WO2020007977A1 - Dérivés de 7-trifluorométhyl-[1,4]diazépane - Google Patents

Dérivés de 7-trifluorométhyl-[1,4]diazépane Download PDF

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WO2020007977A1
WO2020007977A1 PCT/EP2019/067989 EP2019067989W WO2020007977A1 WO 2020007977 A1 WO2020007977 A1 WO 2020007977A1 EP 2019067989 W EP2019067989 W EP 2019067989W WO 2020007977 A1 WO2020007977 A1 WO 2020007977A1
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disorders
phenyl
trifluoromethyl
diazepan
substituents
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PCT/EP2019/067989
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Hamed Aissaoui
Christoph Boss
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Idorsia Pharmaceuticals Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel 7-Trifluoromethyl-[1 ,4]diazepan derivatives of Formula (I) and their use as pharmaceuticals.
  • the invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of Formula (I), and their use as orexin receptor antagonists.
  • Orexins are neuropeptides found in 1998 by two research groups, orexin A is a 33 amino acid peptide and orexin B is a 28 amino acid peptide (Sakurai T. et al., Cell, 1998, 92, 573- 585). Orexins are produced in discrete neurons of the lateral hypothalamus and bind to the G-protein-coupled receptors (OXi and OX2 receptors).
  • the orexin-1 receptor (OX1) is selective for OX-A
  • the orexin-2 receptor (OX2) is capable to bind OX-A as well as OX-B.
  • Orexin receptor antagonists are a novel type of nervous system or psychotropic drugs. Their mode of action in animals and humans involves either blockade of both orexin-1 and orexin-2 receptor (dual antagonists), or individual and selective blockade of either the orexin-1 or the orexin-2 receptor (selective antagonists) in the brain. Orexins were initially found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behaviour (Sakurai T. et al., Cell, 1998, 92, 573-585).
  • orexin neuropeptides and orexin receptors play an essential and central role in regulating circadian vigilance states.
  • orexin neurons collect sensory input about internal and external states and send short intrahypothalamic axonal projections as well as long projections to many other brain regions.
  • the particular distribution of orexin fibers and receptors in basal forebrain, limbic structures and brainstem regions - areas related to the regulation of waking, sleep and emotional reactivity- suggests that orexins exert essential functions as regulators of behavioral arousal; by activating wake-promoting cell firing, orexins contribute to orchestrate all brain arousal systems that regulate circadian activity, energy balance and emotional reactivity.
  • Human memory is comprised of multiple systems that have different operating principles and different underlying neuronal substrates. The major distinction is between the capacity for conscious, declarative memory and a set of unconscious, non-declarative memory abilities. Declarative memory is further subdivided into semantic and episodic memory. Non-declariative memory is further subdivided into priming and perceptual learning, procedural memory for skills and habits, associative and non-associative learning, and some others. While semantic memory refers to the general knowledge about the world, episodic memory is autobiographical memory of events. Procedural memories refer to the ability to perform skill-based operations, as e.g. motor skills.
  • Long-term memory is established during a multiple stage process through gradual changes involving diverse brain structures, beginning with learning, or memory acquisition, or formation. Subsequently, consolidation of what has been learned may stabilize memories. When long-term memories are retrieved, they may return to a labile state in which original content may be updated, modulated or disrupted. Subsequently, reconsolidation may again stabilize memories. At a late stage, long-term memory may be resistant to disruption. Long-term memory is conceptually and anatomically different from working memory, the latter of which is the capacity to maintain temporarily a limited amount of information in mind. Behavioural research has suggested that the human brain consolidates long-term memory at certain key time intervals.
  • the initial phase of memory consolidation may occur in the first few minutes after we are exposed to a new idea or learning experience.
  • the next, and possibly most important phase may occur over a longer period of time, such as during sleep; in fact, certain consolidation processes have been suggested to be sleep-dependent [R. Stickgold et al., Sleep-dependent memory consolidation; Nature 2005,437, 1272-1278].
  • Learning and memory processes are believed to be fundamentally affected in a variety of neurological and mental disorders, such as e.g. mental retardation, Alzheimer’s disease or depression. Indeed, memory loss or impairment of memory acquisition is a significant feature of such diseases, and no effective therapy to prevent this detrimental process has emerged yet.
  • Orexin-1 receptor antagonism also attenuated the expression of amphetamine- and cocaine-induced CPP [Gozzi A et al., PLoS One 2011, 6(1), e16406; Hutcheson DM et al., Behav Pharmacol
  • hypocretin/orexin contributes to the expression of some but not all forms of stress and arousal [Furlong T M et al., Eur J Neurosci 2009, 30(8), 1603-1614] Stress response may lead to dramatic, usually time-limited physiological, psychological and behavioural changes that may affect appetite, metabolism and feeding behavior [Chrousos, GP et al., JAMA 1992, 267(9), 1244-1252]
  • the acute stress response may include behavioural, autonomic and endocrinological changes, such as promoting heightened vigilance, decreased libido, increased heart rate and blood pressure, or a redirection of blood flow to fuel the muscles, heart and the brain [Majzoub, JA et al., European Journal of Endocrinology 2006, 155 (suppl_1) S71-S76].
