WO2024105021A1 - Nouveaux dérivés de pyrrolo[1,2-d][1,2,4]triazin-1-one servant de modulateurs allostériques négatifs des récepteurs mglu7 - Google Patents

Nouveaux dérivés de pyrrolo[1,2-d][1,2,4]triazin-1-one servant de modulateurs allostériques négatifs des récepteurs mglu7 Download PDF

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WO2024105021A1
WO2024105021A1 PCT/EP2023/081732 EP2023081732W WO2024105021A1 WO 2024105021 A1 WO2024105021 A1 WO 2024105021A1 EP 2023081732 W EP2023081732 W EP 2023081732W WO 2024105021 A1 WO2024105021 A1 WO 2024105021A1
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alkylene
alkyl
group
hydrogen
heterocycle
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PCT/EP2023/081732
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Jean-Laurent Paparin
Jean-Philippe Rocher
Floris Petrus Johannes Theodorus Rutjes
Freek Jan JANSSEN
Max Theodorus Gerardus Maria DERKS
Antoine Michel Lauder LACOUR
Marnix Ruben VAN DER KOLK
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Addex Pharma S.A.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals

Definitions

  • the present invention relates to novel compounds of Formula (I), wherein P, Q, A, B, m, n, R 1 , R 2 and R 3 are defined as in Formula (I); which are negative allosteric modulators of the metabotropic glutamate receptor subtype 7 (mGlu7) and which are useful for the treatment or prevention of neurological, ear and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGlu7 subtype of metabotropic receptors is involved.
  • the invention is also directed to pharmaceutical compositions comprising such compounds, to processes of preparing such compounds and such compositions, and to the use of such compounds for the prevention or treatment of neurological, ear and psychiatric disorders and diseases in which mGlu7 is involved.
  • Glutamate is the primary amino-acid transmitter in the mammalian central nervous system (CNS). Glutamate is associated with numerous physiological functions learning and memory, sensory perception, development of synaptic plasticity, motor control, respiration, and regulation of cardiovascular function. Furthermore, glutamate is at the centre of several different neurological and psychiatric diseases, where there is an imbalance in glutamatergic neurotransmission.
  • iGluRs ionotropic glutamate receptor channels
  • NMD A ionotropic glutamate receptor channels
  • AMPA kainate receptors
  • mGluRs metabotropic glutamate receptors
  • mGluRs metabotropic glutamate receptors
  • mGluRs do not mediate but rather “modulate” synaptic transmission acting at different levels of the tripartite synapse formed by the junction of axon terminals, dendritic spines, and astrocytes.
  • the mGluRs are seven-transmembrane domaincontaining G protein-coupled receptors (GPCRs) belonging to family 3 GPCRs along with the calcium-sensing, GABAB, and pheromone receptors. Glutamate activates the mGluRs through binding to a site on the large extracellular amino-terminal domain of the receptor, herein called the orthosteric binding site. This activation induces a conformational change of the rest of the receptor which results in the activation of the G-protein and subsequently to a large variety of intracellular signalling pathways.
  • the mGluR family is composed of eight members.
  • group I comprising mGlul and mGlu5; group II comprising mGlu2 and mGlu3; group III comprising mGlu4, mGlu6, mGlu7, and mGlu8
  • group II comprising mGlu2 and mGlu3
  • group III comprising mGlu4, mGlu6, mGlu7, and mGlu8
  • the mGlu7 subtype is the most widely distributed and is present pre-synaptically at a broad range of synapses that are postulated to be critical for both normal CNS functions and a range of psychiatric and neurological disorders (Ohishi et al. (1995) J. Comp. Neurol. 360(4):555-570; Kinzie et al. (1995) Neuroscience, 69(1): 167-176; Corti et al. (1998) Eur. J. Neurosci, 10(12):3629-3641).
  • mGlu7 is negatively coupled to adenylate cyclase via activation of Gai-protein, and its activation as a pre-synaptic autoreceptor leads to inhibition of glutamate and GABA release in the synapse (Dalezios et al. (2002) Cereb. Cortex, 12(9):961-974; Cartmell and Schoepp (2000) J. Neurochem., 75:889-907; Somogyi et al. (2003) Eur. J. Neurosci. 17(12):2503-2520) therefore shaping the synaptic responses at glutamatergic synapses as well as being a key regulator of inhibitory GABAergic transmission with the final goal of fine tuning the overall excitability of the brain.
  • AMN082 was described as being a potent, selective and systemically active mGlu7 allosteric agonist (Mitsukawa et al. (2005) Proc. Natl. Acad. Sci. USA, 102: 18712- 18717).
  • modulators of the mGlu7 are reported to hold potential for the treatment of neurological, psychiatric, mood disorders as well as pain and otic disorders, based on experimental studies on laboratory animals, deemed relevant to clinical syndromes.
  • Combined expression of mGlu7 in brain regions and pharmacological manipulations of mGlu7 in genetically modified mice and wild-type animals reveal an important role for mGlu7 in numerous CNS disorders, including depression, schizophrenia, anxiety, obsessive compulsive disorders and associated symptoms (reviewed by Pallazo et al. (2016) Curr. Neuropharmacol.
  • mGlu7 has been shown to be located on limbic system nuclei such as the amygdala, hippocampus and the locus coerulus, regions that are known to be critical for the manifestation of anxiolysis and antidepressant actions (Kinoshita et al. (1998) J. Comp. Neurol., 393(3):332-352; Makoff et al. (1996) Brain Res. Mol. Brain Res., 40(l):165- 170; Kinzie et al. (1995) Neuroscience, 69(1): 167-176).
  • mGlu7 knockout animals exhibit an anxiolytic and anti-depressant phenotype but also some deficits in amygdala-dependent behaviors (fear response and conditioned taste aversion) (Cryan et al. (2003) Eur. J. Neuroscience, 17:2409-2417). Therefore, a pharmacological agent aiming at modulating mGlu7 activity may represent a novel therapeutic approach for the treatment of neurological and psychiatric disorders such as anxiety and depression.
  • mGlu7 ablation causes dysregulation of the HPA axis and increases hippocampal BDNF protein levels, indicating that this receptor might be implicated in stress-related psychiatric disorders such as anxiety, depression, post-traumatic stress syndrome, behaviours induced by innate fear such as acquisition and extinction of conditioned fear or conditioned taste aversion.
  • stress-related psychiatric disorders such as anxiety, depression, post-traumatic stress syndrome
  • behaviours induced by innate fear such as acquisition and extinction of conditioned fear or conditioned taste aversion.
