WO2014006120A1 - Nouveaux modulateurs allostériques positifs de récepteur nicotinique à l'acétylcholine - Google Patents

Nouveaux modulateurs allostériques positifs de récepteur nicotinique à l'acétylcholine Download PDF

Info

Publication number
WO2014006120A1
WO2014006120A1 PCT/EP2013/064093 EP2013064093W WO2014006120A1 WO 2014006120 A1 WO2014006120 A1 WO 2014006120A1 EP 2013064093 W EP2013064093 W EP 2013064093W WO 2014006120 A1 WO2014006120 A1 WO 2014006120A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound according
disease
pharmaceutically acceptable
pyridin
phenyl
Prior art date
Application number
PCT/EP2013/064093
Other languages
English (en)
Inventor
Jørgen ESKILDSEN
Anette Graven Sams
Ask Püschl
Original Assignee
H. Lundbeck A/S
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
Priority claimed from PCT/EP2012/063219 external-priority patent/WO2013007621A1/fr
Application filed by H. Lundbeck A/S filed Critical H. Lundbeck A/S
Publication of WO2014006120A1 publication Critical patent/WO2014006120A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6

Definitions

  • New positive allosteric modulators of nicotinic acetylcholine receptor New positive allosteric modulators of nicotinic acetylcholine receptor.
  • the present invention relates to compounds useful in therapy, to compositions comprising said compounds, and to methods of treating diseases comprising administration of said compounds.
  • the compounds referred to are positive allosteric modulators (PAMs) of the nicotinic acetylcholine ol receptor.
  • Nicotinic acetylcholine receptors belong to the super family of ligand gated ionic channels, and gate the flow of cations including calcium.
  • the nAChRs are endogenously activated by acetylcholine (ACh) and can be divided into nicotinic receptors of the neuromuscular junction and neuronal nicotinic receptors (NNRs).
  • the NNRs are widely expressed throughout the central nervous system (CNS) and the peripheral nervous system (PNS).
  • NNRs have been suggested to play an important role in CNS function by modulating the release of many neurotransmitters, for example, ACh, norepinephrine, dopamine, serotonin, and GABA, among others, resulting in a wide range of physiological effects.
  • nAChRs Seventeen subunits of nAChRs have been reported to date, which are identified as ⁇ 2- ⁇ 10, ⁇ 1 - ⁇ 4, ⁇ , ⁇ and ⁇ . From these subunits, nine subunits, o2 through a 7 and ⁇ 2 through ⁇ 4, prominently exist in the mammalian brain. Many functionally distinct nAChR complexes exist, for example five ol subunits can form a receptor as a homomeric functional pentamer or combinations of different subunits can form heteromeric receptors such as ⁇ 4 ⁇ 2 and ⁇ 3 ⁇ 4 receptors (Gotti, C. et al., Prog. Neurobiol., 2004, 74: 363-396;
  • the homomeric a7 receptor is one of the most abundant NNRs, along with ⁇ 4 ⁇ 2 receptors, in the brain, wherein it is heavily expressed in the hippocampus, cortex, thalamic nuclei, ventral tegmental area and substantia nigra (Broad, L. M. et al., Drugs of the Future, 2007, 32(2): 161 -170, Poorthuis RB, Biochem Pharmacol. 2009, 1 ;78(7):668-76).
  • NNRs have been demonstrated to regulate interneuron excitability and modulate the release of excitatory as well as inhibitory neurotransmitters.
  • a7 NNRs have been reported to be involved in neuroprotective effects in experimental models of cellular damage (Shimo- hama, S., Biol Pharm Bull. 2009, 32(3):332-6). Studies have shown that a7 subunits, when expressed recombinant in-vitro, activate and desensitize rapidly, and exhibit relatively higher calcium permeability compared to other NNR combinations (Papke, R.L. et al., J Pharmacol Exp Ther. 2009, 329(2)791 -807).
  • the NNRs in general, are involved in various cognitive functions, such as learning, memory and attention, and therefore in CNS disorders, e.g. Alzheimer's disease (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD), Tourette's syndrome, schizophrenia, bipolar disorder, pain and tobacco dependence (Keller, J. J. et al., Be- hav. Brain Res. 2005, 162: 143-52; Haydar, S.N. et al., Curr Top Med Chem. 2010;10(2):144- 52).
