Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
  • C07D239/72—Quinazolines; Hydrogenated quinazolines
  • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
  • C07D239/88—Oxygen atoms
  • C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
  • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
  • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
  • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D265/20—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 4
  • C07D265/22—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
  • C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
  • C07D279/08—1,3-Thiazines; Hydrogenated 1,3-thiazines condensed with carbocyclic rings or ring systems

Definitions

• the present invention is directed to dihydro-quinazoline, -benzothiazine and - benzoxazine derivatives for use in the prevention or treatment of neurological, psychiatric, sleep disorders and diseases, advantageously in which central orexin neurotransmission is compromised or in which central and peripheral orexin receptors are involved.
• the present invention is also directed to pharmaceutical compositions comprising these compounds for use in the prevention and/or treatment of neurological disorders and diseases.
• the present invention is also directed to dihydrobenzothiazine and dihydro-benzoxazine derivatives and the use of these compounds as a medicament.
• Orexin 1 and 2 (0X1 and 0X2, also known as hypocretin 1 and 2 or orexin A and B) are hypothalamic neuropeptides specifically produced in the lateral hypothalamic area (Sakurai et al. 1998). Orexins act on the two G protein-coupled receptors (GPCRs), the orexin 1 receptor (0X1 R) and the orexin 2 receptor (0X2R), participating in a broad range of physiological functions such as sleep/wakefulness (Gao et al. 2021 ; de Lecea et al. 1998; Lin et al. 1999; Ohno et Sakurai 2008), feeding behavior (Sakurai et al. 1998), reward -seeking (Cason et al.
• GPCRs G protein-coupled receptors
• OX1 R is mainly involved in motivation and reward and the OX2R in the modulation of sleep/wake cycle and energy homeostasis (Perrey et Zhang 2020).
• SB-334867 an experimental 0X1 R selective antagonist
• SB-334867 an experimental 0X1 R selective antagonist
• 0X1 R antagonists In contrary to 0X1 R antagonists, a potential therapeutic role of 0X1 R agonists in REM sleep behavior disorder (RBD) is hypothesized due to the interaction between o- synuclein and 0X1 R in pathogenesis. 0X1 R dysfunction can induce the occurrence of RBD and is a potent early sign of Parkinson's disease (PD), but whether the pathogenetic mechanism involved in RBD remains unexplored. In contrast, o-synuclein has been verified to form Lewy bodies in orexin neurons, whose activity and function depend on orexin receptor 1 (0X1 R) (Fan et al. 2023).
• 0X1 R agonists may be a useful strategy to slow or stop the neurodegenerative process of PD and treating RBD.
• NT1 narcolepsy type 1 characterized by excessive daytime sleepiness, cataplexy, hypnagogic/hypnopompic hallucinations, sleep paralysis, and disturbed nighttime sleep (Cao et Guilleminault 2017; Siegel 1999; Thorpy 2020).
• Cerebrospinal fluid (CSF) orexin-1 levels are predictive for narcolepsy (abnormal levels in 89.5% of the overall patient population and 94.7% of HLA DQBI*0602 positive cases (Kanbayashi et al. 2002; Nishino 2007).
• NT1 low or absent CSF hypocretin levels serve as a specific biomarker when in narcolepsy type 2 (NT2) or other variants of central of hypersomnolence disorders or hypersomnias (i.e. idiopathic hypersomnia or secondary or recurrent hypersomnia associated with psychiatric diseases), where this specific biomarker is currently absent (Zhang et al. 2018). Since this finding, orexin agonists have attracted attention of potential treatments development for narcolepsy. In 2008, the first OX2R selective agonists classes were filed to be patented, stimulating the discovery of several compounds, but all acting only as OX2R agonists (Bogen et al. 2021 ; Fujimoto et al. 2022; Yanagisawa 2012; Yukitake et al. 2019; Zhang et al. 2021 ).
• TAK-994 and TAK-861 are active compounds and act as a highly selective agonist of the OX2R.
• TAK-994 is >700- fold selectivity over the OX1 R.
• TAK-994 was the first oral selective OX2R agonist developed.
• the international patent application W02022140317 relates to substituted piperidino compounds, particularly, substituted piperidino compounds having agonist activity, once again only OX2R are targeted.
• Parkinson's Disease is the second most common chronic neurodegenerative disease characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta (Hornykiewicz et Kish 1987).
• the incidence of PD in the population over 55 years old is about 1% and the cardinal symptoms of PD include resting tremor, bradykinesia, muscle rigidity, postural instability, and usually associatedd with cognitive impairment, mental disorder, and other nonmotor symptoms (Beitz 2014; Meerwaldt et Hovestadt 1988).
• the cause of PD is not fully understood, but several factors including gene mutation, oxidative stress, mitochondrial dysfunction, neurotransmitter toxicity, failure of protein homeostasis appear to be associated with the development of PD.
• the most common treatment for PD is symptom management.
• the dopamine precursor levodopa is the most widely used clinical drug (Hornykiewicz 1975), which could only attenuate the symptoms, but fails to halt the progressive degeneration of dopaminergic neurons in the substantia nigra.
• Orexinergic receptors are located in many brain structures, such as cortex, hippocampus, amygdala, thalamus, hypothalamus, and basal ganglia (Hervieu et al. 2001 ; Hu et al. 2015). It is known that orexins play important roles in the regulation of sleep, feeding behavior, energy homeostasis, neuroendocrine, and autonomic control and the activity of orexinergic system decreases with aging, which has been implicated in many neurodegenerative disorders (Liu et al. 2018).
• orexinergic systems also play an important role in motor control (Berhe, Gebre, et Assefa 2020; Hu et al. 2015; Song et al. 2015; Wang, Cao, et Wu 2021 ).