  • mGlu7 receptors have also been implicated in pathways affected during pain. Given its high and wide expression both in the peripheral and central nervous systems, mGlu7 was found to play a role in regulating pain behaviour. The role of mGlu7 in pain was also recently demonstrated using AMN082 injection directly into the central nucleus of the amygdala (CeA) or in the periaqueductal gray (PAG). Under normal conditions, activation of amygdala mGlu7 facilitates pain responses, as shown by a decrease in the spinal withdrawal reflex thresholds and increased audible and ultrasonic vocalizations evoked by brief compression of the knee (Palazzo et al. (2008) Neuropharmacol., 55(4):537-545).
  • GRM7 variants were also identified to be in association of noise- induced hearing loss, as reported by Lu et al. (BMC Med. Genet. (2016), 19(1):4) and tinnitus, as reported by Haider et al. (Front. Aging Neurosci. (2017), 9:346).
  • mGlu7 expression studied by immunohistochemistry, is located in the neurons of the spiral ganglion, in the inner and outer hair cells of the organ of Corti, and the hair cells of the vestibular apparatus formed by the sacculus, the utriculus and the crista ampullaris (Friedman et al. (2008) WO2008131439).
  • mGlu7 receptor modulators are of potential use in the experimental treatment of otic disorders linked to the inner ear and auditory nervous system such as age-related hearing loss (presbycusis), noise-induced hearing loss, acute and chronic hearing loss, tinnitus, Meniere’s disease and vestibular disorders.
  • mGlu7 shows the highest degree of evolutionary conservation of all mGluRs (Flor et al. (1997) Neuropharmacol., 36: 153-159), suggesting an important role for this receptor in CNS functioning. Moreover, it has a relatively low affinity for glutamate (Okamato et al. (1994) J. Biol. Chem., 269: 1231-1236), thus it may remain inactive during normal transmission, only becoming active during times of excessive glutamate release (Ferraguti F. and Shigemoto R. (2006) Cell Tissue Res., 326:483-504). Taken together these data strongly highlight the potential of mGlu7 modulators in clinical indications such as neuroprotection (to treat stroke and head injury, ischemic damage and neurotoxicity).
  • the invention relates to compounds having metabotropic glutamate receptor 7 modulator activity.
  • the present invention provides a compound according to Formula (I): a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an A-oxide form thereof, wherein:
  • R 1 is selected from the group of (for example the group consisting of) hydrogen, - CH 3 and -CF 3 ;
  • R 2 and R 3 are each independently selected from the group of (for example the group consisting of) hydrogen, halogen, -(Ci-Ce)alkyl, -(Ci-Ce)haloalkyl and -CF 3 ;
  • P represents a cycloalkyl, aryl, heteroaryl or heterocycle of formula: wherein each cycloalkyl ring, aryl ring, heteroaryl ring or heterocycle ring is optionally substituted with m radicals A, wherein m is an integer equal to zero, 1, 2, 3 or 4; wherein Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 are each independently selected from C, N, O or S; provided that at least one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 is N; the or each (A) m is independently selected from the group of (for example the group consisting of) hydrogen, halogen, -CN, -OH, -NO2, -CF 3 , -SH, -NH2 and an optionally substituted radical selected from the group of (for example the group consisting of) - (Ci-Ce)alkyl, -(Ci-Ce)
  • Q represents an aryl or heteroaryl of formula: wherein each aryl ring or heteroaryl ring is optionally substituted with n radicals B, wherein n is an integer equal to zero, 1, 2, 3, 4 or 5; wherein B 1 is a radical B; the or each (B) n is independently selected from the group of (for example the group consisting of) hydrogen, halogen, -CN, -OH, -NO2, -CF3, -SH, -NH2 and an optionally substituted radical selected from the group of (for example the group consisting of) - (Ci-Ce)alkyl, -(Ci-Ce)haloalkyl, -(C2-Ce)alkynyl, -(C2-Ce)alkenyl, -(C3-C7)cycloalkyl, - (Ci-C6)alkylene-(C3-C7)cycloalkyl, -(C3-C8)cycloalkenyl, -(C
  • R 8 , R 9 , R 10 and R 11 are each independently hydrogen or an optionally substituted radical selected from the group of (for example the group consisting of) -(Ci- Ce)haloalkyl, -(Ci-Ce)alkyl, -(Ci-Ce)cyanoalkyl, -(C3-C7)cycloalkyl, -(Ci-Ce)alkylene- (C3-C7)cycloalkyl, heteroaryl, -(Ci-C6)alkylene-heteroaryl, aryl, -(Ci-Ce)alkylene- heterocycle, heterocycle, -(Ci-Ce)alkylene-aryl, -(Co-C6)alkylene-0-(Co-Ce)alkyl and - (Co-C 6 )alkylene-N-((Co-C 6 )alkyl)2; wherein optionally any two radicals A are combined with the intervening atoms to form a 3
  • the compounds of general Formula (I) show potent activity and selectivity on the mGlu7 receptor.
  • the compounds of the invention demonstrate advantageous properties over compounds of the prior art. Improvements have been observed in one or more of the following characteristics of the compounds of the invention: the potency on the target, the selectivity for the target, the bioavailability, the brain penetration, and the pharmacodynamics.
  • P represents a heteroaryl of formula: wherein each radical is optionally substituted with m radicals A, wherein m is an integer equal to zero, 1, 2, 3 or 4.
  • Q represents an aryl or heteroaryl of formula: , wherein each radical is optionally substituted with n radicals B, wherein n is an integer equal to zero, 1, 2, 3, 4 or 5; and wherein B 1 is a radical B.
  • Q represents an aryl or heteroaryl of formula: wherein each radical is optionally substituted with n radicals B, wherein n is an integer equal to zero, 1, 2, 3, 4 or 5.
  • P represents a heteroaryl of formula: wherein each radical is optionally substituted with m radicals A, wherein m is an integer equal to zero, 1, 2, 3 or 4; and represents an aryl or heteroaryl of formula: wherein each radical is optionally substituted with n radicals B, wherein n is an integer equal to zero, 1, 2, 3, 4 or 5.
  • the cycloalkyl, heterocycle, aryl and heteroaryl ring systems of (A) m may be selected from the group of (for example the group consisting of) azetidinyl, 2- azabicyclo[2.2. l]heptan-2-yl, 7-azabicyclo[2.2.
  • the cycloalkyl, heterocycle, aryl and heteroaryl ring systems of (B) n may be selected from the group of (for example the group consisting of) azetidinyl, 2- azabicyclo[2.2. l]heptan-2-yl, 7-azabicyclo[2.2.
  • B 1 may be a radical B as described above.
  • B 1 may be hydrogen, -(Ci- Ce)alkyl, -(C3-C7)cycloakyl or -O-(Ci-C6)haloalkyl.