  • AD Alzheimer's disease
  • PD Parkinson's disease
  • ADHD attention deficit hyperactivity disorder
  • Tourette's syndrome schizophrenia, bipolar disorder, pain and tobacco dependence
  • a7-NNRs have been shown to be involved in the neuroprotective effects of nicotine both in vitro (Jonnala, R. B.
  • neurodegeneration underlies several progressive CNS disorders, including, but not limited to, AD, PD, amyotrophic lateral sclerosis, Huntington's disease, dementia with Lewy bodies, as well as diminished CNS function resulting from traumatic brain injury.
  • a7 NNRs the impaired function of a7 NNRs by beta-amyloid peptides linked to AD has been implicated as a key factor in development of the cognitive deficits associated with the disease (Liu, Q.-S., et al., PNAS, 2001 ,98: 4734-4739).
  • modulating the activity of a7 NNRs demonstrates promising potential to prevent or treat a variety of diseases indicated above, such as AD, other dementias, other neurodegenerative diseases, schizophrenia and neurodegeneration, with an underlying pathology that involves cognitive function including, for example, aspects of learning, memory, and attention (Thomsen, M.S. et al., Curr Pharm Des. 2010 Jan;16(3):323- 43; Olincy, A.
  • NNR ligands including a7 ligands, have also been implicated in weight control, diabetis inflammation, obsessive-compulsive disorder (OCD), angiogenesis and as potential analgesics (Marrero, M.B. et al., J. Pharmacol. Exp. Ther. 2010, 332(1 ):173-80; Vincler, M., Exp. Opin. Invest. Drugs, 2005, 14 (10): 1 191 -1 198; Rosas-Ballina, M., J. Intern Med. 2009 265(6):663-79; Arias, H.R., Int. J. Biochem. Cell Biol. 2009, 41 (7):1441 -51 ; Tizabi, Y., Biol Psychiatry. 2002, 51 (2):164-71 ).
  • Nicotine is known to enhance attention and cognitive performance, reduced anxiety, enhanced sensory gating, and analgesia and neuroprotective effects when administered. Such effects are mediated by the non-selective effect of nicotine at multiple nicotinic receptor subtypes.
  • nicotine also exerts adverse events, such as cardiovascular and gastrointestinal problems (Karaconji, I.B. et al., Arh Hig Rada Toksikol. 2005, 56(4):363-71 ). Consequently, there is a need to identify subtype-selective compounds that retain the beneficial effects of nicotine, or an NNR ligand, while eliminating or decreasing adverse effects.
  • NNR ligands are a7 NNR agonists, such as DMXB-A,
  • NNR ligands Despite the beneficial effects of NNR ligands, it remains uncertain whether chronic treatment with agonists affecting NNRs may provide suboptimal benefit due to sustained acti- vation and desensitization of the NNRs, in particular the a7 NNR subtype.
  • administering a positive allosteric modulator (PAM) can reinforce endogenous cholinergic transmission without directly stimulating the target receptor. Nicotinic PAMs can selectively modulate the activity of ACh at NNRs, preserving the activation and deactivation kinetics of the receptor. Accordingly, a7 NNR-selective PAMs have emerged (Faghih, R., Recent Pat CNS Drug Discov. 2007, 2(2):99-106).
  • NNR PAMs such as 5-hydroxyindole (5-HI), ivermectin, galantamine, and SLURP-1 , a peptide derived from acetylcholinesterase (AChE).
  • 5-HI 5-hydroxyindole
  • ivermectin ivermectin
  • galantamine ivermectin
  • SLURP-1 a peptide derived from acetylcholinesterase
  • Genistein a kinase inhibitor was also reported to increase a7 responses.
  • PNU-120596 a urea derivative, was reported to increase the potency ACh as well as improve auditory gating deficits induced by amphetamine in rats.
  • NS1738, JNJ-1930942 and compound 6 have been reported to potentiate the response of ACh and exert beneficial effect in experimental models of sensory and cognitive processing in rodents.
  • Other NNR PAMs include derivatives of quinuclidine, indole, benzopyrazole, thiazole, and benzoisothiazoles (Hurst, R. S. et al., J. Neurosci.
  • WO 2009/043784 recites co ll structure which compounds are said to be PAMs of the a7 NNR.
  • the a7 NNR PAMs presently known generally demonstrate weak activity, have a range of non-specific effects, or can only achieve limited access to the central nervous system where a7 NNRs are abundantly expressed. Accordingly, it would be beneficial to identify and provide new PAM compounds of a7 NNRs and compositions for treating diseases and disorders wherein a7 NNRs are involved. It would further be particularly beneficial if such compounds can provide improved efficacy of treatment while reducing adverse effects associated with compounds targeting neuronal nicotinic receptors by selectively modulating a7 NNRs.