• Most of the central motor control structures are innervated by orexinergic fibers (Hu et al. 2015; Liu et al. 2018).
• all the basal ganglia nuclei including the globus pallidus, the subthalamic nucleus, the substantia nigra, and the striatum are innervated by orexigenic fibers (Alrouji et al. 2023; Liu et al. 2018).
• 6-hydroxydopamine (6-OHDA)-induced rat model of PD revealed that the number of orexinergic neurons in the lateral hypothalamus decreases significantly (Long-Biao et al. 2010), when the loss of orexinergic neurons in this animal model of PD seems to resemble the process in parkinsonian patients. Furthermore, the orexin levels in plasma and cerebrospinal fluid decrease dramatically in parkinsonian patients (Drouot et al. 2003; Fronczek et al. 2007). These reports implied the important role of orexinergic systems in PD.
• Orexin-A has neuroprotective effects in cellular models of PD. Orexin-A protects SH-SY5Y cells against 6-OHDA (Esmaeili-Mahani et al. 2013; Pasban-Aliabadi, Esmaeili-Mahani, etAbbasnejad 2017) or MPPC (Feng et al. 2014; Liu et al. 2018) induced toxicity.
• orexin-A exerted neuroprotective effects, which may imply orexin-A as a potential therapeutic target for PD and OX1 R agonists as potential target for treatment of PD.
• orexin-A may act as an immunomodulatory regulator of microglia reducing hypothalamic neuron death in the condition of inflammation.
• orexin-A exerts protective effects by attenuating neuroinflammation in AD and cerebral ischemia (Couvineau et Laburthe 2012; Xiong et al. 2013).
• the anti-inflammatory properties may also be involved in the neuroprotective effects of orexin in PD.
• the potential therapeutic effects of orexins on both motor and non-motor disorders in animal models of PD have also been indicated.
• Cerebroventricular administration of orexin-A alleviates sensory motor deficits in a 6- OHDA-treated rat model of PD (Hadadianpour et al. 2017). Similar results were observed in the MPTP-induced mouse model of PD.
• the application of orexin-A into the cerebral ventricles improves motor performance in both pole and open field tests by attenuating the loss of dopaminergic neurons and fibers (Liu et al. 2018).
• Intrapallidal administration of both orexin-A and orexin-B could also alleviate motor deficits in MPTP-treated parkinsonian mice (Ying Wang et al. 2019).
• chemogenetic activation of orexinergic neurons could reverse the abnormal locomotor activity in the pre-clinical stage in A53T mice (Stanojlovic, Pallais, et Kotz 2019).
• cognitive impairments, one of the common non-motor disorders in PD could also be ameliorated by orexins.
• cognitive impairments, one of the common non- motor disorders in PD could also be ameliorated by orexins.
• orexin-A into CA1 or chemogenetic activation of orexinergic neurons increases the firing activity of CA1 neurons (Chen, Chen, et Du 2017) and ameliorates hippocampal- dependent memory impairment in the A53T mouse model of PD (Stanojlovic, Pallais, et Kotz 2019).
• the first subject-matter of the invention relates to a compound of formula (I): wherein: - X represents –NH-, –S- or –O-; - Y and R 2 , independently of each other represents a hydrogen atom, a halogen atom, –NO 2 or –NH 2 ; - R 1 , R 3 , R 4 each represent, independently of each other, a hydrogen atom or a halogen atom; - R 5 , R 6 , R 7 , R 8 , R 9 each represent, independently of each other, a hydrogen atom, a halogen atom, –OR 10 or a (C 1 –C 30 )alkyl chain, especially (C 1 –C 20 )alkyl, optionally broken up and/or followed and/or preceded by one or more moieties chosen from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclic, –C ⁇ C–, –C(R 11
• the present invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising at least one compound of formula (I) as described above and a pharmaceutically acceptable carrier for use in the prevention and/or treatment of neurological diseases, preferably associated with psychiatric and/or sleep disorders and diseases, advantageously in which central orexin neurotransmission is compromised or in which central and peripheral orexin receptors are involved.
• the first subject-matter of the invention relates to a compound of formula (I): wherein: - X represents –NH-, –S- or –O-; - Y and R 2 , independently of each other represents a hydrogen atom, a halogen atom, –NO 2 or –NH 2 ,; - R 1 , R 3 , R 4 each represent, independently of each other, a hydrogen atom or a halogen atom; - R 5 , R 6 , R 7 , R 8 , R 9 each represent, independently of each other, a hydrogen atom, a halogen atom, –OR 10 or a (C 1 –C 30 )alkyl chain, especially (C 1 –C 20 )alkyl, optionally broken up and/or followed and/or preceded by one or more moieties chosen from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclic, –C ⁇ C–,
• halogen atom means fluorine, chlorine, bromine and iodine atoms.
• alkyl group means a saturated, linear or branched hydrocarbon chain.
• (C 1 –C x )alkyl means an alkyl group such as defined above, containing 1 to X carbon atoms.
• (C 1 –C 6 )alkyl means an alkyl group such as defined above, containing 1 to 6 carbon atoms, such as, for example, methyl, ethyl, isopropyl, tert–butyl, pentyl, etc.
• aryl means an aromatic group, especially a hydrocarbon group, especially containing 6 to 20 carbon atoms, preferably 6 to 10 carbon atoms, and comprising one or more fused rings, such as, for example, a phenyl or naphthyl group.
• fused rings such as, for example, a phenyl or naphthyl group.
• heteroaryl means an aromatic group comprising one or more fused rings and comprising 5 to 10 cyclic atoms, including one or more heteroatoms, advantageously 1 to 4 and even more advantageously 1 or 2, such as, for example, sulfur, nitrogen, oxygen, phosphorus or selenium atoms, and preferably sulfur, nitrogen or oxygen, the other cyclic atoms being carbon atoms.