  • the cycloalkyl, heterocycle, aryl and heteroaryl ring systems of R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 or R 11 may be selected from the group of (for example the group consisting of) azetidinyl, benzimidazolyl, benzisothiazolyl benzisoxazolyl, benzofuryl, benzopyrazolyl, benzothiazolyl, benzothiophenyl, benzotri azolyl, benzoxazolyl, dihydrofuranyl, dihydrothienyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, furazanyl, furyl, imidazolidinyl, imidazolinyl, imidazolonyl, imidazolyl, imidazopyridazinyl, imidazopyridyl, indolyl, isoindoly
  • R 1 may be hydrogen.
  • R 2 and R 3 may each be independently selected from the group of (for example the group consisting of) hydrogen, methyl and halogen.
  • R 4 , R 5 and R 6 may each independently be hydrogen or -(Ci-Ce)alkyl.
  • the or each (A) m may be independently selected from the group of (for example the group consisting of) hydrogen, halogen and -(Co-Ce)alkylene-OR 4 ; wherein R 4 may be -(Ci-Ce)alkyl.
  • an optionally substituted radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl, -(C3- C7)cycloalkyl, aryl
  • R 8 and R 9 may each be independently selected from the group of (for example the group consisting of) hydrogen, -(Ci-Ce)haloalkyl, -(Ci-Ce)alkyl and -(C3-C7)cycloalkyl.
  • the or each (B) n may be independently selected from the group of (for example the group consisting of) heterocycle, -(Co-Ce)alkylene-OR 8 , and -(Ci-Ce)alkyl; wherein R 8 may be -(Ci-Ce)alkyl, -(Ci-Ce)haloalkyl or -(C3-C7)cycloalkyl.
  • B 1 may be -(Ci-Ce)alkyl.
  • the compounds of Formula (I) are the compounds according to Formula (II): a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an A -ox ide form thereof, wherein Z 1 is selected from C or N and (A) m , Q, R 2 , R 3 and (B) n are as defined in any statement set out above.
  • the compounds of Formula (I) may be the compounds according to Formula (III): a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an A -ox ide form thereof, wherein X is N or C, and P, (A) m , R 2 , R 3 and (B) n are as defined in any statement set out above.
  • the compound of Formula (I) may be the compounds according to Formula (IV): a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an A -ox ide form thereof, wherein Z 1 is selected from C or N, X is selected from C or N, and (A) m , R 2 , R 3 and (B) n are as defined in any statement set out above.
  • the compounds of Formula (I) may be the compounds according to Formula (V): a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an A -ox ide form thereof wherein:
  • Z 1 is selected from C or N, and (A) m , R 2 , R 3 and (B) n are as defined in any statement set out above.
  • R 8 and R 9 may each be independently hydrogen, -(Ci-Ce)alkyl, -(C3-C7)cycloalkyl or- (Ci-Ce)haloalkyl.
  • the or each (A) m may be independently selected from the group of (for example the group consisting of) hydrogen, halogen and -(Co-Ce)alkylene-OR 4 , wherein R 4 may be -(Ci-Ce)alkyl.
  • the or each (B) n may be independently selected from the group of (for example the group consisting of) hydrogen, halogen, heterocycle, -(Co-Ce)alkylene- OR 8 , and -(Ci-Ce)alkyl; wherein R 8 may be -(Ci-Ce)alkyl, -(Ci-Ce)haloalkyl or -(C3- C7)cycloalkyl.
  • B 1 may be -(Ci-Ce)alkyl.
  • the compounds of Formula (II) are according to Formula (VI): a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an V-oxide form thereof wherein:
  • Z 1 is selected from C or N, and (A) m , R 2 , R 3 and (B) n are as defined in any statement set out above.
  • R 8 and R 9 may each be independently hydrogen, -(Ci-Ce)alkyl, -(C3-C7)cycloalkyl or - (Ci-Ce)haloalkyl.
  • the or each (A) m may be independently selected from the group of (for example the group consisting of) H and -(Co-Ce)alkylene-OR 4 , wherein R 4 may be - (Ci-C 6 )alkyl.
  • the or each (B) n may be independently selected from the group of (for example the group consisting of) hydrogen, halogen, heterocycle, -(Co-Ce)alkylene- OR 8 , and -(Ci-Ce)alkyl; wherein R 8 may be -(Ci-Ce)alkyl, -(Ci-Ce)haloalkyl or -(C3- C7)cycloalkyl.
  • the compounds of Formula (VI) are the compounds according to Formula (VII) or Formula (VIII): a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an V-oxide form thereof; wherein (A) m , Z 1 , R 2 , R 3 and (B) n are as defined in any statement set out above.
  • Z 1 is selected from C or N
  • R 2 is hydrogen, methyl or halogen
  • R 3 is methyl
  • R 4 , R 5 and R 6 may be each independently hydrogen, -(Ci-Ce)alkyl, or -(Ci- Ce)haloalkyl; the or each (B) n may be independently selected from the group of (for example the group consisting of) hydrogen, halogen and an optionally substituted radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl, heterocycle and -(Co-Ce)alkylene-OR 8 ; and
  • R 8 may be hydrogen, -(Ci-Ce)alkyl, -(C3-C7)cycloalkyl or -(Ci-C6)haloalkyl.
  • the or each (A) m may be independently selected from the group of (for example the group consisting of) hydrogen, halogen and -(Co-Ce)alkylene-OR 4 , wherein R 4 may be -(Ci-Ce)alkyl.
  • the or each (B) n may be independently selected from the group of (for example the group consisting of) hydrogen, halogen, heterocycle, -(Co-Ce)alkylene- OR 8 , and -(Ci-Ce)alkyl; wherein R 8 may be -(Ci-Ce)alkyl, -(Ci-Ce)haloalkyl or -(C3- C7)cycloalkyl.
  • B 1 may be -(Ci-Ce)alkyl.
  • Z 1 may be selected from C or N
  • R 2 may be hydrogen, methyl or halogen
  • R 3 may be methyl
  • the or each (A) m may be independently selected from the group of (for example the group consisting of) hydrogen, fluorine and -O-methyl
  • the or each (B) n may be independently selected from the group of (for example the group consisting of) hydrogen, fluorine, methyl, heterocycle, -O-methyl, -O-(C3- C7)cycloalkyl, and O-CHF 2 .
  • the or each (B) n may be independently selected from the group of (for example the group consisting of) hydrogen, fluorine, methyl, azetidinyl, -O-methyl, -O-cylopropyl , and O-CHF 2 .
  • Particular preferred compounds of the invention are compounds as mentioned in the following list, as well as a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an A -ox ide form thereof:
  • the compounds according to any statement above may exhibit metabotropic glutamate receptor 7 modulator activity.