  • calcium or sodium channel blockers i.e. compounds related to a pharmacological mechanism distinguished from the compounds of the present invention.
  • the objective of the present invention is to provide compounds that are positive alio steric modulators (PAMs) of the nicotinic acetylcholine receptor subtype a7.
  • PAMs positive alio steric modulators
  • R1 , R2, R3, R4 and R5 are H;
  • R6 is selected from methyl and hydroxymethyl
  • A7 is C-R7, A8 is N and A9 is C-R9;
  • R7, R10 and R1 1 are H
  • R9 is OR12, wherein R12 represents a monocyclic saturated ring moiety having 4-6 ring atoms wherein one of said ring atoms is O and the rest is C;
  • the invention relates to a compound according to formula
  • the invention relates to a compound according to formula [I], and pharmaceutically acceptable salts thereof, for use in the treatment of a disease or disorder selected from psychosis; schizophrenia; cognitive disorders; cognitive impairment associated with schizophrenia; attention deficit hyperactivity disorder (ADHD); autism spectrum disorders, Alzheimer's disease (AD); mild cognitive impairment (MCI); age associated memory impairment (AAMI); senile dementia; AIDS dementia; Pick's disease; dementia associated with Lewy bodies; dementia associated with Down's syndrome; Huntington's disease; Parkinson's disease (PD); obsessive-compulsive disorder (OCD); traumatic brain injury; epilepsy; post- traumatic stress; Wernicke-Korsakoff syndrome (WKS); post-traumatic amnesia; cognitive deficits associated with depression; diabetes, weight control, inflammatory disorders, reduced angiogenesis; amyotrophic lateral sclerosis and pain.
  • a disease or disorder selected from psychosis; schizophrenia; cognitive disorders; cognitive impairment associated with schizophrenia; attention deficit hyperactivity disorder (ADHD); autism spectrum disorders, Alzheimer'
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to formula [I] and pharmaceuetically acceptable salts thereof, and one or more pharmaceutically acceptable carrier or excipient.
  • the invention relates to a kit comprising a compound according to formula [I], and pharmaceutically acceptable salts thereof, together with a compound selected from the list consisting of acetylcholinesterase inhibitors; glutamate receptor antagonists; dopamine transport inhibitors; noradrenalin transport inhibitors; D2 antagonists; D2 partial ago- nists; PDE10 antagonists; 5-HT2A antagonists; 5-HT6 antagonists; KCNQ antagonists; lithium; sodium channel blockers and GABA signaling enhancers.
  • a compound selected from the list consisting of acetylcholinesterase inhibitors; glutamate receptor antagonists; dopamine transport inhibitors; noradrenalin transport inhibitors; D2 antagonists; D2 partial ago- nists; PDE10 antagonists; 5-HT2A antagonists; 5-HT6 antagonists; KCNQ antagonists; lithium; sodium channel blockers and GABA signaling enhancers.
  • the invention relates to a method for the treatment of a disease or disorder selected from psychosis; schizophrenia; cognitive disorders; cognitive impairment associated with schizophrenia; attention deficit hyperactivity disorder (ADHD); autism spectrum disorders, Alzheimer's disease (AD); mild cognitive impairment (MCI); age associated memory impairment (AAMI); senile dementia; AIDS dementia; Pick's disease; dementia associated with Lewy bodies; dementia associated with Down's syndrome; Huntington's disease; Parkinson's disease (PD); obsessive-compulsive disorder (OCD); traumatic brain injury; epi- lepsy; post-traumatic stress; Wernicke-Korsakoff syndrome (WKS); post-traumatic amnesia; cognitive deficits associated with depression; diabetes, weight control, inflammatory disorders, reduced angiogenesis; amyotrophic lateral sclerosis and pain, which method comprises the administration of a therapeutically effective amount of a compound according to formula [I], and pharmaceutically acceptable salts thereof.