• acyl means a group of formula -CO-R in which R represents a (C 1 –C 6 ) alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group, and preferably a (C 1 –C 6 ) alkyl or aryl group, and still more preferably a (C 1 –C 6 ) alkyl group.
• cycloalkyl means a saturated mono– or polycyclic hydrocarbon chain (especially a bicyclic or tricyclic chain). When it is a polycyclic group, the rings can be fused, bridged or joined by a spiro ring junction two by two. Examples include cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl groups.
• heterocyclic group means a non-aromatic, saturated or unsaturated, monocyclic or polycyclic group (comprising fused, bridged or spiro rings) in which one or several atom(s) of the ring(s) carbon atoms each is replaced with heteroatoms, in particular this term means a 5 to 10–membered ring, saturated or unsaturated, but not aromatic, and containing one or more, advantageously 1 to 4, more advantageously 1 or 2 heteroatoms, the heteroatoms being for example, sulfur, nitrogen or oxygen atoms. It can particularly be a pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl group.
• the aryl, heteroaryl and heterocyclic group when substituted, can be substituted with one or more groups chosen from the group consisting of a halogen atom, a (C 1 –C 6 )alkyl group, an aryl group, -NO 2 , –CN, –OR 19 , –SR 20 , –NR 16 R 17 , –B(OH) 2 , –SO 3 R 17 , and –COOR 18 , in particular chosen from the group consisting of a halogen atom, -NO 2 , –CN, –OR 19 , – SR 20 , –NR 16 R 17 , –B(OH) 2 , –SO 3 R 17 , with R 16 to R 20 representing, independently of each other, a hydrogen atom or a (C 1 –C 6 )alkyl group.
• “pharmaceutically acceptable” means what is used in the preparation of a pharmaceutical composition, which is generally safe, nontoxic and not biologically or otherwise undesirable and which is acceptable for both veterinary and human pharmaceutical use.
• “Pharmaceutically–acceptable salts” of a compound mean of salts that are pharmaceutically acceptable, such as defined here, that have the desired pharmacological activity of the parent compound.
• Such salts include: (1) hydrates and solvates, (2) pharmaceutically–acceptable acid addition salts formed with pharmaceutically– acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or formed with pharmaceutically–acceptable organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2–hydroxy ethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2–naphthalene sulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl–L–tartaric acid, tartaric acid, p–tol
• Acceptable organic bases include diethanolamine, ethanolamine, N–methylglucamine, triethanolamine, tromethamine and the like.
• Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
• the compounds according to the invention will be in the form of pharmaceutically–acceptable base addition salts, the base being such as NaOH or KOH, and especially NaOH.
• An “optically pure compound” means an enantiomer in an enantiomeric excess of more than 95%, preferably of more than 96%, more preferably of more than 97%, even more preferably of more than 98%, particularly preferably of more than 99%.
• the present invention also includes all pharmaceutically acceptable isotopic variations of a compound of formula I in which one or more atoms is replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• Such compounds are identical to those disclosed herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen such as 2 H and 3 H, carbon such as 11 C, 13 C and 14 C, nitrogen such as 13 N and 15 N, oxygen such as 15 O, 17 O and 18 O, sulfur such as 35 S, fluorine such as 18 F, iodine such as 123 I and 125 I, and chlorine such as 36 Cl.
• isotopically-labelled compounds of formula I for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies.
• a subject administered with a compound of the present invention, or a pharmaceutically acceptable salt thereof is generally a mammal, such as a human being, male or female.
• the amount of compound administered to the subject is an amount sufficient to agonize the orexin receptor in the subject.
• the amount of compound can be an “effective amount”, wherein the subject compound is administered in an amount that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
• An effective amount does not necessarily include considerations of toxicity and safety related to the administration of the compound. It is recognized that one skilled in the art may affect neurological and psychiatric disorders associated with orexin receptor activation by treating a subject presently afflicted with the disorders, or by prophylactically treating a subject likely to be afflicted with the disorders, with an effective amount of a compound of the present invention.
• treatment and “treating” refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the neurological and psychiatric disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms, as well as the prophylactic therapy of the mentioned conditions, particularly in a subject that is predisposed to such disease or disorder.
• administration of and or “administering a” compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the subject.
• compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier, i.e.
• the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• the orexin receptors (OX1R, OX2R) have been implicated in a wide range of biological functions. This has suggested a potential role for these receptors in a variety of disease processes in humans or other species.
• the compounds of the present invention could therefore have utility in treating, preventing, ameliorating, controlling or reducing the risk of a variety of disorders associated with orexin receptors, including one or more of the following conditions or diseases: narcolepsy with or without cataplexy, narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), Gelineau syndrome (Maladie de Gelineau), narcoleptic syndrome, accompanied by narcolepsy-like symptoms, cataplexy in narcolepsy, excessive daytime sleepiness (EDS) in narcolepsy, hypersomnia, idiopathic hypersomnia, recurrent hypersomnia, Kleine-Levin syndrome, hypersomnia associated with a psychiatric disorder, hypersomnia due to a medical disorder, hypersomnia due to a medication or substance, and insufficient sleep syndrome and any conditions in accordance with The International Classification of Sleep Disorders, Third Edition (ICSD-3) classifies eight different Central Disorders
• neurological, psychiatric, sleep disorders and diseases refers to psychiatric and/or sleep neurological disorders and diseases, i.e. neurological diseases associated with sleep and/or psychiatric disorders.
• the disorders and diseases in which the central orexin neurotransmission is compromised or central and peripheral orexin receptors are involved.