  • the disclosed compounds also include all pharmaceutically acceptable isotopic variations, in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass usually found in nature.
  • isotopes suitable for inclusion in the disclosed compounds include, without limitation, isotopes of hydrogen, such as 2 H and 3 H; isotopes of carbon, such as n C, 13 C and 14 C; isotopes of nitrogen, such as 15 N; isotopes of oxygen, such as 17 O and 18 O; isotopes of phosphorus, such as 31 P, 32 P and 33 P; isotopes of sulfur, such as 35 S; isotopes of fluorine, such as 18 F; isotopes of chlorine, such as 36 C1; and isotopes of iodine, such as 125 I.
  • the invention includes various isotopically labelled compounds as defined herein, for example those into which radioactive isotopes, such as 3 H and 14 C, or those into which non-radioactive isotopes, such as 2 H and 13 C are present.
  • Such isotopically labelled compounds are useful in metabolic studies (with 14 C), reaction kinetic studies (with for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • n C, 18 F, 15 O and 13 N or labelled compounds may be particularly desirable for PET studies for examining substrate receptor occupancy.
  • substitution with heavier isotopes, particularly deuterieum e.g., 2 H or D
  • Isotopically-labelled compounds of Formula (I) to (VIII) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically-labelled reagents in place of the non-labelled reagent previously employed.
  • a pharmaceutical composition comprising a compound according to any statement set out above.
  • the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier and/or excipient.
  • the pharmaceutical composition may comprise a therapeutically effective amount of the compound according to any statement set out above.
  • a method of treating or preventing a condition in a mammal comprising administering to a mammal in need of such treatment or prevention, an effective amount of a compound/composition according to any statement set out above.
  • the treatment or prevention may be affected or facilitated by the modulatory effect of a mGlu7 allosteric modulator such as a mGlu7 negative allosteric modulator.
  • the condition may be one or more of a central nervous system disorder or an otic disease or disorder or a pain disorder.
  • the central nervous system disorder may be anxiety disorder such as agoraphobia, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), panic disorder, or post-traumatic stress disorder (PTSD).
  • anxiety disorder such as agoraphobia, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), panic disorder, or post-traumatic stress disorder (PTSD).
  • the central nervous system disorder may be psychotic disorder such as schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform disorder or substance induced psychotic disorder.
  • the otic disease and disorder may be one or more of an inner ear impairment, age- related hearing impairment (presbycusis), Meniere’s disease, sudden hearing loss, noise induced hearing loss, otitis media, autoimmune inner ear disease, acute tinnitus, chronic tinnitus, drug-induced hearing loss, hidden hearing loss, cisplatin-induced hearing loss, aminoglycosides-induced hearing loss, ototoxicity, central auditory processing disorder or vestibular disorder.
  • an inner ear impairment age- related hearing impairment (presbycusis), Meniere’s disease, sudden hearing loss, noise induced hearing loss, otitis media, autoimmune inner ear disease, acute tinnitus, chronic tinnitus, drug-induced hearing loss, hidden hearing loss, cisplatin-induced hearing loss, aminoglycosides-induced hearing loss, ototoxicity, central auditory processing disorder or vestibular disorder.
  • a method of treating, preventing, ameliorating, controlling or reducing the risk of various neurological and psychiatric disorders associated with glutamate dysfunction in a mammal comprising administering to a mammal in need of such treatment or prevention, an effective amount of a compound/composition according to any statement set out above.
  • the treatment or prevention may be affected or facilitated by the modulatory effect of mGlu7 negative allosteric modulators.
  • the methods are for the treatment or prevention of a condition in a human.
  • (Ci-Ce) means a carbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • (Co-Ce) means a carbon radical having 0, 1, 2, 3, 4, 5 or 6 carbon atoms.
  • C means a carbon atom
  • N means a nitrogen atom
  • O means an oxygen atom
  • S means a sulphur atom.
  • a subscript is the integer 0 (zero) the radical to which the subscript refers, indicates that the radical is absent, i.e. there is a direct bond between the radicals.
  • bonds refers to a saturated covalent bond.
  • bonds When two or more bonds are adjacent to one another, they are assumed to be equal to one bond.
  • alkyl includes both straight and branched chain alkyl radicals and may be methyl, ethyl, //-propyl, z-propyl, //-butyl, i- butyl, .s-butyl, /-butyl, //-pentyl, /-pentyl, /-pentyl, //eo-pentyl, //-hexyl, /-hexyl or /- hexyl.
  • (Co-C3)alkyl refers to an alkyl radical having 0, 1, 2 or 3 carbon atoms and may be methyl, ethyl, //-propyl or /-propyl.
  • alkylene includes both straight and branched difunctional saturated hydrocarbon radicals and may be methylene (-CH2- ), ethylene (-CH2-CH2-), //-propylene (-CH2-CH2-), /-propylene (-CH-(CH3)-CH2- ), //-butylene (-CH2-CH2-CH2-), /-butylene (-CH2-CH-(CH3)-CH2-), /-butylene (- CH2-C-(CH 3 )-CH 2 -), //-pentylene (-CH2-CH2-CH2-CH2-), /-pentylene (-CH 2 - CH(CH3)-CH2-CH2-), //eo-pentylene (-CH2-C(CH3)2-CH2-), //-hexylene (-CH2-CH2- CH2-CH2-CH2-), /-hexylene (-CH 2 -CH-(CH 3 )-CH2-CH2-) or //e
  • cycloalkyl refers to an optionally substituted carbocycle containing no heteroatoms, including mono-, bi-, and tricyclic saturated carbocycles, as well as fused ring systems.
  • fused ring systems can include one ring that is partially or fully unsaturated such as a benzene ring to form fused ring systems such as benzo- fused carbocycles.
  • Cycloalkyl includes such fused ring systems as spirofused ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[l.l.
  • (C3-C7)cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • alkenyl includes both straight and branched chain alkenyl radicals.
  • (C2-C6)alkenyl refers to an alkenyl radical having 2 to 6 carbon atoms and one or two double bonds, and may be, but is not limited to vinyl, allyl, propenyl, i-propenyl, butenyl, i-butenyl, crotyl, pentenyl, i- pentenyl or hexenyl.
  • alkenylene includes both straight and branched chain disubstituted alkenyl radicals.
  • (C2- Ce)alkenylene refers to an alkenylene radical having 2 to 6 carbon atoms and one or two double bonds, and may be, but is not limited to vinylene, allylene, propenylene, i- propenylene, butenylene, i-butenylene, crotylene, pentenylene, i-pentenylene or hexenyl ene.