  • orexin system regulates homeostatic functions such as sleep-wake cycle, energy balance, emotions and reward. Orexins are also involved in mediating the acute behavioral and autonomous nervous system response to stress [Zhang Wet al., "Multiple components of the defense response depend on orexin: evidence from orexin knockout mice and orexin neuron-ablated mice.” Auton Neurosci 2006, 126-127, 139-145] Mood disorders including all types of depression and bipolar disorder are characterized by disturbed“mood” and feelings, as well as by sleeping problems (insomnia as well as hypersomnia), changes in appetite or weight and reduced pleasure and loss of interest in daily or once enjoyed activities [Liu X et al., Sleep 2007, 30(1): 83-90] Thus, there is a strong rationale that disturbances in the orexin system may contribute to the symptoms of mood disorders.
  • the orexin system is also involved in stress-related appetitive/reward seeking behaviour (Berridge CW et al., Brain Res 2009, 1314, 91-102).
  • a modulatory effect on stress may be complementary to an effect on appetitive/reward seeking behaviour as such.
  • an OX1 selective orexin receptor antagonist was able to prevent footshock stress induced reinstatement of cocaine seeking behaviour [Boutrel, B et al., Proc Natl Acad Sci 2005, 102(52), 19168-19173].
  • stress is also known to play an integral part in withdrawal which occurs during cessation of drug taking (Koob, GF et al., Curr Opin Investig Drugs 2010, 11(1), 63-71).
  • Orexins have been found to increase food intake and appetite [Tsujino, N, Sakurai, T, Pharmacol Rev 2009, 61(2) 162-176]. As an additional environmental factor, stress can contribute to binge eating behaviour, and lead to obesity [Adam, TC et al. Physiol Bebav 2007, 91 (4) 449-458]. Animal models that are clinically relevant models of binge eating in humans are described for example in W. Foulds Mathes et al.; Appetite 2009, 52, 545-553.
  • orexins may play a role into several other important functions relating to arousal, especially when an organism must respond to unexpected stressors and challenges in the environment [Tsujino N and Sakurai T. Pharmacol Rev. 2009, 61:162-176; Carter ME, Borg JS and deLecea L, Curr Op Pharmacol. 2009, 9: 39-45; C Boss, C Brisbare-Roch, F Jenck, Journal of Medicinal Chemistry 2009, 52: 891- 903].
  • the orexin system interacts with neural networks that regulate emotion, reward and energy homeostasis to maintain proper vigilance states. Dysfunctions in its function may thus relate to many mental health disorders in which vigilance, arousal, wakefulness or attention is disturbed.
  • the compound further attenuated cardiovascular responses to conditioned fear and novelty exposure in rats [Furlong T M et al., Eur J Neurosci 2009, 30(8), 1603-1614] It is also active in an animal model of conditioned fear: the rat fear-potentiated startle paradigm (W02009/047723) which relates to emotional states of fear and anxiety diseases such as anxieties including phobias and post traumatic stress disorders (PTSDs).
  • W02009/047723 relates to emotional states of fear and anxiety diseases
  • PTSDs post traumatic stress disorders
  • amyloid cascade hypothesis links Ab to Alzheimer's disease and, thus, to the cognitive dysfunction, expressed as impairment of learning and memory.
  • the compound has also been shown to induce antidepressant-like activity in a mouse model of depression, when administered chronically [Nollet et al., NeuroPharm 2011, 61 (1 -2):336-46].
  • the compound has been shown to attenuate the natural activation induced by orexin A in fasted hungry rats exposed to food odors [MJ Prud’Neill et al., Neuroscience 2009, 162(4), 1287-1298].
  • the compound also displayed pharmacological activity in a rat model of nicotine selfadministration [LeSage MG et al., Psychopharmacology 2010, 209(2), 203-212]
  • Another dual orexin receptor antagonist N-biphenyl-2-yl-1- ⁇ [(1-methyl-1 H-benzimidazol-2-yl)sulfanyl]acetyl ⁇ -L-prolinamide inhibited nicotine- reinstatement for a conditioned reinforcer and reduced behavioral (locomotor sensitization) and molecular (transcriptional responses) changes induced by repeated amphetamine administration in rodents [Winrow et al., Neuropharmacology 2009, 58(1), 185-94]
  • diazepan derivatives as orexin receptor antagonists are described in Journal of Medicinal Chemistry, 2010, 53, 5320-5332. These compounds contain a methyl- substituent in position 7 of the di-azepan core whereas compounds form the present invention contain a trifluoromethyl-group in position 7 of the di-azepan core. Replacing a methyl-substituent by a trifluoromethyl- substituent surprisingly resulted in highly potent dual orexin receptor antagonists even though such a replacement may be expected to result in different properties of the final compound due to the electronically distinct nature of a trifluoromethyl-group as compared to a methyl-group.
  • the present invention provides novel 7-trifluoromethyl-[1,4]diazepan derivatives, which are non-peptide antagonists of human orexin receptors. These compounds are in particular of potential use in the treatment of disorders relating to orexinergic dysfunctions, comprising especially sleep disorders, anxiety disorders, addiction disorders, cognitive dysfunctions, mood disorders, or appetite disorders.