• the present invention may provide methods for treating or controlling: narcolepsy with or without cataplexy, narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), Gelineau syndrome (Maladie de Gélineau), narcoleptic syndrome, accompanied by narcolepsy-like symptoms, cataplexy in narcolepsy, excessive daytime sleepiness (EDS) in narcolepsy, hypersomnia, idiopathic hypersomnia, recurrent hypersomnia, Kleine-Levin syndrome, hypersomnia associated with a psychiatric disorder, hypersomnia due to a medical disorder, hypersomnia due to a medication or substance, and insufficient sleep syndrome and any conditions in accordance with The International Classification of Sleep Disorders, Third Edition (ICSD-3) classifies eight different Central Disorders of Hypersomnolence (CDH)(American Academy of Sleep Medicine 2014) ; pathologic daytime sleepiness and/or unappropriated
• the dihydro-quinazoline, -benzothiazine and benzoxazine derivatives as compounds of the present invention may also potentially have utility in treating, preventing, ameliorating, controlling or reducing the risk of a variety of other disorders associated with orexin receptors, including one or more of the following conditions or diseases including enhancing sleep quality, improving sleep quality, increasing sleep efficiency, consolidating sleep maintenance, improving sleep initiation, decreasing sleep latency or onset, decreasing difficulties in falling asleep, increasing sleep continuity, decreasing the number of awakenings during sleep, decreasing intermittent waking during sleep, decreasing nocturnal arousals, decreasing the time spent awake following the initial onset of sleep, increasing the total amount of sleep, reducing the fragmentation of sleep, altering the timing, frequency or duration of sleep stages, or duration of slow-wave sleep and / or REM sleep, promoting slow wave sleep, enhancing EEG - delta activity during sleep, decreasing nocturnal arousals, especially early morning awakenings, increasing daytime alertness, reducing daytime drowsiness, treating or reducing
• a preferred embodiment of the invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer or mixture of stereoisomers thereof, for use in the prevention and/or treatment of narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), hypersomnia, idiopathic hypersomnia, recurrent hypersomnia, Kleine-Levin syndrome, hypersomnia associated with a psychiatric disorder, hypersomnia due to a medical disorder, hypersomnia due to a medication or substance, Parkinson's disease and other synucleinopathies, preferably narcolepsy type 1 (NT1), narcolepsy type 2 (NT2) and Parkinson's disease.
• NT1 narcolepsy type 1
• NT2 narcolepsy type 2
• Parkinson's disease preferably narcolepsy type 1 (NT1), narcolepsy type 2 (NT2) and Parkinson's disease
• a preferred embodiment of the invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer or mixture of stereoisomers thereof, for use in the prevention and/or treatment of REM sleep behavior disorder (RBD).
• RBD REM sleep behavior disorder
• the neurological diseases are selected from the group consisting of narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), hypersomnia, idiopathic hypersomnia, recurrent hypersomnia, Kleine-Levin syndrome, hypersomnia associated with a psychiatric disorder, hypersomnia due to a medical disorder, hypersomnia due to a medication or substance, Parkinson's disease and other synucleinopathies, preferably narcolepsy type 1 (NT1), narcolepsy type 2 (NT2) and Parkinson's disease.
• NT1 narcolepsy type 1
• NT2 narcolepsy type 2
• Parkinson's disease preferably narcolepsy type 1 (NT1), narcolepsy type 2 (NT2) and Parkinson's disease.
• the neurological diseases preferably the neurological disorders and diseases in which central orexin neurotransmission is compromised or in which central and peripheral orexin receptors are involved, are selected from the group consisting of narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), hypersomnia, idiopathic hypersomnia and recurrent hypersomnia.
• the neurological disorders targeted are those requiring an agonist of the orexin 1 receptor (OX1R) and/or the orexin 2 receptor (OX2R), preferably both receptors.
• R 2 when one of Y or R 2 represents a halogen atom, –NO 2 or – NH 2 , preferably –NO 2 or –NH 2 , the other represents a hydrogen atom. In some embodiments, when Y represents a halogen atom, –NO 2 or –NH 2 , preferably –NO 2 or – NH 2 , R 2 represents a hydrogen atom. In some embodiments, when R 2 represents a halogen atom, –NO 2 or –NH 2 , preferably –NO 2 or –NH 2 , Y represents a hydrogen atom. R 4 represents preferably a hydrogen atom.
• R 1 , R 2 , R 3 , R 4 each represent a hydrogen atom or R 1 , R 3 , R 4 , Y each represent a hydrogen atom.
• R 1 , R 2 , R 3 , R 4 can each represent a hydrogen atom.
• R 1 , R 3 , R 4 , Y each represent a hydrogen atom.
• R 5 , R 6 , R 7 , R 8 , R 9 each represent, independently of each other, a hydrogen atom or –OR 10 .
• at least four residues out of R 5 , R 6 , R 7 , R 8 and R 9 each represent a hydrogen atom.
• R 5 , R 6 , R 7 , R 8 , R 9 each represent, a hydrogen atom.
• R 5 represents –OR 10 with R 10 representing a hydrogen atom, a (C 1 –C 30 )alkyl or phenyl group, preferably a (C 1 –C 20 )alkyl or a phenyl group.
• R 5 represents –OR 10 with R 10 representing a hydrogen atom, a (C 1 – C 30 )alkyl or phenyl group, preferably a (C 1 –C 20 )alkyl or a phenyl group
• R 6 , R 7 , R 8 , R 9 each represent, a hydrogen atom
• R 6 represents –OR 10 with R 10 representing a hydrogen atom, a (C 1 –C 30 )alkyl or phenyl group, preferably a (C 1 –C 20 )alkyl or a phenyl group.