  • alkynyl includes both straight and branched chain alkynyl radicals.
  • alkynylene includes both straight and branched chain disubstituted alkynylene radicals.
  • aryl refers to an optionally substituted monocyclic or bicyclic hydrocarbon ring system containing at least one unsaturated aromatic ring. Examples and suitable values of the term “aryl” are phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indyl, indenyl and the like.
  • heteroaryl refers to an optionally substituted monocyclic or bicyclic unsaturated, aromatic ring system containing at least one heteroatom selected independently from N, O or S.
  • heteroaryl may be, but are not limited to benzimidazolyl, benzisothiazolyl benzisoxazolyl, benzofuryl, benzopyrazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, furazanyl, furyl, imidazolonyl, imidazolyl, imidazopyridazinyl, imidazopyridyl, indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolonyl, oxazolopyridazin
  • alkylene-aryl refers respectively to a substituent that is attached via the alkyl radical to an aryl, heteroaryl or cycloalkyl radical, respectively.
  • (Ci-C6)alkylene-aryl includes aryl-Ci-Ce-alkyl radicals such as benzyl, 1- phenylethyl, 2-phenylethyl, 1 -phenylpropyl, 2-phenylpropyl, 3 -phenylpropyl, 1- naphthylmethyl and 2-naphthylmethyl.
  • (Ci-C6)alkylene-heteroaryl includes heteroaryl-Ci-Ce-alkyl radicals, wherein examples of heteroaryl are the same as those illustrated in the above definition, such as 2-furylmethyl, 3 -furylmethyl, 2- thienylmethyl, 3 -thienylmethyl, 1 -imidazolylmethyl, 2-imidazolylmethyl, 3- imidazolylmethyl, 2-oxazolylmethyl, 3-oxazolylmethyl, 2-thiazolylmethyl, 3- thiazolylmethyl, 2-pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl, 1- quinolylmethyl and the like.
  • heterocycle refers to an optionally substituted, monocyclic, bicyclic or tricyclic saturated, partially saturated or unsaturated ring system containing at least one heteroatom selected independently from N, O and S.
  • Bicyclic or tricyclic ring systems may be formed by annelation of two or more rings, by a bridging atom (e.g. O, S, N) or by a bridging group (e.g. alkylene).
  • heterocyclic moieties include, but are not limited to: azetidinyl, dihydrofuranyl, dihydrothienyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolinyl, isoxazolidinyl, isoxazolinyl, morpholinyl, oxazolidinyl, oxazolinyl, oxetanyl, piperazinonyl, piperazinyl, piperidinonyl, piperidinyl, pyranyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiazolidinyl, thiazolinyl, thiomorpholinyl, thiopyrany
  • a 5- or 6-membered ring containing one or more atoms independently selected from C, N, O and S includes aromatic and heteroaromatic rings as well as carbocyclic and heterocyclic rings which may be saturated or unsaturated.
  • Such rings include spirocyclic and bridged bicyclic systems.
  • rings may be, but are not limited to dihydrofuranyl, dihydrothienyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, furazanyl, furyl, imidazolidinyl, imidazolinyl, imidazolonyl, imidazolyl, isothiazolinyl, isothiazolyl, isoxazolidinyl, isoxazolinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolinyl, oxazolonyl, oxazolyl, phenyl, piperazinonyl, piperazinyl, piperidinonyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridonyl, pyridyl, pyrimid
  • a 3- to 10-membered ring containing one or more atoms independently selected from C, N, O and S includes aromatic and heteroaromatic rings as well as carbocyclic and heterocyclic rings which may be saturated or unsaturated.
  • Such rings may be, but are not limited to azetidinyl, benzimidazolyl, benzisothiazolyl benzisoxazolyl, benzofuryl, benzopyrazolyl, benzothiazolyl, benzothiophenyl, benzotri azolyl, benzoxazolyl, dihydrofuranyl, dihydrothienyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, furazanyl, furyl, imidazolidinyl, imidazolinyl, imidazolonyl, imidazolyl, imidazopyridazinyl, imidazopyridyl, indolyl, isoindolyl, isoquinolinyl, isothiazolinyl, isothiazolyl, isoxazolidinyl, isoxazolinyl, isoxazolyl, morpholinyl
  • halo or halogen may be fluoro, chloro, bromo or iodo.
  • haloalkyl means an alkyl radical as defined above, substituted with one or more halo radicals.
  • (Ci- C6)haloalkyl may include, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl and difluoroethyl.
  • the term “O-Ci-Ce-haloalkyl” may include, but is not limited to, fluoromethoxy, difluoromethoxy, trifluorom ethoxy and fluoroethoxy.
  • cyanoalkyl means an alkyl radical as defined above, substituted with one or more cyano.
  • the term “optionally substituted” refers to radicals further bearing one or more substituents which may be, acyl, (Ci-Ce)alkyl, - (Ci-Ce)haloalkyl, -(C3-C7)cycloalkyl, -(Ci-C6)alkylene-(C3-C7)cycloalkyl, -(C3- C7)cycloalkyl-(Ci-C6)alkylene, -(Co-C6)alkylene-(C3-C7)spiroalkyl-(Co-C6)alkylene, hydroxy, (Ci-C6)alkylene-oxy, dimethylamino(Ci-C3)alkyl, mercapto, aryl, heterocycle, heteroaryl, (Ci-C6)alkylene-aryl, (Ci-C6)alkylene-heterocycle, (Ci- C6)alkylene-heteroaryl, halogen, hal
  • solvate refers to a complex of variable stoichiometry formed by a solute (e.g. a compound of Formula (I)) and a solvent.
  • the solvent is a pharmaceutically acceptable solvent such as water; such solvent may not interfere with the biological activity of the solute.
  • salt refers to an acid addition or base addition salt of a compound of the invention. “Salts” include in particular “pharmaceutically acceptable salts”.
  • the pharmaceutically acceptable salts of the invention can be synthesized from a basic or acidic moiety, by conventional chemical methods.
  • the compounds of the invention may also form internal salts, e.g., zwitterionic molecules.
  • certain compounds may exist in one or more particular geometric, optical, enantiomeric, diastereoisomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including, but not limited to, cis- and /ra//.s-forms; E- and Z-forms; endo- and exo-forms, R-, S-, and /7/c.w-forms; D- and Z-forms; d- and /-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; a- and P-forms; axial and equatorial forms; and combinations thereof, collectively referred to as “isomers” or “isomeric forms”.
  • radical tautomer For example, the radical tautomer
  • H may be in any isotopic form, including, but not limited to, 'H, 2 H (D), and 3 H (T);
  • C may be in any isotopic form, including, but not limited to, 12 C, 13 C, 14 C;
  • O may be in any isotopic form, including, but not limited to, 16 O and 18 O; and the like.