  • a first aspect of the invention relates to compounds of the Formula (I)
  • X represents O or S
  • substituents are attached in orfbo-position to the point of attachment of Ar 1 to the rest of the molecule; wherein said substituent independently is phenyl or 5- or 6-membered heteroaryl (especially triazolyl, or pyrimidyl); wherein said phenyl or 5- or 6-membered heteroaryl substituent is independently unsubstituted, mono-, di-, or tri-substituted, wherein the substituents are independently selected from (C jalkyl, (Ci- 4 )alkoxy, halogen (especially fluoro), cyano, (Ci-3)fluoroalkyl, or (Ci-3)fluoroalkoxy;
  • the compounds of Formula (I) contain a stereogenic center which is situated in position 4 of the diazepane core. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
  • the present invention also includes isotopically labelled, especially 2 H (deuterium) labelled compounds of formulae (I) and (II), which compounds are identical to the compounds of formulae (I) and (II), except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • Isotopically labelled, especially 2 H (deuterium) labelled compounds of formulae (I) and (II) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope 2 H (deuterium) may lead to greater metabolic stability, resulting e.g.
  • the compounds of formulae (I) and (II) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a subembodiment, the compounds of formulae (I), and (II) are not isotopically labelled at all. Isotopically labelled compounds of formulae (I) and (II) can be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.
  • a dotted line shows the point of attachment of the radical drawn.
  • salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects.
  • Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound.
  • Salt selection for basic drugs Int. J. Pharm. (1986), 33, 201-217;“Handbook of Phramaceutical Salts. Properties, Selection and Use.”, P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008; and“Pharmaceutical Salts and Co-crystals”, Johan Wouters and Luc Quere (Eds.), RSC Publishing, 2012.
  • halogen means fluorine, chlorine, or bromine, preferably fluorine or chlorine.
  • alkyl refers to a saturated straight or branched chain alkyl group containing one to six carbon atoms.
  • the term“(C x-y )alkyl” (x and y each being an integer), refers to an alkyl group as defined before, containing x to y carbon atoms.
  • a (C jalkyl group contains from one to four carbon atoms.
  • alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec.-butyl and tert.- butyl. Preferred is methyl.
  • alkoxy refers to an alkyl-O- group wherein the alkyl group is as defined before.
  • the term“(C x.y )alkoxy” (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms.
  • a (Ci- 4 )alkoxy group means a group of the formula (Ci ⁇ )alkyl-O- in which the term“(Ci-4)alkyl” has the previously given significance.
  • alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy and tert.-butoxy. Preferred is methoxy.
  • fluoroalkyl refers to an alkyl group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine.
  • the term“ ( C x-y )f I u o roa I ky I” (x and y each being an integer) refers to a fluoroalkyl group as defined before containing x to y carbon atoms.
  • a (Ci -3)fl uoroal kyl group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine.
  • fluoroalkyl groups include trifluoromethyl, 2- fluoroethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl. Preferred are (Ci)fluoroalkyl groups such as trifluoromethyl.
  • fluoroalkoxy refers to an alkoxy group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine.
  • the term“(C x-y )fluoroalkoxy” (x and y each being an integer) refers to a fluoroalkoxy group as defined before containing x to y carbon atoms.
  • a (Ci-3)fluoroalkoxy group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine.
  • fluoroalkoxy groups include trifluoromethoxy, difluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy.
  • (Ci)fluoroalkoxy groups such as trifluoromethoxy and difluoromethoxy.
  • heteroaryl if not explicitly stated otherwise, means a 5- to 10-membered monocyclic, or bicyclic, aromatic ring containing 1 to a maximum of 3 heteroatoms independently selected from oxygen, nitrogen and sulfur.
  • heteroaryl groups are 5-membered monocyclic heteroaryl groups such as furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, and triazolyl; 6-membered monocyclic heteroaryl such as pyridyl, pyrimidyl, pyridazinyl, and pyrazinyl; and 8- to 10- membered bicyclic heteroaryl such as indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl (or benzooxazolyl), benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, be
  • a second aspect of the present invention relates to the compounds of embodiments 1) which are in the absolute (S)-configuration as depicted in Formula (II):
  • a third embodiment relates to compounds according to embodiments 1) or 2), wherein X is oxygen.
  • Another embodiment relates to compounds according to embodiments 1) or 2), wherein X is sulfur.
  • Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein
  • Ar 1 represents phenyl which is mono-, di-, or tri-substituted
  • said ortho-substituent is a 5-membered heteroaryl (especially triazolyl) which is unsubstituted, or mono-, di-, or tri-substituted (especially unsubstituted), wherein the substituents independently are selected from (Ci- 4 )alkyl, (Cu)alkoxy, halogen (especially fluoro), cyano, (Ci- 3 )fluoroalkyl, and (Ci- 3 )fluoroalkoxy;
  • said ortho-substituent is a 6-membered heteroaryl (especially pyrimidyl) which is unsubstituted, or mono-, di-, or tri-substituted (especially unsubstituted), wherein the substituents indepenedently are selected from (Ci ⁇ )alkyl, (Cu)alkoxy, halogen (especially fluoro), cyano, (Ci- 3 )fluoroalkyl, and (Ci- 3 )fluoroalkoxy; or
  • said ortho-s u bsti tu en t is phenyl which is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents independently are selected from (Ci 4 )alkyl, (Ci 4 )alkoxy, halogen (especially fluoro), cyano, (Ci- 3 )fluoroalkyl, and (Ci- 3 )fluoroalkoxy;
  • Ar 1 represents 5-membered heteroaryl (especially thiazolyl) which is mono-, di-, or tri-substituted;
  • said ortho-s u bsti tu en t is phenyl which is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents independently are selected from (C jalkyl, (C jalkoxy, halogen (especially fluoro), cyano, (C jfluoroalkyl, and (Ci- 3 )fluoroalkoxy;
  • Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein
  • Ar 1 represents phenyl which is di-substituted
  • said ortho-substituent is unsubstituted 5-membered heteroaryl (especially [1,2,3]- triazol-2-yl); or
  • said ortho-substituent is unsubstituted 6-membered heteroaryl (especially pyrimidin-2- yi);
  • Ar 1 represents thiazolyl (especially thiazol-4-yl) which is di-substituted; wherein • one of said substituents is attached in orfbo-position to the point of attachment of Ar 1 to the rest of the molecule; wherein
  • said orfbo-substituent is phenyl which is unsubstituted, or mono-substituted with halogen (especially fluoro);
  • Ar 1 represents a group independently selected from the following groups A, B, C, D, E, F, or G:
  • the invention thus, relates to compounds of the Formula (I) as defined in embodiment 1), compounds of the Formula (II) as defined in embodiment 2), or to such compounds further limited by the characteristics of any of embodiments 3) to 8) under consideration of their respective dependencies; to pharmaceutically acceptable salts thereof; and to the use of such compounds as medicaments especially in the treatment of mental health disorders relating to orexinergic dysfunctions, which disorders are as defined below and which are especially selected from sleep disorders, anxiety disorders, addiction disorders, cognitive dysfunctions, mood disorders, or appetite disorders.
  • the following embodiments relating to the compounds of Formula (I) are thus possible and intended and herewith specifically disclosed in individualized form:
  • Another embodiment relates to compounds according to embodiment 1 ) selected from:
  • Another embodiment relates to compounds according to embodiment 1 ) selected from:
  • Another embodiment relates to the compound according to embodiment 1) which is [(S)-4-(5-Chloro- benzooxazol-2-yl)-7-trifluoromethyl-[1,4]diazepan-1-yl]-(5-methyl-2-[1,2,3]triazol-2-yl-phenyl)-methanone:
  • the compounds of formulae (I) and (II) according to any one of embodiments 1) to 12) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such especially oral) or parenteral administration (including topical application or inhalation).
  • compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5,“Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of formulae (I) and (II) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • the present invention also relates to a method for the prevention or treatment of a disease or disorder mentioned herein comprising administering to a subject a pharmaceutically active amount of a compound of formulae (I) and (II) according to any one of embodiments 1) to 12).
  • the administered amount of such a compound of formulae (I) and (II) according to any one of embodiments 1) to 12) is comprised between 1 mg and 1000 mg per day, particularly between 5 mg and 500 mg per day, more particularly between 25 mg and 400 mg per day, especially between 10 mg and 200 mg per day.
  • 1 mg and 1000 mg per day particularly between 5 mg and 500 mg per day, more particularly between 25 mg and 400 mg per day, especially between 10 mg and 200 mg per day.
  • the compounds according to formulae (I) and (II) according to any one of embodiments 1) to 12) are useful for the prevention or treatment of disorders relating to orexinergic dysfunctions.
  • disorders relating to orexinergic dysfunctions are diseases or disorders where an antagonist of a human orexin receptor is required, notably mental health disorders relating to orexinergic dysfunctions.
  • the above mentioned disorders may in particular be defined as comprising sleep disorders, anxiety disorders, addiction disorders, cognitive dysfunctions, mood disorders, or appetite disorders.
  • the above mentioned disorders comprise especially anxiety disorders, addiction disorders and mood disorders, notably anxiety disorders and addiction disorders.
  • the above mentioned disorders comprise especially sleep disorders.
  • disorders relating to orexinergic dysfunctions are selected from treating, controlling, ameliorating or reducing the risk of epilepsy, including absence epilepsy; treating or controlling pain, including neuropathic pain; treating or controlling Parkinson's disease; treating or controlling psychosis including acute mania and bipolar disorder; treating or controlling stroke, particularly ischemic or haemorrhagic stroke; blocking an emetic response i.e. nausea and vomiting; and treating or controlling agitation, in isolation or co-morbid with another medical condition.
  • Anxiety disorders can be distinguished by the primary object or specificity of threat, ranging from rather diffuse as in generalized anxiety disorder, to circumscribed as encountered in phobic anxieties (PHOBs) or post-traumatic stress disorders (PTSDs).
  • Anxiety disorders may, thus, be defined as comprising generalized anxiety disorders (GAD), obsessive compulsive disorders (OCDs), acute stress disorders, posttraumatic stress disorders (PTSDs), panic anxiety disorders (PADs) including panic attacks, phobic anxieties (PHOBs), specific phobia, social phobia (social anxiety disorder), avoidance, somatoform disorders including hypochondriasis, separation anxiety disorder, anxiety disorders due to a general medical condition, and substance induced anxiety disorders.