• R 6 represents –OR 10 with R 10 representing a hydrogen atom, a (C 1 – C 30 )alkyl or phenyl group, preferably a (C 1 –C 20 )alkyl or a phenyl group
• R 5 , R 7 , R 8 , R 9 each represent, a hydrogen atom
• R 7 represents –OR 10 with R 10 representing a hydrogen atom, a (C 1 –C 30 )alkyl or phenyl group, preferably a (C 1 –C 20 )alkyl or a phenyl group.
• R 7 represents –OR 10 with R 10 representing a hydrogen atom, a (C 1 – C 30 )alkyl or phenyl group, preferably a (C 1 –C 20 )alkyl or a phenyl group
• R 5 , R 6 , R 8 , R 9 each represent, a hydrogen atom
• one residue out of R 5 , R 6 , R 7 , R 8 and R 9 represents -OR 10 with R 10 representing a hydrogen atom, a (C 1 –C 30 )alkyl or phenyl group, preferably a (C 1 – C 20 )alkyl or a phenyl group.
• X can represent -NH-. In some embodiments, X can represent - S-. In some embodiments, X can represent -O-. Preferably, X represents –NH- or –S-.
• the compound of formula (I) is selected from the group consisting of:
• the compound of formula (I) is selected from the group consisting of:
• the compound of formula (I) is selected from the group consisting of: , and mixtures thereof.
• the neurological, psychiatric, sleep disorders and diseases in which central orexin neurotransmission is compromised or in which orexin receptors are involved is selected from the group consisting of narcolepsy type 1, narcolepsy type 2, idiopathic hypersomnia, recurrent hypersomnia, attention- deficit hyperactivity disorder, anxiety and mood disorders, Alzheimer's disease or any other neurodegenerative disorders or cognitive impairment and tauopathies, Parkinson's disease and other synucleinopathies, Guillain-Barre syndrome, chronic fatigue syndrome, long COVID-19 and medical or health conditions associated with circadian rhythmicity as well as mental and physical disorders associated with travel across time zones and with rotating shift-work schedules, restless legs syndrome, fibromyalgia, cardiac failure, diseases related to bone loss, sepsis, syndromes which are manifested by unrefresh
• the dosage of active ingredient in the compositions of this invention may be varied, however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained.
• the active ingredient may be administered to subjects (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy.
• the selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment.
• the dose will vary from subject to subject depending upon the nature and severity of disease, the subject's weight, special diets then being followed by a subject, concurrent medication, and other factors which those skilled in the art will recognize.
• dosage levels of between 0.0001 to 100 mg/kg of body weight per day are administered to the subject, e.g., humans, adolescent humans and elderly humans, to obtain effective agonism of orexin receptors.
• a therapeutic dose of a compound of formula (I) comprised between 0.1 mg/kg/day and 100 mg/kg/day is administrated to a patient in need thereof.
• the present invention also relates to a pharmaceutical composition comprising at least one compound of formula (I) as described above and a pharmaceutically acceptable carrier for use in the prevention and/or treatment of neurological, psychiatric, sleep disorders and diseases in which central orexin neurotransmission is compromised or in which central and peripheral orexin receptors are involved.
• the dosage range will generally be from 0.5 mg to 10.0 g per subject per day which may be administered in single or multiple doses. In one embodiment, the dosage range will be from 0.5 mg to 500 mg per subject per day, preferably from 0.5 mg to 200 mg per subject per day, and more preferably from 5 mg to 50 mg per subject per day.
• Pharmaceutical compositions of the present invention may be provided in a solid dosage formulation such as comprising from 0.5 mg to 500 mg of active ingredient, or comprising from 1 mg to 250 mg of active ingredient.
• the pharmaceutical composition may be provided in a solid dosage formulation comprising 1 mg, 5 mg, 10 mg, 50 mg, 80 mg, 100 mg, 200 mg active ingredient.
• the pharmaceutical composition for use according to the invention comprises between 0.5 mg to 800 mg, preferably between 20 mg to 400 mg of the compound of formula (I).
• the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, such as 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
• the compounds may be administered on a regimen of 1 to 4 times per day, such as once or twice per day.
• the compounds may be administered once or multiple times during the day.
• the compounds may be administered upon awakening or otherwise in the morning, or during waking hours.
• the compounds may be administered 25 mg, 30 mg or 250 mg, 1 hour after awakening, 30 minutes after awakening or immediately after awakening.
• the pharmaceutical composition according to the invention is suitable for oral or parenteral administration.
• the pharmaceutical composition according to the invention is in the form of a solution, such as an injectable solution, or a tablet or a capsule or a transdermal delivery system.
• the compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of the present invention or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.
• Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention.
• a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention is contemplated.
• the combination therapy may also include therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly.
• the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the present invention.
• the above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.
• the weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
• the weight ratio of the compound of the present invention to the other agent will generally range from 1000:1 to 1:1000, preferably from 200:1 to 1:200.
• Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent.
• the compounds of the present invention may be administered in combination with compounds which are known in the art to be useful for treating or controlling narcolepsy, including e.g., methylphenidate, amphetamine, atomoxetine, reboxetine, viloxazine, phenelzine, protriptyline, gamma–hydroxybutyric acid, sodium oxybate, or other oxybate salts, modafinil, armodafinil, adrafinil, pitolisant, samelisant, nalfurafin, caffeine, and salts thereof, and combinations thereof, and the like.