  • ADHD attention deficit hyperactivity disorder
  • MCI mild cognitive impairment
  • AAMI age associated memory impairment
  • the invention relates to the use of a compound according to formula [I], and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment of a disease or disorder selected from psychosis; schizophrenia; cognitive disorders; cognitive impairment associated with schizophrenia; attention deficit hyperactivity disorder (ADHD); autism spectrum disorders, Alzheimer's disease (AD); mild cognitive im- pairment (MCI); age associated memory impairment (AAMI); senile dementia; AIDS dementia; Pick's disease; dementia associated with Lewy bodies; dementia associated with Down's syndrome; Huntington's disease; Parkinson's disease (PD); obsessive-compulsive disorder (OCD); traumatic brain injury; epilepsy; post-traumatic stress; Wernicke-Korsakoff syndrome (WKS); post-traumatic amnesia; cognitive deficits associated with depression; diabetes, weight control, inflammatory disorders, reduced angiogenesis; amyotrophic lateral sclerosis and pain.
  • a disease or disorder selected from psychosis; schizophrenia; cognitive disorders; cognitive impairment associated with schizophrenia; attention deficit hyperactivity disorder
  • alkyl is intended to indicate a straight, branched and/or cyclic saturated hydrocarbon.
  • C 1-6 alkyl is intended to indicate such hydrocarbon having 1 , 2, 3, 4, 5 or 6 carbon atoms.
  • Examples of Ci -6 alkyl include methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-methyl- propyl and tert-butyl.
  • substituted Ci -6 alkyl include e.g. fluoromethyl and hy- droxymethyl.
  • hydroxy is intended to indicate -OH.
  • a "monocyclic moiety” is intended to cyclic moiety comprising only one ring, said cyclic moiety can be saturated or unsaturated.
  • ring atom is intended to indicate the atoms constituting a ring, and ring atoms are selected from C, N, O and S.
  • benzene and toluene both have 6 carbons as ring atoms whereas pyridine has 5 carbons and 1 nitrogen as ring atoms.
  • enantiomeric excess represents the % excess of a compound in a mixture of compound enantiomers. If for example an enantiomeric excess is 90% then the ratio of the compound to its enantiomer is 95:5 and if an enantiomeric excess is 95% then the ratio of the compound to its enantiomer is 97.5:2.5. Likewise, “diastereomeric excess” represents % excess of a compound in a mixture of compound diastereomers.
  • pharmaceutically acceptable salts include pharmaceutically acceptable acid addition salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids.
  • suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroace- tic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, ma- leic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesul- fonic, p-toluenesulfonic acids, theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheo
  • pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • solid carriers include lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose.
  • liquid carriers include, but are not limited to, syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyeth- ylene and water.
  • the carrier may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the term "therapeutically effective amount" of a compound means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the administra- tion of said compound.
  • An amount adequate to accomplish this is defined as “therapeutically effective amount”.
  • Effective amounts for each purpose will depend on the severity of the dis- ease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician.
  • treatment means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder.
  • the term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or relief the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications.
  • treatment and “treating” refers to prophylactic (preventive) treatment. In another aspect, “treatment” and “treating” refers to (curative) treatment.
  • the patient to be treated is preferably a mammal, in particular a human being.
  • cognitive disorders is intended to indicate disorders characterized by abnormalities in aspects of perception, problem solving, language, learning, working memory, memory, social recognition, attention and pre-attentional processing, such as by not limited to Attention Deficit Hyperactivity Disorder (ADHD), autism spectrum disorders, Alzheimer's disease (AD), mild cognitive impairment (MCI), age associated memory impairment (AAMI), senile dementia, vascular dementia, frontotemporal lobe dementia, Pick's disease, dementia associated with Lewy bodies, and dementia associated with Down's syn- drome, cognitive impairment associated with Multiple Sclerosis, cognitive impairment in epilepsy, cognitive impairment associated with fragile X, cognitive impairment associated with neurofibromatosis, cognitive impairment associated with Friedreich's Ataxia, progressive supranuclear palsy (PSP), HIV associated dementia (HAD), HIV associated cognitive impairment (HIV-CI), Huntington's Disease, Parkinson's disease (PD), obsessive-compulsive dis- order (OCD), traumatic brain injury, epilepsy, post
  • the cognitive enhancing properties of a compound can be assessed e.g. by the atten- tional set-shifting paradigm which is an animal model allowing assessment of executive func- tioning via intra-dimensional (ID) versus extra-dimensional (ED) shift discrimination learning.
  • the study can be performed by testing whether the compound is attenuating "attentional per- formance impairment" induced by subchronic PCP administration in rats as described by Rodefer, J.S. et al., Eur. J. Neurosci. 2005, 21 :1070-1076.
