WO2020099511A1 - Dérivés de benzimidazole-2-méthyl-morpholine - Google Patents

Dérivés de benzimidazole-2-méthyl-morpholine Download PDF

Info

Publication number
WO2020099511A1
WO2020099511A1 PCT/EP2019/081229 EP2019081229W WO2020099511A1 WO 2020099511 A1 WO2020099511 A1 WO 2020099511A1 EP 2019081229 W EP2019081229 W EP 2019081229W WO 2020099511 A1 WO2020099511 A1 WO 2020099511A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
phenyl
disorders
alkyl
substituents
Prior art date
Application number
PCT/EP2019/081229
Other languages
English (en)
Inventor
Hamed Aissaoui
Christoph Boss
Original Assignee
Idorsia Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Idorsia Pharmaceuticals Ltd filed Critical Idorsia Pharmaceuticals Ltd
Publication of WO2020099511A1 publication Critical patent/WO2020099511A1/fr

Links

Classifications

    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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

Definitions

  • the present invention relates to novel benzimidazole-2-methyl-morpholine 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 (supplj) S71-S76].
  • 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].
  • 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 OXi 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].
  • Orexin receptor antagonists comprising a 2-substituted saturated cyclic amide derivatives (such as 2-substituted pyrrolidine-1 -carboxamides) are known for example from W02008/020405, W02008/038251 , W02008/081399, W02008/087611 , W02008/117241, W02008/139416, W02009/004584, W02009/016560, W02009/016564, W02009/040730, W02009/104155, WO2010/004507, WO2010/038200, WO2001/096302, W02002/044172, W02002/089800, W02002/090355, W02003/002559, W02003/032991 , W02003/041711 , W02003/051368, W02003/051873, W02004/026866, W02004/041791 , W02004/041807, W02004/041816, W
  • W02003/002559 discloses N-aroyl cyclic amine derivatives encompassing morpholine derivatives as orexin receptor antagonists.
  • a particular pyrrolidine derived orexin-1 selective compound within the scope of W02003/002559 is disclosed in Langmead et. al, Brit. J. Pharmacol. 2004, 141 , 340-346: 1-(5-(2-fluoro-phenyl)- 2-methyl-thiazol-4-yl)-1 -[(S)-2-(5-phenyl-[1 ,3,4]oxadiazol-2-ylmethyl)-pyrrolidin-1 -yl)-methanone.
  • W02003/002561 discloses certain N-aroyl cyclic amine derivatives, encompassing a benzimidazol-2-yl-methyl substituted morpholine derivative, as orexin receptor antagonists.
  • a linker group such as at least a methylene group (or longer groups such as -CH 2 -NH-CO-, -CH2-NH-, -CH2-O-, -CH2-S-, etc.) link the cyclic amide to the respective aromatic ring system substituent.
  • WO2013/182972 discloses pyrrolidine derivatives that have a benzimidazole ring directly attached to a pyrrolidine amide in position 2.
  • one compound is wrongly indexed as containing both a morpholine core and a benzimidazole substituent (CAS Reg. No. 1347329-274), however, this compound corresponds to Example 78 which contains a methylenelinker between the morphioline core and the benzimidazole group.
  • the present compounds that have a benzimidazole ring directly attached in position 5 to a 2-methyl-morpholine amide may be potent dual orexin receptor antagonists.
  • a first aspect of the invention relates to compounds of the Formula (I)
  • R 1 represents hydrogen or (Ci-3)alkyl (especially R 1 represents hydrogen);
  • phenyl or 5- or 6-membered heteroaryl wherein said phenyl or 5- or 6-membered heteroaryl independently is mono-, di-, or tri-substituted;
  • substituents are attached in ortho-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; 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 (Ci_4)alkyl, (Ci )alkoxy (especially methoxy), halogen, cyano, (Ci-3)fluoroalkyl, and (Ci-3)fluoroalkoxy;
  • (R 5 ) n represents one to three optional substituents (i.e. n represents the integer 0, 1 , 2, or 3) independently selected from (C jalkyl (especially methyl), (Ci-4)alkoxy (especially methoxy), halogen, (Ci ⁇ )alkyl-thio- (especially H 3 C-S-), (Ci-3)fluoroalkyl (especially trifluoromethyl), (Ci-3)fluoroalkoxy (especially trifluoromethoxy), (Ci-3)fluoroalkyl-thio- (especially F 3 C-S-), and cyano.
  • substituents i.e. n represents the integer 0, 1 , 2, or 3 independently selected from (C jalkyl (especially methyl), (Ci-4)alkoxy (especially methoxy), halogen, (Ci ⁇ )alkyl-thio- (especially H 3 C-S-), (Ci-3)fluoroalkyl (especially trifluoromethyl), (Ci-3)flu
  • a second aspect of the invention relates to compounds according to embodiment 1), wherein the absolute configuration of the morpholine moiety is as depicted in Formula (II)
  • Formula (II) i.e. said morpholine is in enantiomerically enriched absolute (5R)-configuration.
  • said morpholine is in enantiomerically enriched absolute (5R)-configuration and the configuration in position 2 of said morpholine moiety is either in enantiomerically enriched absolute (2R) or (2S) (preferably in 2S) configuration, wherein said two enantiomerically enriched diastereoisomers are depicted in Formula (lla) and (lib):
  • the compounds of Formula (I) contain at least two stereogenic centers which are situated in position 2 and 5 of the morpholine moiety.
  • a compound of Formula (II) represents either a compound of Formula (lla), or a compound of Formula (lib), or any mixture thereof.
  • the compounds of formulae (I), (II), (lla), and (lib) may contain one or more further stereogenic or asymmetric centers, such as one or more additional asymmetric carbon atoms.
  • the compounds of formulae (I), (II), (lla), and (lib) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
  • a third aspect of the invention relates to compounds according to embodiment 1), wherein the absolute configuration is as depicted in Formula (lla) (i.e. the morpholine is in enantiomerically enriched absolute (2S,5R)- configuration):