  • F may be in any isotopic form, including, but not limited to, 19 F and 18 F; and the like.
  • negative allosteric modulator of mGlu7 or “allosteric modulator of mGlu7” refers also to a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an N- oxide form thereof.
  • Allosteric modulators of mGlu7 described herein, and the pharmaceutically acceptable salts, solvates and hydrates thereof can be used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent.
  • Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions.
  • the allosteric modulators of mGlu7 will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein. Techniques for formulation and administration of the compounds of the instant invention can be found in Remington: the Science and Practice of Pharmacy, 19 th edition, Mack Publishing Co., Easton, PA (1995).
  • the amount of allosteric modulators of mGlu7, administered to the subject will depend on the type and severity of the disease or condition and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. Effective dosages for commonly used CNS drugs are well known to the skilled person.
  • the total daily dose usually ranges from about 0.05 - 2000 mg.
  • compositions which provide from about 0.01 to 1000 mg of the active ingredient per unit dose.
  • the compositions may be administered by any suitable route.
  • orally in the form of capsules and the like parenterally in the form of solutions for injection, topically in the form of onguents or lotions, ocularly in the form of eye-drops, rectally in the form of suppositories, intranasally or transcutaneously in the form of a delivery system like patches.
  • the allosteric modulators of mGlu7 thereof can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, pills, powders, syrups, solutions, suspensions and the like.
  • the tablets, pills, capsules, and the like contain from about 0.01 to about 99 weight percent of the active ingredient and a binder such as gum tragacanth, acacias, com starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • the disclosed allosteric modulators of mGlu7, or salts thereof can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • aqueous or organic media for example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable salts of the compounds.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered for example, by subcutaneously implantation or by intramuscular injection.
  • the compounds may be formulated as an emulsion in an acceptable oil, or ion exchange resins, or as sparingly soluble derivatives, for example, as sparingly soluble salts.
  • allosteric modulators of mGlu7 or pharmaceutical formulations containing these compounds are in unit dosage form for administration to a mammal.
  • the unit dosage form can be any unit dosage form known in the art including, for example, a capsule, an IV bag, a tablet, or a vial.
  • the quantity of active ingredient in a unit dose of composition is an effective amount and may be varied according to the particular treatment involved. It may be appreciated that it may be necessary to make routine variations to the dosage depending on the age and condition of the patient.
  • the dosage will also depend on the route of administration which may be by a variety of routes including oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal and intranasal.
  • the compounds according to the invention may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes. In all of the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (Green T.W. and Wuts P.G.M., (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of process as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of Formula (I) to (VIII).
  • the compounds according to the invention may be represented as a mixture of enantiomers, which may be resolved into the individual pure R- or ⁇ -enantiomers. If for instance, a particular enantiomer is required, it may be prepared by asymmetric synthesis or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group such as an amino or an acidic functional group such as carboxyl
  • this resolution may be conveniently performed by fractional crystallization from various solvents as the salts of an optical active acid or by other methods known in the literature (e.g. chiral column chromatography) .
  • an intermediate or a starting material may be performed by any suitable method known in the art (Eliel E. L., Wilen S. H. and Mander L.N. (1984) Stereochemistry of Organic Compounds, Wiley-Interscience). Many of the heterocyclic compounds of the invention can be prepared using synthetic routes well known in the art (Katrizky A. R. and. Rees C. W. (1984) Comprehensive Heterocyclic Chemistry, Pergamon Press).
  • the product from the reaction can be isolated and purified by employing standard techniques, such as extraction, chromatography, recrystallization and distillation.
  • the compounds of the invention may be prepared by general route of synthesis as disclosed in the following methods.
  • compounds of Formula (I) may be prepared according to the synthetic sequence illustrated in Scheme 1.
  • Ethyl I //-pyrrol e- 2-carboxylate gl may be oxidized in the presence of A-bromosuccinimide, in an appropriate solvent such as acetonitrile, at an appropriate temperature, to afford the intermediate ethyl 4-bromo- l //-pyrrol e-2-carboxylate g2.
  • Intermediate g4 may be prepared by reacting the corresponding intermediate g2 with hydrazine g3 in an appropriate solvent such as ethanol, at an appropriate temperature.
  • Intermediate g4 may react with tri ethyl orthoformate g5 to afford bromopyrrolo[l,2-t/][l,2,4]triazinone derivatives g6 by condensation at an appropriate temperature.
  • Intermediates g6 can then be converted into intermediates g8 by suitable reactions known by people skilled in the art of organic synthesis, for example by Suzuki cross coupling reaction, mediated by palladium-complex catalysts such as PdCh dppf) in the presence of a base such as potassium carbonate, in an appropriate solvent such as a mixture of 1,4-dioxane/water.
  • Final compounds glO may be obtained either by Ullmann coupling reaction with an appropriate aryl halide or heteroaryl halide g9, mediated by copper-complex catalysts such as Cui, in the presence of a base such as potassium phosphate, at an appropriate temperature or by the alkylation of g8 in the presence of a base such as potassium carbonate or cesium carbonate, in an appropriate solvent such as DMF.
  • final compounds glO may be prepared according to the synthetic sequence illustrated in Scheme 2.
  • Bromopyrrolo[l,2-d][l,2,4]triazinone derivatives g6, prepared according to Scheme 1 Step 3, may be converted into intermediates gll either by Ullmann coupling reaction, mediated by copper-complex catalysts such as Cui, in the presence of a base such as potassium phosphate or by alkylation of g6 in the presence of a base such as potassium carbonate.
  • final compounds g!4 may be prepared according to the synthetic sequence illustrated in Scheme 3.
  • a base such as potassium phosphate
  • an appropriate solvent such as 1,4-di oxane
  • Step 1 To a mixture of ethyl 3,5-dimethyl-U/-pyrrole-2- carboxylate (350.0 mg, 2.093 mmol) and K2CO3 (307 mg, 2.22 mmol) in ACN (20 mL) at 0°C was added NBS (384 mg, 2.16 mmol) in portions. A white precipitation was formed when the reaction has warmed up to rt. The reaction was then stirred for 40 hours at rt, diluted with water and stirred for 30 min. The precipitate was collected by vacuum filtration, washed with EtOELEhO (1 :2) and dried to afford the title compound (515 mg, 2.09 mmol, 99.9%) as a white solid.