• compounds which are known in the art to be useful for treating or controlling narcolepsy including e.g., methylphenidate, amphetamine, atomoxetine, reboxetine, viloxazine, phenelzine, protriptyline, gamma–hydroxybutyric acid, sodium oxybate, or other oxybate salt
• the present invention also relates to a compound of formula (II): wherein: - X represents -NH-, –S- or –O-, preferably -NH- or -S-; - Y and R 2 , independently of each other represents a hydrogen atom, a halogen atom, –NO 2 or –NH 2 ,; - R 1 , R 3 , R 4 each represent, independently of each other, a hydrogen atom or a halogen atom; - R 5 , R 6 , R 7 , R 8 , R 9 each represent, independently of each other, a hydrogen atom, a halogen atom, –OR 10 or a (C 1 –C 30 )alkyl chain, especially (C 1 –C 20 )alkyl, optionally broken up and/or followed and/or preceded by one or more moieties chosen from the group consisting of aryl, heteroaryl, cycloalkyl, hetero
• the compound of formula (II) is not (this compound has been described (Cox et al. 2020) as having an inhibitory activity of amyloid aggregation), (these four compounds has been described as having an inhibitory effect on cell multiplication (Yale et Kalkstein 1967), (this compound has been described as having an anticancer activity (Chinigo et al. 2008), (this compound has been described as having an anti-tumour activity (Mordarski et Chylinska 1971), (this compound has been used for the treatment of PARP-1 related diseases, see WO 2018044136) (Kim et al.
• each of R 1 , R 2 , R 3 and R 4 represents H
• Y represents an halogen atom
• four of R 5 , R 6 , R 7 , R 8 , and R 9 represent H
• Y and R 2 independently of each other represents a hydrogen atom, –NO 2 or –NH 2 .
• one of Y or R 2 represents a halogen atom, –NO 2 or – NH 2 , preferably –NO 2 or –NH 2
• the other represents a hydrogen atom or a halogen atom.
• R 2 represents a hydrogen atom or a halogen atom.
• R 2 when R 2 represents a halogen atom, –NO 2 or –NH 2 , preferably –NO 2 or –NH 2 , Y represents a hydrogen atom or a halogen atom.
• Y or R 2 when one of Y or R 2 represents a halogen atom, –NO 2 or – NH 2 , preferably –NO 2 or –NH 2 , the other represents a hydrogen atom.
• R 2 when Y represents a halogen atom, –NO 2 or –NH 2 , preferably –NO 2 or – NH 2 , R 2 represents a hydrogen atom.
• R 2 represents a halogen atom, –NO 2 or –NH 2 , preferably –NO 2 or –NH 2
• Y represents a hydrogen atom.
• R 4 represents preferably a hydrogen atom.
• R 5 , R 6 or R 7 represents –OR 10 with R 10 representing a hydrogen atom, a (C 1 –C 30 )alkyl or a phenyl group.
• R 1 , R 2 , R 3 , R 4 each represent a hydrogen atom or R 1 , R 3 , R 4 , Y each represent a hydrogen atom.
• R 1 , R 2 , R 3 , R 4 can each represent a hydrogen atom.
• R 1 , R 3 , R 4 , Y each represent a hydrogen atom.
• R 5 , R 6 , R 7 , R 8 , R 9 each represent, independently of each other, a hydrogen atom or –OR 10 .
• at least four residues out of R 5 , R 6 , R 7 , R 8 and R 9 each represent a hydrogen atom.
• R 5 , R 6 , R 7 , R 8 , R 9 each represent, a hydrogen atom.
• R 5 represents –OR 10 with R 10 representing a hydrogen atom, a (C 1 –C 30 )alkyl or phenyl group, preferably a (C 1 –C 20 )alkyl or a phenyl group.
• R 5 represents –OR 10 with R 10 representing a hydrogen atom, a (C 1 – C 30 )alkyl or phenyl group, preferably a (C 1 –C 20 )alkyl or a phenyl group
• R 6 , R 7 , R 8 , R 9 each represent, a hydrogen atom
• R 6 represents –OR 10 with R 10 representing a hydrogen atom, a (C 1 –C 30 )alkyl or phenyl group, preferably a (C 1 –C 20 )alkyl or a phenyl group.
• R 6 represents –OR 10 with R 10 representing a hydrogen atom, a (C 1 – C 30 )alkyl or phenyl group, preferably a (C 1 –C 20 )alkyl or a phenyl group
• R 5 , R 7 , R 8 , R 9 each represent, a hydrogen atom
• R 7 represents –OR 10 with R 10 representing a hydrogen atom, a (C 1 –C 30 )alkyl or phenyl group, preferably a (C 1 –C 20 )alkyl or a phenyl group.
• R 7 represents –OR 10 with R 10 representing a hydrogen atom, a (C 1 – C 30 )alkyl or phenyl group, preferably a (C 1 –C 20 )alkyl or a phenyl group
• R 5 , R 6 , R 8 , R 9 each represent, a hydrogen atom
• one residue out of R 5 , R 6 , R 7 , R 8 and R 9 represents -OR 10 with R 10 representing a hydrogen atom, a (C 1 –C 30 )alkyl or phenyl group, preferably a (C 1 – C 20 )alkyl or a phenyl group.
• X can represent -NH-. In some embodiments, X can represent - S-. In some embodiments, X can represent -O-. Preferably, X represents –S-.
• the compound of formula (II) is selected from the group consisting of:
• the compound of formula (II) is selected from the group consisting of compounds 99, 100, 145, 146, 148, 149, 151, 152, 153, 154, 155, 157, 158, 161, 167, 182, 185, 191, 194, 195, 196, 243, 244, 292, 293, 301, 302, 304, 305, 308, 310, 311, and pharmaceutically acceptable salts thereof.
• the compound of formula (II) is selected from the group consisting of compounds 99, 148, 152, 153, 154, 155, 157, 161, 167, 191, 194, 195, 196, 301, 302, 304, 305, 308, 310, 311, and pharmaceutically acceptable salts thereof.
• the compound of formula (II) is selected from the group consisting of: , and pharmaceutically acceptable salts thereof.
• the compound of formula (II) is selected from the group consisting of: , , and pharmaceutically acceptable salts thereof.