  • enriched when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a ratio of at least 70:30, especially of at least 90:10 (i.e., in a purity of at least 70% by weight, especially of at least 90% by weight), with regard to the respective other stereoisomer / the entirety of the respective other stereoisomers.
  • substituents (R 5 ) n of the benzimidazole moiety may be attached in the position(s) ortho to the bridgehead atoms (i.e. attached in position(s) 4 and/or 7, corresponding to R 14 and/or R 17 ), and/or in the position(s) meta to the bridgehead atoms, (i.e. attached in position(s) 5 and/or 6, corresponding to R 15 and/or R 16 ). It is understood that the two ortho , and, respectively, the two meta positions are considered equivalent.
  • the group 4-methyl-1H- benzoimidazol-2-yl is understood to signify the same group as 7-methyl-1 H-benzoimidazol-2-yl and 4-methyl-3H- benzoimidazol-2-yl and 7-methyl-3H-benzoimidazol-2-yl.
  • the present invention also includes isotopically labelled, especially 2 H (deuterium) labelled compounds of Formula (I), which compounds are identical to the compounds of Formula (I), 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 Formula (I) 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. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile.
  • the compounds of Formula (I) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of Formula (I) are not isotopically labelled at all. Isotopically labelled compounds of Formula (I) 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.
  • (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.
  • (Ci-4)alkyl-thio- refers to a group of the formula (Ci ⁇ )alkyl-S- in which the term“(Ci ⁇ )alkyl” has the previously given significance.
  • An example is CH3-S-.
  • 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 0 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)fluoroalkyl 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-3)fluoroalkyl-thio- refers to (Ci-3)fluoroalkyl group as defined before, which is linked to the rest of the molecule through a sulfur atom.
  • An example is CF 3 -S-.
  • Ar 1 representing a phenyl group, wherein said phenyl is mono-, di-, or tri-substituted; wherein one of said substituents is attached in ortho- position to the point of attachment of Ar 1 to the rest of the molecule; are such that the other of said substituents, if present, is/are independently selected from (Ci-4)alkyl; (Ci )alkoxy; (C3-6)cycloalkyl; halogen; cyano; (Ci-3)fluoroalkyl; (Ci-3)fluoroalkoxy; unsubstituted pyridinyl; and phenyl which is unsubstituted, or mono- or di-substituted, wherein the substituents are independently selected from (C M )alkyl, (Ci4)alkoxy, cyano, and halogen [notably the other of said substituents, if present, is/are independently selected from (Ci4)alkyl, (Ci4)alkyl
  • phenyl groups which are further substituted in ortho position as used for the group Ar 1 are 1 ,2-phenylene, 4-methyl-1 ,2-phenylene, 5- methyl-1 ,2-phenylene, 4, 5-dimethyl-1 ,2-phenylene, 5-fluoro-1 ,2-phenylene, 5-chloro-1 ,2-phenylene, 5-methoxy- 1 ,2-phenylene, 4-trifluoromethyl-1 ,2-phenylene, 6-fluoro-5-methyl-1 ,2-phenylene, and 6-fluoro-5-methoxy-1,2- phenylene.
  • Examples of the particular phenyl groups which are substituents of the group Ar 1 are especially phenyl groups which are unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from (Ci4)alkyl, (Ci4)alkoxy, halogen, cyano, (Ci-3)fluoroalkyl, and (Ci-3)fluoroalkoxy [notably from (Ci4)alkyl, (Ci4)alkoxy, halogen, and (Ci-3)fluoroalkyl]
  • Particular examples are phenyl, and 4-fluoro-phenyl.
  • 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
  • Examples of the particular 5- or 6-membered heteroaryl groups which are further substituted in ortho position as used for the group Ar 1 are the above mentioned 5- or 6-membered heteroaryl groups, notably the 5-membered heteroaryl groups oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl; and the 6-membered heteroaryl groups pyridyl, pyrimidyl and pyrazinyl.
  • examples are thiazolyl (notably 2-methyl-thiazol-4,5-diyl) and pyridyl (notably 6-methyl-pyridin-2,3-diyl).
  • These groups are at least mono-substituted in ortho position, and preferably and independently carry no further substituent or one further substitutent as explicitly defined.
  • optional further substituent may independently be selected from (Ci-4)alkyl (especially methyl); (C3-6)cycloalkyl (especially cyclopropyl); -NR 10 R 11 , wherein R 10 and R 11 independently represent (Ci-4)alkyl (especially methyl), or R 10 and R 11 together with the nitrogen to which they are attached to form a pyrrolidine ring; and phenyl which is unsubstituted, or mono- or di-substituted, wherein the substituents are independently selected from (Ci ⁇ )alkyl, (Ci4)alkoxy, cyano, and halogen.
  • such optional further substituent may independently be selected from (Ci4)alkyl, (Ci4)alkoxy, (C3-6)cycloalkyl, halogen, cyano, (Ci-3)fluoroalkyl, (Ci-3)fluoroalkoxy, and -NR 10 R 11
  • substituents are independently selected from (Ci4)alkyl, (Ci4)alkoxy, cyano, and halogen (notably methyl, cyclopropyl, and
  • the above groups are preferably attached to the rest of the molecule (i.e. the carbonyl group) in position 4 of oxazolyl, isoxazolyl, or thiazolyl groups; in position 2 of pyridyl or pyrazinyl groups; in position 2 of thiophenyl groups; and in position 5 of pyrimidinyl groups.
  • the rest of the molecule i.e. the carbonyl group
  • oxazolyl, isoxazolyl, or thiazolyl groups in position 2 of pyridyl or pyrazinyl groups
  • thiophenyl groups in position 5 of pyrimidinyl groups.
  • particular examples of such groups are 2-methyl- thiazol-4,5-diyl, as well as 6-methyl-pyridin-2,3-diyl.