  • Step 2 To a solution of ethyl 4-bromo-3,5-dimethyl-UT- pyrrole-2-carboxylate (3.34 g, 13.6 mmol) in EtOH (30 mL) was added hydrazine (62.1 g, 60.9 mL, 35wt%, 679 mmol). The mixture was heated up to 90°C for 3 hours during which the reaction was monitored by TLC. White crystals were formed. The mixture was concentrated, stirred for 30 min and the precipitate was then filtered off and dried to afford the title compound (3.90 g, 16.8 mmol, 124%).
  • Step 3 4-bromo-3,5-dimethyl-U/-pyrrole-2-carbonyhydrazide (2.0 g, 8.6 mmol) was dissolved in triethyl orthoformate (14 mL, 86 mmol) and the reaction was stirred overnight at 150°C. The mixture was then concentrated and the crude product was used without further purification in the next step. To the crude product (2.5g, 8.7 mmol) in EtOH (70 mL) was added KOH (0.49 g, 8.7 mmol) and the reaction was stirred overnight at 80°C. The mixture was concentrated and purified by flash column chromatography (Isolera, 80g column, EtOAc:Hept, 50:50) to afford the title compound (1.3g, 5.4 mmol, 62%) as a pale yellow solid.
  • Step 4 To a solution of 7-bromo-6,8-dimethylpyrrolo[l,2- ][l,2,4]triazin-l(2J7)-one (250 mg, 1.03 mmol) in a mixture of 1,4-dioxane (3.0 mL) and water (0.33 mL) were added 2-(3-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (293 mg, 1.08 mmol), K2CO3 (428 mg, 3.10 mmol) and PdC12(dppf) (83.1 mg, 114 pmol).
  • Step 5 To a solution of 7-(3-(difluoromethoxy)phenyl)-6,8- dimethylpyrrolo[l,2- ][l,2,4]triazin-l(2J7)-one (25 mg, 82 pmol) in 1,4-dioxane (1.2 mL) were added Cui (7.8 mg, 41 pmol), 2-bromo-5-methoxypyrimidine (20 mg, 0.11 mmol), K3PO4 (43 mg, 0.20 mmol) and 1,10-phenanthroline (8.9 mg, 49 pmol). The solution was purged with argon for 5 min after which, the microwave vial was capped and heated overnight at 110°C.
  • Step 4 To a solution of 7-bromo-6,8-dimethylpyrrolo[l,2- ][l,2,4]triazin-l(2J7)-one (50 mg, 0.21 mmol, prepared according to Scheme 1 Step 3 - EXAMPLE 1) in a mixture of 1,4-dioxane (0.6 mL) and water (0.07 mL) were added l-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)azetidine (80 mg, 0.31 mmol) and K2CO3 (86 mg, 0.62 mmol).
  • Step 5 To a solution 7-(3-(azetidin-l-yl)phenyl)-6,8- dimethylpyrrolo[l,2- ][l,2,4]triazin-l(2J7)-one (80 mg, 0.27 mmol) in DMF (1.9 mL) were added Cui (26 mg, 0.14 mmol), 2-bromopyridine (0.13 g, 78 pL, 0.82 mmol) and A 7 ,A 2 -dimethylethane-l,2-diamine (14 mg, 18 pL, 0.16 mmol).
  • EXAMPLE 3 6-bromo-7-[3-(difluoromethoxy)phenyl]-8-methyl-2-pyrimidin-2-yl- pyrrolo[l,2- ⁇ /
  • Step 1 To a solution 7-(3-(difluoromethoxy)phenyl)-8- methylpyrrolo[l,2- ][l,2,4]triazin-l(2J7)-one (59.07 mg, 182.5 pmol, prepared according to Scheme 1 Step 4) in 1,4-dioxane (1.3 mL) were added 2-bromopyrimidine (87.06 mg, 547.6 pmol), K3PO4 (96.86 mg, 456.3 pmol) and 1,10-phenanthroline (19.74 mg, 109.5 pmol).
  • Step 2 NBS (106 mg, 595 pmol) was added to a solution of 7- [3 -(difluoromethoxy)phenyl]-8-methyl-2-pyrimidin-2-yl-pyrrolo[ 1 ,2-d ⁇ [ 1 ,2,4]triazin- 1 - one (183 mg, 495 pmol) in THF (15 mL). The reaction was stirred at rt for 16 hours after which, another portion of NBS (35 mg, 0.20 mmol) was added. The reaction was stirred for another 30 min after which, DCM (5 mL) was added.
  • Table 1 Compounds prepared according to the Examples.
  • LC-MS Liquid chromatography-mass spectrometry
  • Reverse phase was carried out on AccucoreTM Cis cartridge (100 x 3 mm); eluents: FEO + 0.1% Formic acid (A) and MeCN + 0.1% Formic acid (B). Gradient conditions used: Linear gradient from 0-95% B within 10 min. Purity was determined by the area percentage method of the obtained PDA spectra.
  • LC-MS Liquid chromatography-mass spectrometry
  • Reverse phase (Cis); eluents: H2O + 0.1% Formic acid (A) and MeCN + 0.1% Formic acid (B). Gradient conditions used: Linear gradient from 5-100% B within 20 min. Purity was determined by the area percentage method of the obtained PDA spectra.
  • SFC-MS Supercritical fluid chromatography -mass spectrometry
  • the compounds provided in the present invention are negative allosteric modulators of mGlu7. As such, these compounds are expected to have their effect at mGlu7 by virtue of their ability to block the function of the receptor after binding to a site that is not the orthosteric glutamate recognition site.
  • the cDNA encoding the human metabotropic glutamate 7 receptor (hmGlu7) was subcloned into an expression vector containing also the hygromycin resistance gene.
  • the cDNA encoding a G protein allowing redirection of the activation signal to intracellular calcium flux was subcloned into a different expression vector containing also the Puromycin resistance gene.
  • Transfection of both these vectors into HEK293 cells with PolyFect reagent (Qiagen) according to supplier’s protocol, and hygromycin and puromycin treatment allowed selection of antibiotic resistant cells which had integrated stably one or more copies of the plasmids.
  • Positive cellular clones expressing hmGlu7 were identified in a functional assay measuring changes in calcium fluxes in response to glutamate and L-AP4 or known mGlu7 orthosteric antagonists.
  • HEK-293 cells expressing hmGlu7 were maintained in media containing DMEM, Fetal Bovine Serum (10%), GlutamaxTM (2 mM), penicillin (100 units/mL), streptomycin (100 pg/mL), geneticin (100 pg/mL) and hygromycin-B (40 pg/mL) and puromycin (1 pg/mL) at 37°C with 5% CO2 in a humidified atmosphere.