• the present invention also relates to a pharmaceutical composition comprising a compound of formula (II) and a pharmaceutically acceptable carrier.
• the pharmaceutical composition is as defined above for compound of formula (I).
• the present invention also relates to a compound of formula (II) as described above for use as a medicament.
• the present invention also relates to a compound of formula (II) as described above for use in the manufacture of a medicament.
• the present invention provides a method for treating a subject in need thereof comprising administering to said subject a compound of formula (II) or a composition comprising a compound of formula (II).
• the chromatographic separations of may be achieved as known in the art. Their absolute stereochemistry may be determined by the X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.
• racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated.
• the separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
• the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
• the diastereomeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
• the racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
• any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
• the present invention provides a method for treating a subject suffering from neurological diseases, preferably neurological, psychiatric, sleep disorders and diseases, such as narcolepsy and Parkinson’s disease, in which central orexin neurotransmission is compromised or in which central and peripheral orexin receptors are involved, comprising administering to said subject a compound of formula (I) or a composition comprising a compound of formula (I).
• neurological diseases preferably neurological, psychiatric, sleep disorders and diseases, such as narcolepsy and Parkinson’s disease, in which central orexin neurotransmission is compromised or in which central and peripheral orexin receptors are involved.
• said disorders and diseases are as defined above.
• the present invention provides a method for preventing neurological diseases, preferably neurological, psychiatric, sleep disorders and diseases, such as narcolepsy and Parkinson’s disease, in which central orexin neurotransmission is compromised or in which central and peripheral orexin receptors are involved, comprising administering to a subject an effective amount of a compound of formula (I) or a composition comprising an effective amount of a compound of formula (I).
• neurological diseases preferably neurological, psychiatric, sleep disorders and diseases, such as narcolepsy and Parkinson’s disease
• central orexin neurotransmission is compromised or in which central and peripheral orexin receptors are involved
• the methods further comprise administration of a second active compound.
• the invention is also related to compounds of formula (I) or pharmaceutical compositions comprising at least one compound of formula (I) for their use in the manufacture of a medicament for the treatment of from neurological diseases, preferably neurological, psychiatric, sleep disorders and diseases, such as narcolepsy and Parkinson’s disease, in which central orexin neurotransmission is compromised or in which central and peripheral orexin receptors are involved.
• neurological diseases preferably neurological, psychiatric, sleep disorders and diseases, such as narcolepsy and Parkinson’s disease, in which central orexin neurotransmission is compromised or in which central and peripheral orexin receptors are involved.
• said disorders and diseases are as defined above.
• the present invention also relates to the following embodiments: Embodiment 1.
• Embodiment 2 The compound of formula (I) for use according to embodiment 1, characterized in that R 1 , R 2 , R 3 , R 4 each represent a hydrogen atom.
• Embodiment 3 The compound of formula (I) for use according to embodiment 1 or 2, characterized in that R 5 , R 6 , R 7 , R 8 , R 9 , each represent, independently of each other, a hydrogen atom or –OR 10 .
• Embodiment 4. The compound of formula (I) for use according to any one of embodiments 1 to 3, characterized in that at least four residues out of R 5 , R 6 , R 7 , R 8 and R 9 each represent a hydrogen atom.
• Embodiment 9 A pharmaceutical composition comprising at least one compound of formula (I) as defined in any one of embodiments 1 to 8 and a pharmaceutically acceptable carrier for use in the prevention and/or treatment of neurological, psychiatric, sleep disorders and diseases in which central orexin neurotransmission is compromised or in which central and peripheral orexin receptors are involved.
• Embodiment 10 The pharmaceutical composition for use according to embodiment 9, comprising between 0.5 mg to 800 mg, preferably between 20 mg to 400 mg of the compound of formula (I).
• Embodiment 11 The pharmaceutical composition for use according to embodiment 9 or 10, which is suitable for oral or parenteral administration, preferably in the form of a solution, such as an injectable solution, a tablet, a capsule or a transdermal delivery system.
• Embodiment 13 The compound of formula (II) according to embodiment 12, characterized in that R 1 , R 2 , R 3 , R 4 each represent a hydrogen atom and R 5 , R 6 , R 7 , R 8 , R 9 each represent, independently of each other, a hydrogen atom or –OR 10 .
• Embodiment 14 The compound of formula (II) according to embodiments 12 or 13, characterized in that at least four residues out of R 5 , R 6 , R 7 , R 8 and R 9 each represent a hydrogen atom.
• Embodiment 15 The compound of formula (II) according to embodiment 14, characterized in that R 5 , R 6 , R 7 , R 8 , R 9 , each represent, a hydrogen atom.
• Embodiment 17 The compound of formula (II) according to any one of embodiments 12 to 16, characterized in that it is selected from the group consisting of compounds 99, 148, 152, 153 , 154 , 155, 157, 161 , 167 , 191 , 194, 195 , 196 , and mixtures thereof, preferably 99 , 152 , 155 , 194 , and mixtures thereof.
• a compound of formula (II) according to any of embodiments 12 to 17, for use as a medicament.
• One or more features of any embodiments disclosed herein may be combined and/or rearranged within the scope of the invention to produce further embodiments that are also within the scope of the invention.
• Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be within the scope of the present invention.
• the invention is further described by the following non-limiting Examples. Examples Examples are provided below to facilitate a more complete understanding of the invention. The following examples illustrate the exemplary modes of making and practicing the invention.
• Example 1 Chemistry of dihydro-quinazoline derivatives Design, synthesis and preparations of 6-nitro-2,3-dihydro-1H-quinazolin-4-one Polyphosphoric ester preparation (PPE) P2O4 (150 g) was refluxed in diethyl ether (150 mL) and CHCl3 (300 mL) until a clear solution occurred. Then solvents were removed under reduce pressure to give a clear oil.