  • circumscribed threat induced anxiety disorders are phobic anxieties or post-traumatic stress disorders.
  • Anxiety disorders especially include post-traumatic stress disorders, obsessive compulsive disorders, panic attacks, phobic anxieties, and avoidance.
  • Addiction disorders may be defined as addictions to one or more rewarding stimuli, notably to one rewarding stimulus.
  • Such rewarding stimuli may be of either natural or synthetic origin.
  • Examples of such rewarding stimuli are substances / drugs ⁇ of either natural or synthetic origin; such as cocaine, amphetamines, opiates [of natural or (semi-)synthetic origin such as morphine or heroin], cannabis, ethanol, mescaline, nicotine, and the like ⁇ , which substances / drugs may be consumed alone or in combination; or other rewarding stimuli ⁇ of either natural origin (such as food, sweet, fat, or sex, and the like), or synthetic origin [such as gambling, or internet/IT (such as immoderate gaming, or inappropriate involvement in online social networking sites or blogging), and the like] ⁇ .
  • natural origin such as food, sweet, fat, or sex, and the like
  • synthetic origin such as gambling, or internet/IT (such as immoderate gaming, or inappropriate involvement in online social networking sites or blogging), and the like
  • addiction disorders relating to psychoactive substance use, abuse, seeking and reinstatement are defined as all types of psychological or physical addictions and their related tolerance and dependence components.
  • Substance-related addiction disorders especially include substance use disorders such as substance dependence, substance craving and substance abuse; substance-induced disorders such as substance intoxication, substance withdrawal, and substance-induced delirium.
  • substance use disorders such as substance dependence, substance craving and substance abuse
  • substance-induced disorders such as substance intoxication, substance withdrawal, and substance-induced delirium.
  • prevention or treatment of addictions i.e.
  • preventive or curative treatment of patients who have been diagnosed as having an addiction, or as being at risk of developing addictions refers to diminishing addictions, notably diminishing the onset of addictions, to weakening their maintenance, to facilitating withdrawal, to facilitating abstinence, or to attenuating, decreasing or preventing the occurrence of reinstatement of addiction (especially to diminishing the onset of addictions, to facilitating withdrawal, or to attenuating, decreasing or preventing the occurrence of reinstatement of addiction).
  • Mood disorders include major depressive episode, manic episode, mixed episode and hypomanic episode; depressive disorders including major depressive disorder, dysthymic disorders; bipolar disorders including bipolar I disorder, bipolar II disorder (recurrent major depressive episodes with hypomanic episodes), cyclothymic disorder; mood disorders including mood disorder due to a general medical condition (including the subtypes with depressive features, with major depressive-like episode, with manic features, and with mixed features), substance-induced mood disorder (including the subtypes with depressive features, with manic features, and with mixed features).
  • mood disorders are especially major depressive episode, major depressive disorder, mood disorder due to a general medical condition; and substance-induced mood disorder.
  • Mood disorders further include sundown syndrome (or increased agitation) in a patient who has some form of dementia, especially a dementia of Alzheimer's type, in particular middle stage (i.e. stage 3 to 6, preferably stage 3 to 5, in particular stage 3 or 4) Alzheimer dementia.
  • middle stage i.e. stage 3 to 6, preferably stage 3 to 5, in particular stage 3 or 4
  • Alzheimer dementia in particular middle stage (i.e. stage 3 to 6, preferably stage 3 to 5, in particular stage 3 or 4) Alzheimer dementia.
  • Sundown syndrome or“increased agitation” is defined as a late-day (i.e. afternoon and / or evening hours, especially afternoon hours) circadian syndrome of increased confusion, agitation and restlessness in a patient, wherein in general said patient has some form of dementia.
  • Cardinal clinical signs include increased agitation, general confusion and mood swings that typically develop as natural light begins to fade.
  • the term "late day” referred to herein relates to the afternoon and evening, notably the time about sunset and later (but not including the night / the sleep time); for example the time from about 4 pm to about 10 pm, especially from about 4 pm to about 9 pm. In one sub-embodiment, the term relates to the afternoon, especially from about 4 pm to about 7 pm; in another sub-embodiment the term relates to the evening, especially from about 7 pm to about 10 pm.
  • Appetite disorders comprise eating disorders and drinking disorders.
  • Eating disorders may be defined as comprising eating disorders associated with excessive food intake and complications associated therewith; anorexias; compulsive eating disorders; obesity (due to any cause, whether genetic or environmental); obesity- related disorders including overeating and obesity observed in Type 2 (non-insulin-dependent) diabetes patients; bulimias including bulimia nervosa; cachexia; and binge eating disorder.
  • Particular eating disorders comprise metabolic dysfunction; dysregulated appetite control; compulsive obesities; bulimia or anorexia nervosa.
  • eating disorders may be defined as especially comprising anorexia nervosa, bulimia, cachexia, binge eating disorder, or compulsive obesities.
  • Drinking disorders include polydipsias in psychiatric disorders and all other types of excessive fluid intake.
  • Pathologically modified food intake may result from disturbed appetite (attraction or aversion for food); altered energy balance (intake vs. expenditure); disturbed perception of food quality (high fat or carbohydrates, high palatability); disturbed food availability (unrestricted diet or deprivation) or disrupted water balance.