  • the medium was aspirated and the cells were loaded with a 3 pM solution of Fluo4-AM (LuBioScience, Lucerne, Switzerland) in 0.03% pluronic acid. After 1 hour at 37°C/5% CO2, the non incorporated dye was removed by washing cell plate with the assay buffer. All assays were performed in a pH 7.4 buffered- solution containing 20 mM HEPES, 143 mM NaCl, 6 mM KC1, 1 mM MgSCU, 1 mM CaCh, 0.125 mM sulfinpyrazone and 0.1% glucose.
  • the Table 3 below represents the mean IC50 obtained from at least three independent experiments of selected molecules performed in duplicate.
  • the procedure can be performed as described previously by Ritov and Richter-Levin, 2014 with minor modifications.
  • the apparatus consists of annular platform with two opposite, enclosed quadrants (with walls 35 cm height) and two open quadrants (with borders 5 mm height).
  • the plastic tank that holds this platform is filled up with water (22 ⁇ 2°C, 50 cm deep), arising to 10 cm below the platform level.
  • the annular platform and the plastic tank comprise one unified arena.
  • rats are first habituated to the room for 4 min and then placed into one of the open quadrants facing a closed part of the apparatus. Rats are allowed to explore the arena for a 5 mins session.
  • rats behavior is tracked, recorded and analyzed by the EthoVision system (Noldus Information Technology, Wageningen, Netherlands). Behavioral measures that are analyzed include the time spent in the open quadrants, distance traveled in the open quadrants, distance travelled in the closed quadrants and total freezing behavior. The impact of exposure to various stressors and/or compounds are assessed using these parameters. Pre-treatment time and route of administration of the different tested compounds are defined based of their pharmacokinetic properties.
  • the elevated plus maze (EPM) test can be conducted using Sprague-Dawley male rats.
  • the EPM is made of plastic that has two open arms (50 cm x 10 cm) and two closed arms of the same size with walls 40 cm high, elevated 86 cm above the ground. Both arms are made of black Plexiglas.
  • the average illumination level on the open arms is 187 LUX and 100 LUX on the closed arms.
  • rats are brought into a holding room directly next to the testing room and allowed to habituate to the environment for 30 min.
  • rats are placed in the center of the maze, facing one of the open arms and observed for 5 min.
  • rats behavior is tracked, recorded and analyzed by the Etho- Vision system (Noldus Information Technology, Wageningen, Netherlands). Behavioral measures that are analyzed include the time spent in the open arms, number of entries in the open arms as well as the distance travelled. Pre-treatment time and route of administration of the different tested compounds are defined based of their pharmacokinetic properties.
  • the fear-conditioning arena (30 cm * 20 cm * 25 cm, Med Associates) is made of Plexiglas in different contexts.
  • the system is placed in a sound-proof ventilated box.
  • the arena floor consists of grid floor (19 parallel 0.48 cm diameter stainless steel rods, 1.6 cm apart) above a stainless steel waste pan. All rods were wired to a shock generator and scrambler.
  • a speaker was mounted in the chamber wall to provide the source of the auditory stimuli.
  • Fear conditioning procedure was performed over two days. The first day (training), rats were placed in the training context (context A) and after a 120 s acclimation period, they received five pairings of the CS and US.
  • the CS tone (78 dB, 2 kHz, 5 ms rise/fall time) was presented for 30 s and co-terminated with a brief US footshock (O.5 s, 0.66 mA).
  • the inter-tone interval (tone onset to next tone onset) ranged from 60s.
  • the conditioning chambers were cleaned between subjects with 70% ethanol.
  • the time-spent freezing during delivery of the CS tone was scored (CS freezing).
  • the second day (test day) animals were placed in a new context (context B) and were exposed to the CS (120s) after 60s of acclimation. Time-spent in freezing was measured during both acclimation and CS. Tested compounds were administrated prior and/or after training phase as well as testing phase. Pre-treatment time and route of administration of the different tested compounds were adjusted based of their pharmacokinetic properties.
  • NIHL Noise-induced hearing loss
  • Young adult males CBA/CaJ mice are used to assess the effect of tested compound on NIHL. Animals are exposed to octave band noise (8-16khz) at a sound pressure level of HOdB over 2 hours. Tested compounds are administrated prior and/or after noise exposure. Hearing function is measured using auditory brainstrem response (ABR) audiograms or Distorsion Product of Autoacoustic Emissions (DPOAE) at different timepoint 24 hours, 2 and 4 weeks post acoustic trauma. Pre-treatment time and route of administration of the different tested compounds are adjusted based of their pharmacokinetic properties. The experimental groups are compared to the vehicle treated group through the measure of, for example, ABR Threshold, or ABR Threshold shift.
  • ABR auditory brainstrem response
  • DPOAE Distorsion Product of Autoacoustic Emissions
  • Tested compounds are administrated prior colorectal distension. Pre-treatment time and route of administration of the different tested compounds are adjusted based of their pharmacokinetic properties.
  • Typical examples of recipes for the formulation of the invention are as follows: 1. Tablets
  • active ingredient can be replaced by the same amount of any of the compounds according to the present invention, in particular by the same amount of any of the exemplified compounds.
  • An aqueous suspension is prepared for oral administration so that each 1 milliliter contains 1 to 5 mg of one of the active compounds, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water ad 1 mL.
  • a parenteral composition is prepared by stirring 1.5 % by weight of active ingredient of the invention in 10% by volume propylene glycol and water.
  • active ingredient can be replaced with the same amount of any of the compounds according to the present invention, in particular by the same amount of any of the exemplified compounds.
  • Reasonable variations are not to be regarded as a departure from the scope of the invention. It will be obvious that the described invention may be varied in many ways by those skilled in the art.

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Abstract

La présente invention concerne des composés de Formule (I), dans laquelle P, Q, A, B, m, n, R1, R3 et R sont tels que définis dans la Formule (I) ; qui sont des modulateurs allostériques négatifs du sous-type 7 du récepteur de glutamate métabotropique (mGlu7) et qui sont utiles pour le traitement ou la prévention de troubles neurologiques, de l'oreille et de troubles psychiatriques associés à un dysfonctionnement du glutamate et de maladies dans lesquelles le sous-type mGlu7 des récepteurs métabotropiques est impliqué. L'invention concerne également des compositions pharmaceutiques comprenant de tels composés, des procédés de préparation de tels composés et de telles compositions, et l'utilisation de tels composés pour la prévention ou le traitement de troubles et de maladies neurologiques, de l'oreille et de troubles et de maladies psychiatriques dans lesquels mGlu7 est impliqué.
PCT/EP2023/081732 2022-11-14 2023-11-14 Nouveaux dérivés de pyrrolo[1,2-d][1,2,4]triazin-1-one servant de modulateurs allostériques négatifs des récepteurs mglu7 WO2024105021A1 (fr)

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