  • Examples of the particular 5- or 6-membered heteroaryl groups which are substituents of the group Ar 1 are the above mentioned 5- or 6-membered heteroaryl groups; notably the 5-membered heteroaryl groups oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, and the 6- membered heteroaryl groups pyridyl, pyrimidyl, pyrazinyl and pyridazinyl.
  • such groups are especially pyrazolyl, triazolyl, pyridinyl and pyrimidinyl, notably pyrazol-1-yl, pyrimidin-2-yl, and [1,2,3]triazol-2-yl.
  • the above mentioned groups may be unsubstituted or substituted as explicitly defined; wherein pyrazol-1-yl, and [1 ,2,3]triazol-2-yl groups are preferably unsubstituted.
  • pyrazol-1-yl [1 ,2,3]triazol-2-yl
  • pyrimidin-2-yl notably the 5-membered heteroaryl group [1,2,3]triazol-2-yl; and the 6-membered heteroaryl group pyrimidin-2-yl.
  • a second embodiment relates to compounds according to any one of embodiments 1) to 3), wherein R 1 is hydrogen.
  • FIG. 5 Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein (R 5 ) n represents one or two optional substituents (i.e. n represents the integer 0, 1, or 2) (especially (R 5 ) n represents one or two substituents; i.e.
  • n represents the integer 1 or 2) independently selected from (Ci ⁇ )alkyl (especially methyl), (Ci-4)alkoxy (especially methoxy), halogen (especially fluorine, chlorine or bromine), (Ci4)alkyl-thio- (especially H 3 C-S-), (Ci-3)fluoroalkyl (especially trifluoromethyl), (Ci-3)fluoroalkoxy (especially trifluoromethoxy), (Ci-3)fluoroalkyl-thio- (especially F 3 C-S-), and cyano (especially (R 5 ) n represents one or two substituents independently selected from methyl, and halogen).
  • Another embodiment relates to compounds according to any one of embodiments 1) to 5), wherein the fragment
  • R 14 , R 15 , R 16 and R 17 together represent one or two optional substituents (i.e. at least two of R 14 , R 15 , R 16 and R 17 are hydrogen) [notably R 14 , R 15 , R 16 and R 17 together represent one or two substituents (i.e. at least two of R 14 , R 15 , R 16 and R 17 are hydrogen and at least one of R 14 , R 15 , R 16 and R 17 is different from hydrogen)], wherein
  • R 14 and R 17 independently represent hydrogen, (Ci-4)alkyl (especially methyl), (Ci-4)alkoxy (especially methoxy), (Ci ⁇ )alkyl-thio- (especially H 3 C-S-), halogen, (Ci-3)fluoroalkyl (especially trifluoromethyl); and
  • R 15 and R 16 independently represent hydrogen, (Ci-4)alkyl, (Ci4)alkoxy (especially methoxy), (Ci4)alkyl- thio- (especially H 3 C-S-), halogen, (Ci-3)fluoroalkyl (especially trifluoromethyl), (Ci-3)fluoroalkoxy (especially trifluoromethoxy), (Ci-3)fluoroalkyl-thio- (especially F 3 C-S-), or cyano. 7) Another embodiment relates to compounds according to any one of embodiments 1) to 5), wherein the fragment
  • R 14 , R 15 , R 16 and R 17 together represent one or two optional substituents [notably R 14 , R 15 , R 16 and R 17 together represent one or two substituents (i.e. at least two of R 14 , R 15 , R 16 and R 17 are hydrogen and at least one of R 14 , R 15 , R 16 and R 17 is different from hydrogen)], wherein
  • R 14 and R 17 independently represent hydrogen, methyl, methoxy, halogen, or trifluoromethyl
  • R 15 and R 16 independently represent hydrogen, methyl, methoxy, halogen, trifluoromethyl, or trifluoromethoxy.
  • Another embodiment relates to compounds according to any one of embodiments 1) to 5); wherein the fragment
  • Another embodiment relates to compounds according to any one of embodiments 1) to 5); wherein the fragment
  • benzimidazolyl moieties may be present in form of tautomers.
  • Ar 1 represents phenyl or 5- or 6-membered heteroaryl selected from thiazolyl and pyridinyl, wherein said phenyl or 5- or 6-membered heteroaryl independently is mono-, di-, or tri-substituted;
  • substituents are attached in ortho-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 selected from pyrazolyl, triazolyl, pyridinyl, and pyrimidinyl; wherein said phenyl or 5- or 6-membered heteroaryl substituent is independently unsubstituted, mono-, di-, or tri-substituted (especially unsubstituted, or mono-substituted), wherein the substituents are independently selected from (Ci-4)alkyl, (Ci )alkoxy (especially methoxy), halogen, cyano, (Ci-3)fluoroalkyl, and (Ci-3)fluoroalkoxy;
  • substituents are attached in ortho-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 selected from pyrazolyl, triazolyl, pyridinyl, and pyrimidinyl; wherein said phenyl or 5- or 6-membered heteroaryl substituent is independently unsubstituted, or mono-substituted, wherein the substituents are independently selected from (Ci-2)alkyl, (Ci-2)alkoxy, halogen, cyano, trifluoromethyl, and trifluoromethoxy;
  • Another embodiment relates to compounds according to any one of embodiments 1) to 9), wherein
  • Ar 1 represents 5-membered heteroaryl (especially thiazolyl), which is mono- or di-substituted (especially di-substituted);
  • said ortho-substituent is phenyl which is independently unsubstituted, mono-, di-, or tri-substituted (especially mono-substituted), wherein the substituents are independently selected from (Ci-4)alkyl, (Ci4)alkoxy, halogen, cyano, (Ci-3)fluoroalkyl, and (Ci-3)fluoroalkoxy [wherein phenyl is especially mono-substituted with (Ci4)alkyl, (Ci )alkoxy, halogen, (C )fluoroalkyl, or (Ci-3)fluoroalkoxy;
  • o or said ortho-substituent is 6-membered heteroaryl (especially pyridyl) which is independently unsubstituted, mono-, di-, or tri-substituted (especially mono- substituted), wherein the substituents are independently selected from (C jalkyl, (Ci4)alkoxy (especially methoxy), halogen, cyano, (C )fluoroalkyl, and (Ci-3)fluoroalkoxy [wherein said 6-membered heteroaryl is notably pyridyl which is mono-substituted with (Ci4)alkoxy (especially methoxy)];