  • Cognitive dysfunctions include deficits in attention, learning and especially memory functions occurring transiently or chronically in psychiatric, neurologic, neurodegenerative, cardiovascular and immune disorders, and also occurring transiently or chronically in the normal, healthy, young, adult, or especially aging population. Cognitive dysfunctions especially relate to the enhancement or maintenance of memory in patients who have been diagnosed as having, or being at risk of developing, diseases or disorders in which diminished memory (notably declarative or procedural) is a symptom [in particular dementias such as frontotemporal dementia, or dementia with Lewy bodies, or (especially) Alzheimer's disease].
  • prevention or treatment of cognitive dysfunctions relates to the enhancement or maintenance of memory in patients who have a clinical manifestation of a cognitive dysfunction, especially expressed as a deficit of declarative memory, linked to dementias such as frontotemporal dementia, or dementia with Lewy bodies, or (especially) Alzheimer's disease. Furthermore, the term “prevention or treatment of cognitive dysfunctions” also relates to improving memory consolidation in any of the above mentioned patient populations.
  • Sleep disorders comprise dyssomnias, parasomnias, sleep disorders associated with a general medical condition and substance-induced sleep disorders.
  • dyssomnias include intrinsic sleep disorders (especially insomnias, breathing-related sleep disorders, periodic limb movement disorder, and restless leg syndrome), extrinsic sleep disorders, and circadian-rythm sleep disorders.
  • Dyssomnias notably include insomnia, primary insomnia, idiopathic insomnia, insomnias associated with depression, emotional/mood disorders, aging, Alzheimer's disease or cognitive impairment; REM sleep interruptions; breathing-related sleep disorders; sleep apnea; periodic limb movement disorder (nocturnal myoclonus), restless leg syndrome, circadian rhythm sleep disorder; shift work sleep disorder; and jet-lag syndrome.
  • Parasomnias include arousal disorders and sleep-wake transition disorders; notably parasomnias include nightmare disorder, sleep terror disorder, and sleepwalking disorder.
  • Sleep disorders associated with a general medical condition are in particular sleep disorders associated with diseases such as mental disorders, neurological disorders, neuropathic pain, and heart and lung diseases.
  • Substance-induced sleep disorders include especially the subtypes insomnia type, parasomnia type and mixed type, and notably include conditions due to drugs which cause reductions in REM sleep as a side effect. Sleep disorders especially include all types of insomnias, sleep-related dystonias; restless leg syndrome; sleep apneas; jet-lag syndrome; shift work sleep disorder, delayed or advanced sleep phase syndrome, or insomnias related to psychiatric disorders.
  • sleep disorders further include sleep disorders associated with aging; intermittent treatment of chronic insomnia; situational transient insomnia (new environment, noise) or short-term insomnia due to stress; grief; pain or illness.
  • the present compounds may be particularly useful for the treatment of such environmentally conditioned disorder or disease.
  • the compounds of formulae (I) and (II) can be prepared by the methods given below, by the methods given in the experimental part below or by analogous methods.
  • Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by a person skilled in the art by routine optimisation procedures.
  • the final product may be further modified, for example, by manipulation of substituents to give a new final product. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art.
  • the order of carrying out the following reaction schemes, and/or reaction steps may be varied to facilitate the reaction or to avoid unwanted reaction products.
  • Carboxylic acid derivative b is dissolved in a solvent such as DCM and activated to the carboxylic acid chloride by adding a reagent such as oxalylchloride and a catalytic amount of DMF to start the reaction. After termination of the reaction the mixture is evaporated to dryness and re-dissolved in DCM and added at 0°C to a, dissolved in a solvent such as DCM in the presence of an excess of base such as triethylamine or Hunig’s base. The reaction is kept at 0°C for a prolonged time such as 6 h. Then usually the reaction is complet.
  • Compound c is Boc-deprotected under acidic conditions such as 4M HCI in dioxane (preferred method) or TFA in DCM to give precursor d which is converted into final compound f by an SnAr reaction with Ar 1 -Cl in a solvent such as DMF or DMA in the presence of a base such as DIPEA, TEA or potassium carbonate at elevated temperatures such as 100°C for prolonged times of 8 to 24 hours to give final compounds f.
  • acidic conditions such as 4M HCI in dioxane (preferred method) or TFA in DCM
  • precursor d which is converted into final compound f by an SnAr reaction with Ar 1 -Cl in a solvent such as DMF or DMA in the presence of a base such as DIPEA, TEA or potassium carbonate at elevated temperatures such as 100°C for prolonged times of 8 to 24 hours to give final compounds f.
  • the stereoisomers can be separated using methods known to one skilled in the art: e.g. by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase such as a Daicel ChiralPak AD-H (5 pm) column, a Daicel ChiralCel OD-H (5 pm) column, a Daicel ChiralCel OD (10 pm) column, a Daicel ChiralPak IA (5 pm) column, a Daicel ChiralPak IB (5 pm) column, a Daicel ChiralPak IC (5 pm) column, or a (R,R)-Whelk-01 (5 pm) column.
  • Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH, in presence or absence of a base like TEA and/or diethylamine or of an acid like TFA) and eluent B (heptane).
  • EtOH isocratic mixture of eluent A
  • eluent B heptane
  • Alternative conditions are provided in Example 9 and 10 below.
  • FCS Foatal calf serum
  • Step 1 5-Methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid (21 mg; 0.102 mmol) is suspended in DCM (0.5 ml) and oxalyl chloride (14.5 mg; 0.11 mmol) is added at rt followed by a drop of DMF. The mixture is stirred for 30 minutes and then fully concentrated under reduced pressure.
  • Step 2 rac-tert-butyl 4-(5-methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoyl)-5-(trifluoromethyl)-1 ,4-diazepane-1 -carboxylate (45.32 mg; 0.1 mmol) is dissolved in dioxane (1 ml) and a 4M solution of HCI in dioxan (1 ml; 4 mmol) is slowly added and stirring is continued for 2.5 h at rt.
  • Step 3 rac-(5-methyl-2-(2H-1 ,2,3-triazol-2-yl)phenyl)(7-(trifluoromethyl)-1 ,4-diazepan-1-yl)methanone hydrochloride (34 mg; 0.0872 mmol) is dissolved in DMF (1.5 ml) followed by the addition of 2,5- dichlorobenzo[d]oxazole (23.5 mg; 0.124 mmol) and potassium carbonate (42.2 mg; 0.305 mmol). The reaction mixture is stirred at 50°C for 2 h, filtered and purified by prep.
  • Example 9 13.5 mg of (R)-(4-(5-chlorobenzo[d]oxazol-2-yl)-7-(trifluoromethyl)-1 ,4-diazepan-1-yl)(5-methyl-2- (2H-1 ,2,3-triazol-2-yl)phenyl)methanone is obtained as a white solid.
  • Antagonistic activities on both orexin receptors have been measured for each example compound using the following procedure:
  • Chinese hamster ovary (CHO) cells expressing the human orexin-1 receptor and the human orexin-2 receptor, respectively, are grown in culture medium (Ham F-12 with L-Glutamine) containing 300 mg/ml G418, 100 U/ml penicillin, 100 mg/ml streptomycin and 10 % heat inactivated fetal calf serum (FCS).
  • the cells are seeded at 20 ⁇ 00 cells / well into 384-well black clear bottom sterile plates (Greiner). The seeded plates are incubated overnight at 37°C in 5% CO2.
  • Human orexin-A as an agonist is prepared as 1 mM stock solution in MeOH: water (1 :1), diluted in HBSS containing 0.1 % bovine serum albumin (BSA), NaHCOs: 0.375g/l and 20 mM HEPES for use in the assay at a final concentration of 3 nM.
  • BSA bovine serum albumin
  • NaHCOs 0.375g/l
  • 20 mM HEPES for use in the assay at a final concentration of 3 nM.
  • Antagonists are prepared as 10 mM stock solution in DMSO, then diluted in 384-well plates using DMSO followed by a transfer of the dilutions into in HBSS containing 0.1 % bovine serum albumin (BSA), NaHCOs: 0.375g/l and 20 mM HEPES. On the day of the assay, 50 mI of staining buffer (HBSS containing 1% FCS, 20 mM HEPES,
  • NaHCOs 0.375g/l, 5 mM probenecid (Sigma) and 3 mM of the fluorescent calcium indicator fluo-4 AM (1 mM stock solution in DMSO, containing 10% pluronic) is added to each well.
  • the 384-well cell-plates are incubated for 50 min at 37° C in 5% CO2 followed by equilibration at RT for 30 min before measurement.
  • antagonists are added to the plate in a volume of 10 mI/well, incubated for 120 min and finally 10 mI/well of agonist is added. Fluorescence is measured for each well at 1 second intervals, and the height of each fluorescence peak is compared to the height of the fluorescence peak induced by an approximate EC70 (for example 5 nM) of orexin-A with vehicle in place of antagonist.
  • the IC50 value (the concentration of compound needed to inhibit 50 % of the agonistic response) is determined and may be normalized using the obtained IC50 value of a on-plate reference compound. Optimized conditions are achieved by adjustment of pipetting speed and cell splitting regime. The calculated IC50 values may fluctuate depending on the daily cellular assay performance. Fluctuations of this kind are known to those skilled in the art. Average IC50 values from several measurements are given as geometric mean values.
  • Antagonistic activities of example compounds with respect to the Oxi and the 0x2 receptor are displayed in Table 1.
  • Compounds of the present invention may be further characterized with regard to their general pharmacokinetic and pharmacological properties using conventional assays well known in the art; for example relating to their bioavailablility in different species (such as rat or dog); or relating to their ability to cross the blood-brain barrier, using for example a human P-glycoprotein 1 (MDR 1) substrate assay, or an in vivo assay to determine drug concentrations in the brain, e.g.
  • MDR 1 human P-glycoprotein 1
  • the concentration of the compound is measured in plasma ([P]), and brain ([B]), sampled 3 h (or at different time points) following oral administration (e.g. 100 mg/kg) to male wistar rats.