  • autism spectrum disorders is intended to indicate disorders characterized by widespread abnormalities of social interactions and verbal and non-verbal communication, as well as restricted interests, repetitive behavior and attention, such as by not limited to autism, Asperger syndrome, Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS), Rett syndrome, Angelmann syndrome, fragile X, DiGeorge syndrome and Childhood Disintegrative Disorder.
  • PDD-NOS Pervasive Developmental Disorder Not Otherwise Specified
  • inflammatory disorders is intended to indicate disor- ders characterized by abnormalities in the immune system such as by not limited to, allergic reactions and myopathies resulting in abnormal inflammation as well as non-immune diseases with etiological origins in inflammatory processes are thought to include by not be limited to cancer, atherosclerosis, osteoarthritis, rheumatoid arthritis and ischaemic heart disease.
  • PAMs positive allosteric modulators
  • NNRs may be dosed in combination with other drugs in order to achieve more efficacious treatment in certain patient populations.
  • An a7 NNR PAM may act synergis- tically with another drug, this has been described in animals for the combination of compounds affecting nicotinic receptors, including a7 NNRs and D2 antagonism (Wiker, C, Int. J. Neuropsychopharmacol. 2008, 1 1 (6):845-50).
  • compounds of the present invention may be useful treatment in the combination with another drug e.g. selected from acetylcholinesterase inhibitors, glutamate receptor an- tagonists, dopamine transport inhibitors, noradrenalin transport inhibitors, D2 antagonists, D2 partial agonists, PDE10 antagonists, 5-HT2A antagonists, 5-HT6 antagonists and KCNQ antagonists, lithium, sodium channel blockers, GABA signalling enhancers.
  • another drug e.g. selected from acetylcholinesterase inhibitors, glutamate receptor an- tagonists, dopamine transport inhibitors, noradrenalin transport inhibitors, D2 antagonists, D2 partial agonists, PDE10 antagonists, 5-HT2A antagonists, 5-HT6 antagonists and KCNQ antagonists, lithium, sodium channel blockers, GABA signalling enhancers.
  • compounds of the present invention are used for treatment of patients who are already in treatment with another drug selected from the list above.
  • compounds of the present invention are adapted for administration simultaneous with said other drug.
  • compounds of the present invention are adapted for administration sequentially with said other drug.
  • compounds of the present invention are used as the sole medicament in treatment of a patient.
  • compounds of the present invention are used for treatment of patients who are not already in treatment with another drug selected from the list above.
  • the first embodiment is denoted E1
  • the second embodiment is denoted E2 and so forth.
  • R1 , R2, R3, R4 and R5 are H;
  • R6 is selected from methyl and hydroxymethyl
  • A7 is C-R7, A8 is N and A9 is C-R9 ;
  • R7, R10 and R1 1 are H
  • R9 is OR12, wherein R12 represents a monocyclic saturated ring moiety having 4-6 ring atoms wherein one of said ring atoms is O and the rest is C;
  • a compound according to any of embodiments 1 -1 1 for use in the treatment of a disease or disorder selected from psychosis; schizophrenia; cognitive disorders; cognitive impairment associated with schizophrenia; attention deficit hyperactivity disorder (ADHD); au- tism spectrum disorders, Alzheimer's disease (AD); mild cognitive impairment (MCI); age associated memory impairment (AAMI); senile dementia; AIDS dementia; Pick's disease; dementia associated with Lewy bodies; dementia associated with Down's syndrome; Huntington's disease; Parkinson's disease (PD); obsessive-compulsive disorder (OCD); traumatic brain injury; epilepsy; post-traumatic stress; Wernicke-Korsakoff syndrome (WKS); post- traumatic amnesia; cognitive deficits associated with depression; diabetes, weight control, inflammatory disorders, reduced angiogenesis; amyotrophic lateral sclerosis and pain.
  • a disease or disorder selected from psychosis; schizophrenia; cognitive disorders; cognitive impairment associated with schizophrenia; attention deficit hyperactivity disorder (ADHD); au- tism spectrum disorders, Alzheimer'
  • a disease or disorder is selected from schizophrenia; AD; ADHD; autism spectrum disorders; PD; amyotrophic lateral sclerosis; Huntington's disease; dementia associated with Lewy bodies and pain.
  • E16 The compound according to embodiment 15, wherein said disease or disorder is selected from schizophrenia; AD; ADHD and autism spectrum disorders.