  • Ar 1 represents 6-membered heteroaryl (especially pyridinyl) which is mono-, di-, or tri-substituted (especially di-substituted);
  • said ortho-substituent is unsubstituted 5-membered heteroaryl (notably pyrazol-1-yl or
  • Ar 1 represents phenyl which is mono-, di-, or tri-substituted
  • said ortho-substituent is phenyl which is unsubstituted, mono-, di-, or tri-substituted (especially unsubstituted), wherein the substituents are independently selected from (Ci- 4 )alkyl, (Ci_ 4 )alkoxy, halogen, cyano, (Ci- 3 )fluoroalkyl, and ( C i - 3 )fl uo roal koxy ;
  • o or said ortho-substituent is 6-membered heteroaryl (especially selected from pyridinyl or pyrimidinyl) which is unsubstituted, mono-, or di-substituted (especially unsubstituted), wherein the substituents are independently selected from (Cu)alkyl, (Ci- 4 )alkoxy, halogen, and (Ci- 3 )fluoroalkyl (especially mono-substituted with (Ci- 4 )alkyl, or (Cu)alkoxy);
  • o or said ortho-substituent is 5-membered heteroaryl (especially pyrazolyl or triazolyl) which is unsubstituted, mono-, or di-substituted (especially unsubstituted), wherein the substituents are independently selected from (Cu)alkyl, (Cu)alkoxy, halogen, and (Ci- 3 )fluoroalkyl (especially (C jalkyl, notably methyl);
  • Another embodiment relates to compounds according to any one of embodiments 1) to 9), wherein
  • Ar 1 represents 5-membered heteroaryl (especially thiazol-4-yl) which is di-substituted;
  • said ortho-substituent is phenyl which is mono-substituted, wherein the substituent is selected from (Cujalkyl, (Cu)alkoxy, halogen, cyano, (C jfluoroalkyl, and (Ci- 3 )fluoroalkoxy;
  • o or said ortho-substituent is 6-membered heteroaryl (especially pyridyl) which is mono- substituted, wherein the substituent is selected from (Cujalkyl, (Cu)alkoxy (especially methoxy), halogen, cyano, (Ci- 3 )fluoroalkyl, and (Ci- 3 )fluoroalkoxy;
  • Ar 1 represents 6-membered heteroaryl (especially pyridinyl) which is di-substituted
  • said ortho-substituent is unsubstituted 5-membered heteroaryl (especially pyrazol-1-yl or [1 ,2,3]triazol-2-yl); > and the other of said substituents, if present, is/are independently selected from (Ci )alkyl (especially methyl), (Ci-4)alkoxy, halogen, and (Ci-3)fluoroalkyl;
  • Ar 1 represents phenyl which is mono-, di-, or tri-substituted
  • ortho-substituent is unsubstituted 6-membered heteroaryl (notably pyrimidin-2-yl); o or said ortho-substituent is unsubstituted 5-membered heteroaryl (notably pyrazol-1-yl or
  • Ar 1 is a group independently selected from the following groups A, B, C, D, E, F, G, H, I, or J:
  • each of the groups A to J forms a particular sub-embodiment; and wherein the groups A are preferred.
  • Another embodiment relates to compounds according to any one of the embodiments 1) to 9) wherein Ar 1 is a group independently selected from the following groups A, B, C, D, E, or F:
  • each of the groups A to F forms a particular sub-embodiment; and wherein the groups A are preferred.
  • the invention thus, relates to compounds of the Formula (I) as defined in embodiment 1), compounds of the Formula (lla) as defined in embodiments 2) or 3), compounds of the Formula (lib) as defined in embodiment 2); or to such compounds further limited by the characteristics of any one of embodiments 4) to 15), 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), (II), (lla), and (lib) 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:
  • the compounds of formulae (I), (II), (lla), and (lib) according to any one of embodiments 1) to 18) 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 Formula (I) 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), (II), (lla), and (lib) according to any one of embodiments 1) to 18).
  • the administered amount of such a compound of formulae (I), (II), (lla), and (lib) according to any one of embodiments 1) to 18) 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 50 mg and 200 mg per day.
  • the compounds according to formulae (I), (II), (lla), and (lib) according to any one of embodiments 1) to 18) 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.
  • 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), (II), (lla), and (lib) 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.
  • Synthetic approach 1 starts with a Boc-protection of the respective 2-methyl-morpholine derivative a under standard conditions by for example dissolving the 2-methyl-morpholine a in a solvent such as DCM or THF and adding a base to the solution, for example DIPEA, TEA or aqueous Na 2 CC> 3 followed by the addition of B0C2O.
  • a solvent such as DCM or THF
  • a base for example DIPEA, TEA or aqueous Na 2 CC> 3 followed by the addition of B0C2O.
  • the reaction is performed at RT and is usually complete within a few hours and results in the Boc-protected 2- methyl-morpholine derivative b which is then coupled with the appropriate phenylene-diamine-derivative in solvents such as THF, DCM or DMF in the presence of a coupling agent such as HBTU or TBTU or the like and a base, for example DIPEA or TEA to give compound c.
  • solvents such as THF, DCM or DMF
  • a coupling agent such as HBTU or TBTU or the like and a base, for example DIPEA or TEA
  • Compound d is Boc-deprotected under acidic conditions such as 4M HCI in dioxane (preferred method) or TFA in DCM to give precursor e which is converted into final compound f by an amide coupling reaction with Ar 1 -COOH in a solvent such as THF, DMF or DCM in the presence of a coupling agent such as TBTU, HBTU, HATU, EDC or the like and a base such as DIPEA, TEA or N- methylmorpholine.
  • acidic conditions such as 4M HCI in dioxane (preferred method) or TFA in DCM to give precursor e which is converted into final compound f by an amide coupling reaction with Ar 1 -COOH in a solvent such as THF, DMF or DCM in the presence of a coupling agent such as TBTU, HBTU, HATU, EDC or the like and a base such as DIPEA, TEA or N- methylmorpholine.