  • the compounds are formulated e.g. in 100% PEG 400. Samples are collected in the same animal at the same time point (+/- 5 min). Blood is sampled from the vena cava caudalis into containers with EDTA as anticoagulant and centrifuged to yield plasma. Brain is sampled after cardiac perfusion of 10 mL NaCI 0.9% and homogenized into one volume of cold phosphate buffer (pH 7.4). All samples are extracted with MeOH and analyzed by LC- MS/MS. Concentrations are determined with the help of calibration curves.
  • Sedative effects EEG, EMG and behavioural indices of alertness recorded by radiotelemetrv in vivo in Wistar rats.
  • Electroencephalography (EEG) and Electromyography (EMG) signals are measured by telemetry using TL11 M2- F20-EET miniature radiotelemetric implants (Data Science Int.) with two pairs of differential leads.
  • Surgical implantation is performed under general anesthesia with Ketamin/Xylazin, for cranial placement of one differential pair of EEG electrodes and one pair of EMG leads inserted in either side of the muscles of the neck.
  • rats recover in a thermoregulated chamber and receive analgesic treatment with subcutaneous buprenorphine twice a day for 2 d. They are then housed individually and allowed to recover for a minimum of 2 weeks. Thereafter, rats— in their home cage— are placed in a ventilated sound-attenuating box, on a 12-h light / 12-h dark cycle, for acclimatization before continuous EEG / EMG recordings started.
  • the telemetric technology that we use allows accurate and stress-free acquisition of biosignals in rats placed in their familiar home cage environment, with no recording leads restricting their movements.
  • Variables analyzed include four different stages of vigilance and sleep, spontaneous activity in the home cage and body temperature. Sleep and wake stages are evaluated using a rodent scoring software (Somnologica Science) directly processing electrical biosignals on 10 s contiguous epochs. The scoring is based on frequency estimation for EEG and amplitude discrimination for EMG and locomotor activity. Using these measurements, the software determines the probability that all components within each epoch best represent active waking (AW), quiet waking (QW), non-REM-sleep (NREM) or REM-sleep (REM).
  • AW active waking
  • QW quiet waking
  • NREM non-REM-sleep
  • REM REM-sleep
  • the percentage of total time spent in AW, QW, NREM- and REM-sleep is calculated per 6 or 12 h light or dark period.
  • the latency to the onset of the first significant NREM- and REM-sleep episodes and the frequency and duration of those episodes are also calculated.
  • AW, QW, NREM- and REM-sleep, home cage activity and body temperature are measured at baseline for at least one total circadian cycle (12 h-night, 12 h-day) before a test compound is administered. If baseline measurements indicate that animals are stable, test compound or vehicle is given in the evening by oral gavage at the end of the baseline 12- h day period, immediately before the nocturnal rise in orexin and activity in rats. All variables are subsequently recorded for 12 h following administration of the orexin receptor antagonist. Experiment were done using a cross-over design with at least 72 hours between drug or vehicle administration.
  • the compound of Example 10 is a dual orexin 1 (6 nM) and orexin 2 receptor antagonist (11 nM).
  • the compound is devoid of drug-drug interaction potential based on the results in the following assays:
  • the inhibition of CYP3A4 with midazolam as a substrate gives an IC50 of 30 uM and with testosterone as a substrate, it gives 19 uM.
  • the time-dependent inhibition in this assay is increased by a factor of 4.
  • the inhibition of CYP2C9 gives an IC50 of 5.4 uM and the inhibition of CYP2D6 gives an IC50 of 25 uM.
  • the compound was tested in a rat EEG/EMG experiment to assess the impact on sleep-wake stages and the results were compared to Suvorexant.
  • Results at 6 hours are: -22% on active wake, +27% on NREM sleep, +53% on REM sleep; when compared to vehicle controls.
  • Results at 12 hours are: -23% on active wake, +23% on NREM sleep, +62% on REM sleep; when compared to vehicle controls.
  • Results at 6 hours are: -18% on active wake, +19% on NREM sleep, +51% on REM sleep; when compared to vehicle controls.
  • Results at 12 hours are: -16% on active wake, +20% on NREM sleep, +50% on REM sleep; when compared to vehicle controls.

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Abstract

La présente invention concerne des composés de formule (I) dans laquelle X et Ar1 sont tels que décrits dans la description, leur préparation}, des sels pharmaceutiquement acceptables de ceux-ci, et leur utilisation en tant que produits pharmaceutiques, des compositions pharmaceutiques contenant un ou plusieurs composés de formule (I), et en particulier leur utilisation en tant qu'antagonistes du récepteur de l'orexine.
PCT/EP2019/067989 2018-07-06 2019-07-04 Dérivés de 7-trifluorométhyl-[1,4]diazépane WO2020007977A1 (fr)

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CN114276340A (zh) * 2022-01-30 2022-04-05 郑州大学 一种氯苯并恶唑衍生物或其药学上可接受的盐及其应用
CN115141192A (zh) * 2022-06-22 2022-10-04 杭州国瑞生物科技有限公司 一种苏沃雷生的制备方法

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114276340A (zh) * 2022-01-30 2022-04-05 郑州大学 一种氯苯并恶唑衍生物或其药学上可接受的盐及其应用
CN115141192A (zh) * 2022-06-22 2022-10-04 杭州国瑞生物科技有限公司 一种苏沃雷生的制备方法

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