• PPE Polyphosphoric ester preparation
• Binding activities on OX1R and OX2R sites These compounds express an activity on OX1R and/or OX2R as agonist which is determined in accordance with the following general experimental method by Eurofins using Chinese hamster ovary (CHO) cells expressing human OX1R, and human embryonic kidney (HEK), 293 cells expressing human OX2R.
• CHO Chinese hamster ovary
• HEK human embryonic kidney
• OX1 (agonist radioligand) human recombinant (CHO cells); Ligand [125I]orexin A; Ligand concentration: 0.1 nM ; Ligand Kd: 0.87 nM; Non-specific: SB 334867 (1 ⁇ M); Incubation: 60 min at RT scintillation counting; Control inhibitor: Orexin-A; Test concentration/dose: IC/EC 50 calculation are provided if 5 or more concentrations are selected; Test sample requirements: Minimum for 1) Screen: 60 ⁇ l of 10 mM stock -OR- 1 mg (pre-weighed) for 10 ⁇ M final testing.
• Results showing an inhibition (or stimulation) between 25% and 50% are indicative of weak to moderate effects.
• Results showing an inhibition (or stimulation) lower than 25% are not considered significant and mostly attributable to variability of the signal around the control level.
• Results showing an inhibition (or stimulation for assays run in basal conditions) higher than 50% are considered to represent significant effects of the test compounds.
• Low to moderate negative values have no real meaning and are attributable to variability of the signal around the control level.
• High negative values ( ⁇ 50%) that are sometimes obtained with high concentrations of test compounds are generally attributable to nonspecific effects of the test compounds in the assays. On rare occasion they could suggest an allosteric effect of the test compound. Table 2.
• Binding activities on dopamine and norepinephrine transporters, metabotropic glutamate 2, cathepsin-H and sigma-1 receptors It has been reported for a long time ago that norepinephrine cells of the locus coeruleus (Hagan et al.1999; Horvath et al.1999) and dopaminergic cells of the Ventral tegmental area (Nakamura et al.2000) all show to increase their firing rates by orexins. The firing rates of these monoaminergic neurons are well known to be associated with sleep/wakefulness states.
• OX2R could act pre- synaptically at the level of both dopaminergic and glutamatergic axons (Bandarabadi et al. 2022).
• Product 152 at 10 -5 M significantly targets on OX2R as agonist (IC 73%) and on OX1R as agonist (IC 63%) in addition acting on metabotropic glutamate 2 (mGlu2) receptors which target for the treatment of psychiatric disorders including schizophrenia, depression, and anxiety, which are characterized by a glutamatergic dysfunction with a significantly binding effect (IC 54%).
• mGlu2 metabotropic glutamate 2
• mGluR 2 antagonism activity is associated with enhanced theta/gamma oscillations and increased transitions from sleep to waking state (Ahnaou, Ver Donck, et Drinkenburg 2014).
• Product 194 at 10 -5 M significantly targets on OX2R as agonist (IC 84%) and weakly on OX1R as agonist (IC ⁇ 50%), acting on dopamine transporter (DAT) and norepinephrine transporter (NET) as a catecholaminergic reuptake inhibitor, with a binding effect on DAT (IC 89%) and NET (IC 58%).
• Therapeutic approaches targeting cathepsins can contribute to prevent or slow down the pathogenesis of neurodegenerative diseases as seen for neuronal ceroid lipofuscinosis, synucleinopathies (Parkinson's disease, Dementia with Lewy Body and Multiple System Atrophy) as well as Alzheimer's and Huntington's disease (Stoka et al. 2023).
• CTSH Cathepsin H
• narcolepsy is a lysosomal cysteine protease that plays a role in various physiological processes, including the immune response.
• CTSH has been implicated in modulating immune reactions within the central nervous system (Wang et al. 2023).
• Neuroinflammation refers to the inflammatory response in the nervous tissue, often involving glial cell activation and the release of pro-inflammatory molecules.
• CTSH can influence neuroinflammation by participating in the processing and presentation of antigens, which is crucial for the activation of immune cells such as microglia.
• Previous studies had also suggested a potential involvement of CTSH in the pathogenesis of narcolepsy (Mogavero et al. 2023).
• Product 96 at 10 -5 M targets on OX1R as agonist (IC 56%) and moreover on CTSH as antagonist (IC 80%), also acting on dopamine transporter (DAT) and norepinephrine transporter (NET) as a catecholaminergic reuptake inhibitor, with a binding effect on DAT (IC 99%) and NET (IC 77%).
• Sigma-1 receptor (S1R) participating in various physiological and pathological processes, such as neurotransmission, neuroprotection and neuroinflammation is considered as a therapeutic target for a range of neurodegenerative diseases, including amnesia and AD and also various synucleinopathies (Wang et Jia 2023).
• S1R agonists find to have multiple mechanisms of action that could be beneficial in AD, such as anti-inflammatory and antioxidant effects, modulation of neurotransmitters, and a neuroprotective effect by inhibiting A ⁇ aggregation and tau hyperphosphorylation is AD (Cummings, Osse, et Kinney 2023; Malar et al. 2023; Shinoda, Nemoto, et Iwamoto 2023).
• Product 90 at 10 -5 M targets on OX2R as agonist (IC 67%) and on S1R as antagonist (IC 75%).
• Orexin-A protects human neuroblastoma SH-SY5Y cells against 6-hydroxydopamine- induced neurotoxicity: involvement of PKC and PI3K signaling pathways (2012) Rejuvenation Research 20(2): 125-33. Perrey, David A, et Yanan Zhang. 2020. « Therapeutics Development for Addiction: Orexin-1 Receptor Antagonists republic Brain research 1731: 145922-145922. Polito, Rita et al. 2018.

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