  • Synthetic approach 2 starts with an esterification (usually methyl ester formation) of the 2-methyl-morpholine derivative a by dissolving the starting material in THF and adding 5 equivalents of the respective alcohol (usually MeOH) followed by the addition of EDC and DMAP.
  • the reaction is run at RT and is usually complete within a few hours.
  • the methyl-ester derivative g is acylated with Ar 1 -COOH under conditions described above to result in intermediate h.
  • the reaction runs at RT and is usually complete after a few hours to result in the carboxylic acid derivative i.
  • the final compounds f are obtained via precursor j by applying the same conditions as described for the amide-coupling and the cyclization in synthetic approach 1.
  • 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 miti) column, a Daicel ChiralPak IB (5 miti) column, a Daicel ChiralPak IC (5 miti) column, or a (R,R)-Whelk-01 (5 miti) column.
  • a Daicel ChiralPak AD-H 5 pm
  • a Daicel ChiralCel OD-H 5 pm
  • a Daicel ChiralCel OD (10 pm) column e.g. by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase
  • 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, MeCN).
  • eluent A EtOH, in presence or absence of a base like TEA and/or diethylamine or of an acid like TFA
  • eluent B heptane, MeCN
  • Apparatus Agilent 1100 series with mass spectroscopy detection (MS : Finnigan single quadrupole).
  • MS Finnigan single quadrupole
  • Column Waters XBridge C18 (2.5 pm, 4.6 x 30 mm).
  • Conditions MeCN [eluent A]; water + 0.04% TFA [eluent B] Gradient: 95% B ® 5% B over 1.5 min. (flow: 4.5 ml/min.).
  • Detection UV/Vis + MS.
  • Apparatus Agilent 1100 series with mass spectroscopy detection (MS : Finnigan single quadrupole).
  • MS Finnigan single quadrupole
  • Column Waters XBridge C18 (5 pm, 4.6 x 50 mm).
  • Conditions MeCN [eluent A]; 13 mmol/l NH3 in water [eluent B] Gradient: 95% B ® 5% B over 1.5 min. (flow: 4.5 ml/min.).
  • Detection UV/Vis + MS.
  • FCS Foatal calf serum
  • UV Ultra violet The following examples illustrate the preparation of compounds of the invention but do not at all limit the scope thereof.
  • Step 1 rac-(3R * ,6R * )-6-methylmorpholine-3-carboxylic acid hydrochloride (1686 mg; 8.82 mmol) is dissolved in a 1/1 mixture of MeCN / water (34 ml) followed by the addition of TEA (6.14 ml; 44.1 mmol). Stirring is continued for 10 min at rt followed by the dropwise addition of a solution of B0C2O (2139 mg; 9.7 mmol) in MeCN (8 ml) at 0°C. Stirring is continued at rt for 16 h. The reaction mixture is concentrated under reduced pressure followed by careful addition of +M aq sodium hydroxide solution to pH— 11.
  • Step 2 rac-(3R * ,6R * )-4-(tert-butoxycarbonyl)-6-methylmorpholine-3-carboxylic acid (222 mg; 0.905 mmol) is suspended in DCM (1.5 ml) and HATU (361 mg; 0.95 mmol) followed by DIPEA (0.395 ml; 0.226 mmol) are added and stirring is continued for 15 min. To this mixture, 6-chloro-2,3-diaminotoluene (157 mg; 0.95 mmol) dissolved in DCM (1.5 ml) is added and stirring at rt is continued for 16 h. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in EtOAc and washed with brine.
  • Step 3 rac-tert-butyl-(2R*,5R*)-5-((6-amino-3-chloro-2-methylphenyl)carbamoyl)-2-methylmorpholine-4- carboxylate (350 mg; 0.905 mmol) is dissolved in 100% acetic acid (5 ml; 87.4 mmol) and heated to 100°C for 1 h. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in DCM followed by slow and careful addition of sat. aq. sodium hydrogencarbonate solution until gaz evolution stopped. Phases are separated and the organic layer is washed with brine, dried over magnesium sulfate, filtered and the solvent is removed under reduced pressure.
  • Step 4 rac-tert-butyl (2R * ,5S * )-5-(6-chloro-7-methyl-1 H-benzo[d]imidazol-2-yl)-2-methylmorpholine-4-carboxylate (220 mg; 0.6 mmol) is dissolved in dioxane (1 ml) followed by the addition of 4M HCI in dioxane (1 ml; 4 mmol) and stirring is continued at rt for 3 h. The reaction mixture is evaporated to dryness to give 175 mg of rac- (2R * ,5S * )-5-(5-chloro-4-methyl-1 H-benzo[d]imidazol-2-yl)-2-methylmorpholine.
  • Step 5 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (11.8 mg; 0.058 mmol) and HATU (22.5 mg; 0.059 mmol) are suspended in DMA (0.7 ml) followed by the addition of DIPEA (0.03 ml; 0.17 mmol) and of rac-(2R * ,5S * )-5-(6- chloro-7-methyl-1 H-benzo[d]imidazol-2-yl)-2-methylmorpholine (15 mg; 0.056 mmol) dissolved in DMA (0.7 ml). Stirring is continued at rt for 16 h.
  • Antagonistic activities on both orexin receptors have been measured for each example compound using the following procedure: In vitro assay: Intracellular calcium measurements:
  • 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.
  • BSA bovine serum albumin
  • 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 0x 2 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. in rats after oral dosing; or relating to their functional behavior in different disease related animal models ⁇ for example: the sedative effect of the compound using Electroencephalography (EEG) and Electromyography (EMG) signal measurments [F.
  • EEG Electroencephalography
  • EMG Electromyography
  • 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 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de formule (I) dans laquelle Ar1, R1, et (R5)n sont tels que décrits dans la description, leur préparation, leurs sels pharmaceutiquement acceptables, 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/EP2019/081229 2018-11-14 2019-11-13 Dérivés de benzimidazole-2-méthyl-morpholine WO2020099511A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EPPCT/EP2018/081259 2018-11-14
EP2018081259 2018-11-14

