtain the series of concentrations as working standards.
  • the calibration standards were prepared by spiking the working standards into blank plasma or tissue homogenates (1 :9 v/v). Low, medium and high quality control samples were prepared in the same fashion.
  • the calibration standards and the quality controls were stored at -70 °C prior to analysis. Thawed plasma and tissue homogenate samples, calibration standards, quality controls and analyte-free blank samples were extracted by pipetting 50 ⁇ of sample and 2.5 ml of mixture of ethylacetate:hexane (50:50, v/v) in glass vials, followed by vortexing for 3 minutes and centrifugation for 7 minutes (4400 rpm, 10 °C). After evaporation and reconstitution of the organic extract with mobile phase, the samples were analysed using reversed-phase chromatography followed by mass spectrometry with electrospray ionization and selected ion monitoring.

Abstract

La présente invention concerne des composés de formule (I), dans laquelle R1 à R3 sont tels que définis dans les revendications, ou des esters, des sels, des hydrates ou des solvates pharmaceutiquement acceptables de ceux-ci, qui sont utiles en tant qu'inhibiteurs de DAAO, ainsi que des compositions pharmaceutiques les contenant et leur utilisation en tant que modulateurs de l'activité de DAAO, des taux de D-sérine, des produits d'oxydation de D-sérine et une activité du récepteur de NMDA dans le système nerveux d'un sujet mammifère.
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