Publications (1)

Publication Number Publication Date
WO2020099511A1 true WO2020099511A1 (fr) 2020-05-22

Family

ID=68501628

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2019/081229 WO2020099511A1 (fr) 2018-11-14 2019-11-13 Dérivés de benzimidazole-2-méthyl-morpholine

Country Status (1)

Country Link
WO (1) WO2020099511A1 (fr)

Citations (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3282927A (en) 1964-05-21 1966-11-01 Bristol Myers Co 5-phenyl-4-thiazolylpenicillins
WO2001096302A1 (fr) 2000-06-16 2001-12-20 Smithkline Beecham P.L.C. Piperidines utiles en tant qu'antagonistes du recepteur d'orexine
WO2002044172A1 (fr) 2000-11-28 2002-06-06 Smithkline Beecham P.L.C. Derives de la morpholine utilises comme antagonistes des recepteurs de l'orexine
WO2002090355A1 (fr) 2001-05-05 2002-11-14 Smithkline Beecham P.L.C. Amines cycliques n-aroyle
WO2002089800A2 (fr) 2001-05-05 2002-11-14 Smithkline Beecham P.L.C. Derives d'amines cycliques n-aroyl utilises comme antagonistes du recepteur d'orexine
WO2003002559A2 (fr) 2001-06-28 2003-01-09 Smithkline Beecham P.L.C. Composes
WO2003002561A1 (fr) 2001-06-28 2003-01-09 Smithkline Beecham P.L.C. Derives d'amine cycliques n-aroyle utilises comme antagonistes du recepteur de l'orexine
WO2003032991A1 (fr) 2001-10-11 2003-04-24 Smithkline Beecham Plc Derives de n-aroylpiperazine utilises comme antagonistes du recepteur de l'orexine
WO2003041711A1 (fr) 2001-11-10 2003-05-22 Smithkline Beecham P.L.C. Derives bis-amide de piperazine et leur utilisation en tant qu'antagonistes du recepteur d'orexine
WO2003051368A1 (fr) 2001-12-19 2003-06-26 Smithkline Beecham Plc Derives d'amine cyclique n-aroyle utilises en tant qu'antagonistes du recepteur d'orexine
WO2003051873A1 (fr) 2001-12-19 2003-06-26 Smithkline Beecham Plc Composes de piperazine et leur utilisation pharmaceutique
WO2004026866A1 (fr) 2002-09-18 2004-04-01 Glaxo Group Limited Amines cycliques n-aroyle utilisees comme antagonistes du recepteur d'orexine
WO2004041807A1 (fr) 2002-11-06 2004-05-21 Glaxo Group Limited Nouveaux composes
WO2004041816A1 (fr) 2002-11-06 2004-05-21 Glaxo Group Limited Compositions azacycliques utilisees comme antagonistes du recepteur de l'orexine
WO2004041791A1 (fr) 2002-11-06 2004-05-21 Glaxo Group Limited Derives d'amine cyclique n-aryle acetyle utilises comme antagonistes de l'orexine
WO2005118548A1 (fr) 2004-03-01 2005-12-15 Actelion Pharmaceuticals Ltd Derives de 1,2,3,4-tétrahydroisoquinoléine substitués
WO2007105177A1 (fr) 2006-03-15 2007-09-20 Actelion Pharmaceuticals Ltd Dérivés de tétrahydroisoquinoléine pour renforcer la fonction de la mémoire
WO2008020405A2 (fr) 2006-08-15 2008-02-21 Actelion Pharmaceuticals Ltd Composés d'azétidine
WO2008038251A2 (fr) 2006-09-29 2008-04-03 Actelion Pharmaceuticals Ltd Dérivés du 3-aza-bicyclo[3.1.0]hexane
WO2008081399A2 (fr) 2006-12-28 2008-07-10 Actelion Pharmaceuticals Ltd Dérivés 2-aza-bicyclo[3.1.0]hexane
WO2008087611A2 (fr) 2007-01-19 2008-07-24 Actelion Pharmaceuticals Ltd Dérivés de pyrrolidine et de piperidine
WO2008117241A2 (fr) 2007-03-26 2008-10-02 Actelion Pharmaceuticals Ltd Dérivés de thiazolidine
WO2008139416A1 (fr) 2007-05-14 2008-11-20 Actelion Pharmaceuticals Ltd Dérivés de 2-cyclopropyl-thiazole
WO2008150364A1 (fr) 2007-05-23 2008-12-11 Merck & Co., Inc. Antagonistes du récepteur de la cyclopropylpyrrolidine orexine
WO2009003993A1 (fr) 2007-07-03 2009-01-08 Glaxo Group Limited Dérivés de pipéridine utiles comme antagonistes vis-àvis des récepteurs de l'orexine
WO2009004584A1 (fr) 2007-07-03 2009-01-08 Actelion Pharmaceuticals Ltd Composés 3-aza-bicyclo[3.3.0]octane
WO2009003997A1 (fr) 2007-07-03 2009-01-08 Glaxo Group Limited Imidazo [1, 2-c] pyrimidin-2-ylméthylpipéridines comme antagonistes vis-à-vis des récepteurs de l'orexine
WO2009016564A2 (fr) 2007-07-27 2009-02-05 Actelion Pharmaceuticals Ltd Dérivés de 2-aza-bicyclo[3.3.0]octane
WO2009016560A2 (fr) 2007-07-27 2009-02-05 Actelion Pharmaceuticals Ltd Dérivés de trans-3-aza-bicyclo[3.1.0]hexane
WO2009040730A2 (fr) 2007-09-24 2009-04-02 Actelion Pharmaceuticals Ltd Pyrrolidines et pipéridines en tant qu'antagonistes du récepteur de l'orexine
WO2009047723A2 (fr) 2007-10-10 2009-04-16 Actelion Pharmaceuticals Ltd Dérivés de tétrahydroquinoléine pour traiter des troubles de stress post-traumatique
WO2009104155A1 (fr) 2008-02-21 2009-08-27 Actelion Pharmaceuticals Ltd Dérivés de 2-aza-bicyclo[2.2.1]heptane
WO2009124956A1 (fr) 2008-04-10 2009-10-15 Glaxo Group Limited Dérivés de pyridine utilisés pour traiter des troubles liés aux orexines
WO2010004507A1 (fr) 2008-07-07 2010-01-14 Actelion Pharmaceuticals Ltd Composés thiazolidines en tant qu'antagonistes des récepteurs de l'orexine
WO2010038200A1 (fr) 2008-10-01 2010-04-08 Actelion Pharmaceuticals Ltd Composés d'oxazolidine utilisables en tant qu'antagonistes des récepteurs à orexine
WO2010060470A1 (fr) 2008-11-26 2010-06-03 Glaxo Group Limited Dérivés de la pipéridine utiles en tant qu’antagonistes du récepteur de l’orexine
WO2010060471A1 (fr) 2008-11-26 2010-06-03 Glaxo Group Limited Dérivés de la pipéridine utiles en tant qu’antagonistes du récepteur de l’orexine
WO2010060472A1 (fr) 2008-11-26 2010-06-03 Glaxo Group Limited Dérivés de l’imidazopyridazine agissant en tant qu’antagonistes de l’orexine
WO2010063663A1 (fr) 2008-12-02 2010-06-10 Glaxo Group Limited Dérivés de n-{[(1r,4s,6r)-3-(2-pyridinylcarbonyl)-3-azabicyclo[4.1.0]hept-4-yl]methyl}-2-heteroarylamine et leurs utilisations
WO2010063662A1 (fr) 2008-12-02 2010-06-10 Glaxo Group Limited Dérivés de n-{[(1s,4s,6s)-3-(2-pyridinylcarbonyl)-3-azabicyclo[4.1.0]hept-4-yl]methyl}-2-heteroarylamine et leurs utilisations
WO2010072722A1 (fr) 2008-12-23 2010-07-01 Glaxo Group Limited Dérivés de pipéridine pouvant être utilisés en tant qu'agonistes de l'orexine
WO2010122151A1 (fr) 2009-04-24 2010-10-28 Glaxo Group Limited 3 -azabicyclo [4.1.0] heptanes utilisés comme antagonistes de l'orexine
WO2013068935A1 (fr) * 2011-11-08 2013-05-16 Actelion Pharmaceuticals Ltd Dérivés de 2-(1,2,3-triazol-2-yl)benzamide et de 3-(1,2,3-triazol-2-yl)picolinamide en tant qu'antagonistes des récepteurs d'oréxine
WO2013182972A1 (fr) 2012-06-04 2013-12-12 Actelion Pharmaceuticals Ltd Dérivés de benzimidazole-proline

Patent Citations (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3282927A (en) 1964-05-21 1966-11-01 Bristol Myers Co 5-phenyl-4-thiazolylpenicillins
WO2001096302A1 (fr) 2000-06-16 2001-12-20 Smithkline Beecham P.L.C. Piperidines utiles en tant qu'antagonistes du recepteur d'orexine
WO2002044172A1 (fr) 2000-11-28 2002-06-06 Smithkline Beecham P.L.C. Derives de la morpholine utilises comme antagonistes des recepteurs de l'orexine
WO2002090355A1 (fr) 2001-05-05 2002-11-14 Smithkline Beecham P.L.C. Amines cycliques n-aroyle
WO2002089800A2 (fr) 2001-05-05 2002-11-14 Smithkline Beecham P.L.C. Derives d'amines cycliques n-aroyl utilises comme antagonistes du recepteur d'orexine
WO2003002559A2 (fr) 2001-06-28 2003-01-09 Smithkline Beecham P.L.C. Composes
WO2003002561A1 (fr) 2001-06-28 2003-01-09 Smithkline Beecham P.L.C. Derives d'amine cycliques n-aroyle utilises comme antagonistes du recepteur de l'orexine
WO2003032991A1 (fr) 2001-10-11 2003-04-24 Smithkline Beecham Plc Derives de n-aroylpiperazine utilises comme antagonistes du recepteur de l'orexine
WO2003041711A1 (fr) 2001-11-10 2003-05-22 Smithkline Beecham P.L.C. Derives bis-amide de piperazine et leur utilisation en tant qu'antagonistes du recepteur d'orexine
WO2003051368A1 (fr) 2001-12-19 2003-06-26 Smithkline Beecham Plc Derives d'amine cyclique n-aroyle utilises en tant qu'antagonistes du recepteur d'orexine
WO2003051873A1 (fr) 2001-12-19 2003-06-26 Smithkline Beecham Plc Composes de piperazine et leur utilisation pharmaceutique
WO2004026866A1 (fr) 2002-09-18 2004-04-01 Glaxo Group Limited Amines cycliques n-aroyle utilisees comme antagonistes du recepteur d'orexine
WO2004041807A1 (fr) 2002-11-06 2004-05-21 Glaxo Group Limited Nouveaux composes
WO2004041816A1 (fr) 2002-11-06 2004-05-21 Glaxo Group Limited Compositions azacycliques utilisees comme antagonistes du recepteur de l'orexine
WO2004041791A1 (fr) 2002-11-06 2004-05-21 Glaxo Group Limited Derives d'amine cyclique n-aryle acetyle utilises comme antagonistes de l'orexine
WO2005118548A1 (fr) 2004-03-01 2005-12-15 Actelion Pharmaceuticals Ltd Derives de 1,2,3,4-tétrahydroisoquinoléine substitués
WO2007105177A1 (fr) 2006-03-15 2007-09-20 Actelion Pharmaceuticals Ltd Dérivés de tétrahydroisoquinoléine pour renforcer la fonction de la mémoire
WO2008020405A2 (fr) 2006-08-15 2008-02-21 Actelion Pharmaceuticals Ltd Composés d'azétidine
WO2008038251A2 (fr) 2006-09-29 2008-04-03 Actelion Pharmaceuticals Ltd Dérivés du 3-aza-bicyclo[3.1.0]hexane
WO2008081399A2 (fr) 2006-12-28 2008-07-10 Actelion Pharmaceuticals Ltd Dérivés 2-aza-bicyclo[3.1.0]hexane
WO2008087611A2 (fr) 2007-01-19 2008-07-24 Actelion Pharmaceuticals Ltd Dérivés de pyrrolidine et de piperidine
WO2008117241A2 (fr) 2007-03-26 2008-10-02 Actelion Pharmaceuticals Ltd Dérivés de thiazolidine
WO2008139416A1 (fr) 2007-05-14 2008-11-20 Actelion Pharmaceuticals Ltd Dérivés de 2-cyclopropyl-thiazole
WO2008150364A1 (fr) 2007-05-23 2008-12-11 Merck & Co., Inc. Antagonistes du récepteur de la cyclopropylpyrrolidine orexine
WO2009003993A1 (fr) 2007-07-03 2009-01-08 Glaxo Group Limited Dérivés de pipéridine utiles comme antagonistes vis-àvis des récepteurs de l'orexine
WO2009004584A1 (fr) 2007-07-03 2009-01-08 Actelion Pharmaceuticals Ltd Composés 3-aza-bicyclo[3.3.0]octane
WO2009003997A1 (fr) 2007-07-03 2009-01-08 Glaxo Group Limited Imidazo [1, 2-c] pyrimidin-2-ylméthylpipéridines comme antagonistes vis-à-vis des récepteurs de l'orexine
WO2009016564A2 (fr) 2007-07-27 2009-02-05 Actelion Pharmaceuticals Ltd Dérivés de 2-aza-bicyclo[3.3.0]octane
WO2009016560A2 (fr) 2007-07-27 2009-02-05 Actelion Pharmaceuticals Ltd Dérivés de trans-3-aza-bicyclo[3.1.0]hexane
WO2009040730A2 (fr) 2007-09-24 2009-04-02 Actelion Pharmaceuticals Ltd Pyrrolidines et pipéridines en tant qu'antagonistes du récepteur de l'orexine
WO2009047723A2 (fr) 2007-10-10 2009-04-16 Actelion Pharmaceuticals Ltd Dérivés de tétrahydroquinoléine pour traiter des troubles de stress post-traumatique
WO2009104155A1 (fr) 2008-02-21 2009-08-27 Actelion Pharmaceuticals Ltd Dérivés de 2-aza-bicyclo[2.2.1]heptane
WO2009124956A1 (fr) 2008-04-10 2009-10-15 Glaxo Group Limited Dérivés de pyridine utilisés pour traiter des troubles liés aux orexines
WO2010004507A1 (fr) 2008-07-07 2010-01-14 Actelion Pharmaceuticals Ltd Composés thiazolidines en tant qu'antagonistes des récepteurs de l'orexine
WO2010038200A1 (fr) 2008-10-01 2010-04-08 Actelion Pharmaceuticals Ltd Composés d'oxazolidine utilisables en tant qu'antagonistes des récepteurs à orexine
WO2010060470A1 (fr) 2008-11-26 2010-06-03 Glaxo Group Limited Dérivés de la pipéridine utiles en tant qu’antagonistes du récepteur de l’orexine
WO2010060471A1 (fr) 2008-11-26 2010-06-03 Glaxo Group Limited Dérivés de la pipéridine utiles en tant qu’antagonistes du récepteur de l’orexine
WO2010060472A1 (fr) 2008-11-26 2010-06-03 Glaxo Group Limited Dérivés de l’imidazopyridazine agissant en tant qu’antagonistes de l’orexine
WO2010063663A1 (fr) 2008-12-02 2010-06-10 Glaxo Group Limited Dérivés de n-{[(1r,4s,6r)-3-(2-pyridinylcarbonyl)-3-azabicyclo[4.1.0]hept-4-yl]methyl}-2-heteroarylamine et leurs utilisations
WO2010063662A1 (fr) 2008-12-02 2010-06-10 Glaxo Group Limited Dérivés de n-{[(1s,4s,6s)-3-(2-pyridinylcarbonyl)-3-azabicyclo[4.1.0]hept-4-yl]methyl}-2-heteroarylamine et leurs utilisations
WO2010072722A1 (fr) 2008-12-23 2010-07-01 Glaxo Group Limited Dérivés de pipéridine pouvant être utilisés en tant qu'agonistes de l'orexine
WO2010122151A1 (fr) 2009-04-24 2010-10-28 Glaxo Group Limited 3 -azabicyclo [4.1.0] heptanes utilisés comme antagonistes de l'orexine
WO2013068935A1 (fr) * 2011-11-08 2013-05-16 Actelion Pharmaceuticals Ltd Dérivés de 2-(1,2,3-triazol-2-yl)benzamide et de 3-(1,2,3-triazol-2-yl)picolinamide en tant qu'antagonistes des récepteurs d'oréxine
WO2013182972A1 (fr) 2012-06-04 2013-12-12 Actelion Pharmaceuticals Ltd Dérivés de benzimidazole-proline

Non-Patent Citations (50)

* Cited by examiner, † Cited by third party
Title
"Current Topics in Behavioral Neurosciences", vol. 3, 2009, article "Behavioral Neuroscience of Drug Addiction", pages: 179 - 195
"Pharmaceutical Salts and Co-crystals", 2012, RSC PUBLISHING
"Salt selection for basic drugs", INT. J. PHARM., vol. 33, 1986, pages 201 - 217
ADAM, TC ET AL., PHYSIOL BEHAV, vol. 91, no. 4, 2007, pages 449 - 458
ASTON-JONES G ET AL., BRAIN RES, vol. 1314, 2010, pages 130 - 138
BERRIDGE CW ET AL., BRAIN RES, vol. 1314, 2009, pages 91 - 102
BORGLAND SL ET AL., NEURON, vol. 49, no. 4, 2006, pages 589 - 601
BOUTREL B ET AL.: "Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior", PROC NATL ACAD SCI, vol. 102, no. 52, 2005, pages 19168 - 19173
BOUTREL, B ET AL., PROC NATL ACAD SCI, vol. 102, no. 52, 2005, pages 19168 - 19173
BRISBARE-ROCH ET AL., NATURE MEDICINE, vol. 13, 2007, pages 150 - 155
C BOSSC BRISBARE-ROCHF JENCK, JOURNAL OF MEDICINAL CHEMISTRY, vol. 52, 2009, pages 891 - 903
CARTER ME ET AL.: "The brain hypocretins and their receptors: mediators of allostatic arousal", CURR OP PHARMACOL., vol. 9, 2009, pages 39 - 45, XP025916388, DOI: 10.1016/j.coph.2008.12.018
CARTER MEBORG JSDELECEA L., CURR OP PHARMACOL., vol. 9, 2009, pages 39 - 45
CHEMELLI R.M. ET AL., CELL, vol. 98, 1999, pages 437 - 451
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 1347329-27-4
CHROUSOS, GP ET AL., JAMA, vol. 267, no. 9, 1992, pages 1244 - 1252
FENDT M ET AL., NEUROSCIENCE BIOBEHAV REV., vol. 23, 1999, pages 743 - 760
FENG P ET AL., J PSYCHOPHARMACOL, vol. 22, no. 7, 2008, pages 784 - 791
FURLONG T M ET AL., EUR J NEUROSCI, vol. 30, no. 8, 2009, pages 1603 - 1614
GOZZI A ET AL., PLOS ONE, vol. 6, no. 1, 2011, pages e16406
H DIETRICHF JENCK, PSYCHOPHARMACOLOGY, vol. 212, no. 2, 2010, pages 145 - 154
HAMAMOTO H. ET AL., TETRAHEDRON ASYMMETRY, vol. 11, 2000, pages 4485 - 4497
HOLLANDER JA ET AL., PROC NATL ACAD SCI, vol. 105, no. 49, 2008, pages 19480 - 19485
HUTCHESON DM ET AL., BEHAV PHARMACOL, vol. 22, no. 2, 2011, pages 173 - 181
JE KANG ET AL.: "Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle", SCIENCE, vol. 326, no. 5955, 2009, pages 1005 - 1007
KOOB, GF ET AL., CURR OPIN INVESTIG DRUGS, vol. 11, no. 1, 2010, pages 63 - 71
LANGMEAD, BRIT. J. PHARMACOL., vol. 141, 2004, pages 340 - 346
LAWRENCE AJ ET AL., BR J PHARMACOL, vol. 148, no. 6, 2006, pages 752 - 759
LIU X ET AL., SLEEP, vol. 30, no. 1, 2007, pages 83 - 90
MAJZOUB, JA ET AL., EUROPEAN JOURNAL OF ENDOCRINOLOGY, vol. 155, no. 1, 2006, pages S71 - S76
MJ PRUD'HOMME ET AL., NEUROSCIENCE, vol. 162, no. 4, 2009, pages 1287 - 1298
NOLLET ET AL., NEUROPHARM, vol. 61, no. 1-2, 2011, pages 336 - 46
QUARTA D ET AL.: "The orexin-1 receptor antagonist SB-334867 reduces amphetamine-evoked dopamine outflow in the shell of the nucleus accumbens and decreases the expression of amphetamine sensitization", NEUROCHEM INT, vol. 56, no. 1, 2010, pages 11 - 15, XP026906710, DOI: 10.1016/j.neuint.2009.08.012
R. STICKGOLD ET AL.: "Sleep-dependent memory consolidation", NATURE, vol. 437, 2005, pages 1272 - 1278
REMINGTON: "The Science and Practice of Pharmacy", 2005, LIPPINCOTT WILLIAMS & WILKINS
SAKURAI T. ET AL., CELL, vol. 92, 1998, pages 573 - 585
SALOMON RM ET AL., BIOL PSYCHIATRY, vol. 54, no. 2, 2003, pages 96 - 104
SMITH RJ ET AL.: "Orexin/hypocretin is necessary for context-driven cocaine-seeking", NEUROPHARMACOLOGY, vol. 58, no. 1, 2010, pages 179 - 184, XP026736770, DOI: 10.1016/j.neuropharm.2009.06.042
SMITH RJ ET AL.: "Orexin/hypocretin signaling at the orexin 1 receptor regulates cue-elicited cocaine-seeking", EUR J NEUROSCI, vol. 30, no. 3, 2009, pages 493 - 503
SPEALMAN ET AL., PHARMACOL. BIOCHEM. BEHAV., vol. 64, 1999, pages 327 - 336
SUTCLIFFE, JG ET AL., NAT REV NEUROSCI, vol. 3, no. 5, 2002, pages 339 - 349
T.S. SHIPPENBERGG.F. KOOB: "Neuropsychopharmacology: The fifth generation of progress", 2002, article "Recent advances in animal models of drug addiction", pages: 1381 - 1397
TSUJINO NSAKURAI T., PHARMACOL REV., vol. 61, 2009, pages 162 - 176
TSUJINO NSAKURAI T: "Orexin/hypocretin: a neuropeptide at the interface of sleep, energy homeostasis, and reward systems", PHARMACOL REV., vol. 61, 2009, pages 162 - 176, XP055180000, DOI: 10.1124/pr.109.001321
TSUJINO, NSAKURAI, T, PHARMACOL REV, vol. 61, no. 2, 2009, pages 162 - 176
VINKERS CH ET AL., EUROPEAN J PHARMACOL., vol. 585, 2008, pages 407 - 425
W. FOULDS MATHES ET AL., APPETITE, vol. 52, 2009, pages 545 - 553
WINROW ET AL., NEUROPHARMACOLOGY, vol. 58, no. 1, 2009, pages 185 - 94
Y. KAYABA ET AL., AM. J. PHYSIOL. REGUL. INTEGR. COMP. PHYSIOL., vol. 285, 2003, pages R581 - 593
ZHANG W ET AL.: "Multiple components of the defense response depend on orexin: evidence from orexin knockout mice and orexin neuron-ablated mice", AUTON NEUROSCI, 2006, pages 126 - 127,139-145

Similar Documents

Publication Publication Date Title
US11040966B2 (en) Benzimidazole-proline derivatives
EP3077390B1 (fr) Forme de sel cristalline de (s)-(2-(6-chloro-7-méthyl-1 h-benzo[d]imidazol- 2-yl)-2-méthylpyrrolidin-1-yl)(5-méthoxy-2-(2h-1,2,3-triazol-2-yl)phényl)méthanone comme antagoniste des récepteurs à l'oréxine
AU2014358742B2 (en) Crystalline form of (S)-(2-(6-chloro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1 -yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and its use as orexin receptor antagonists
WO2013050938A1 (fr) Dérivés de 3,7-diazabicyclo[3.3.1]nonane et de 9-oxa-3,7- diazabicyclo[3.3.1]nonane
US9211279B2 (en) Proline sulfonamide derivatives as orexin receptor antagonists
WO2020007977A1 (fr) Dérivés de 7-trifluorométhyl-[1,4]diazépane
WO2020007964A1 (fr) Dérivés de 2-(2-azabicyclo [3.1.0] hexan-1-yl)-1h-benzimidazole
WO2020099511A1 (fr) Dérivés de benzimidazole-2-méthyl-morpholine
WO2023218023A1 (fr) Dérives d'hydrazine-n-carboxamide cycliques substitués par thiazoloaryl-méthyle

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19801039

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19801039

Country of ref document: EP

Kind code of ref document: A1