  • E18 The compound according to any of embodiments 1 -1 1 , for use concomitantly or sequentially with a therapeutically effective amount of a compound selected from the list con- sisting of acetylcholinesterase inhibitors; glutamate receptor antagonists; dopamine transport inhibitors; noradrenalin transport inhibitors; D2 antagonists; D2 partial agonists; PDE10 antagonists; 5-HT2A antagonists; 5-HT6 antagonists; KCNQ antagonists; lithium; sodium channel blockers and GABA signaling enhancers in the treatment of a disease or disorder according to any of embodiments 14-17.
  • a pharmaceutical composition comprising a compound according to any of embodiments 1 -1 1 , and one or more pharmaceutically acceptable carrier or excipient.
  • composition according to embodiment 19 which composition additionally com- prises a second compound selected from the list consisting of acetylcholinesterase inhibitors; glutamate receptor antagonists; dopamine transport inhibitors; noradrenalin transport inhibitors; D2 antagonists; D2 partial agonists; PDE10 antagonists; 5-HT2A antagonists; 5-HT6 antagonists; KCNQ antagonists; lithium; sodium channel blockers and GABA signaling enhancers.
  • acetylcholinesterase inhibitors glutamate receptor antagonists
  • dopamine transport inhibitors noradrenalin transport inhibitors
  • D2 antagonists D2 partial agonists
  • PDE10 antagonists 5-HT2A antagonists
  • 5-HT6 antagonists 5-HT6 antagonists
  • KCNQ antagonists lithium; sodium channel blockers and GABA signaling enhancers.
  • composition according to embodiment 20, wherein said second compound is an acetylcholinesterase inhibitor is an acetylcholinesterase inhibitor.
  • a kit comprising a compound according to any of embodiments 1 -1 1 , together with a second compound selected from the list consisting of acetylcholinesterase inhibitors; glutamate receptor antagonists; dopamine transport inhibitors; noradrenalin transport inhibitors; D2 antagonists; D2 partial agonists; PDE10 antagonists; 5-HT2A antagonists; 5-HT6 antagonists; KCNQ antagonists; lithium; sodium channel blockers and GABA signaling enhancers.
  • said second compound is an acetylcholinesterase inhibitor.
  • E25 The method according to embodiment 24, wherein said disease or disorder is selected from schizophrenia; AD; ADHD; autism spectrum disorders; PD; amyotrophic lateral sclerosis; Huntington's disease; dementia associated with Lewy bodies and pain.
  • said disease or disorder is selected from schizophrenia; AD; ADHD and autism spectrum disorders.
  • E28 The method according to any of embodiments 24-27, wherein said treatment further comprises the administration of a therapeutically effective amount of a second compound selected from the list consisting of acetylcholinesterase inhibitors; glutamate receptor antagonists; dopamine transport inhibitors; noradrenalin transport inhibitors; D2 antagonists; D2 partial agonists; PDE10 antagonists; 5-HT2A antagonists; 5-HT6 antagonists; KCNQ antagonists; lithium; sodium channel blockers and GABA signaling enhancers.
  • a second compound selected from the list consisting of acetylcholinesterase inhibitors; glutamate receptor antagonists; dopamine transport inhibitors; noradrenalin transport inhibitors; D2 antagonists; D2 partial agonists; PDE10 antagonists; 5-HT2A antagonists; 5-HT6 antagonists; KCNQ antagonists; lithium; sodium channel blockers and GABA signaling enhancers.
  • a disease or disorder selected from psychosis; schizophrenia; cognitive disorders; cognitive impairment associated with schizophrenia; attention deficit hyperactivity disorder (ADHD); autism spectrum disorders, Alzheimer's disease (AD); mild cognitive impairment (MCI); age associated memory impairment (AAMI); senile dementia; AIDS dementia; Pick's disease; dementia associated with Lewy bodies; dementia associated with Down's syndrome; Huntington's disease; Parkinson's disease (PD); obsessive- compulsive disorder (OCD); traumatic brain injury; epilepsy; post-traumatic stress; Wernicke- Korsakoff syndrome (WKS); post-traumatic amnesia; cognitive deficits associated with de- pression; diabetes, weight control, inflammatory disorders, reduced angiogenesis; amyotrophic lateral sclerosis and pain.
  • ADHD attention deficit hyperactivity disorder
  • MCI mild cognitive impairment
  • AAMI age associated memory impairment
  • senile dementia AIDS dementia
  • Pick's disease dementia associated with Lewy bodies
  • dementia associated with Down's syndrome Huntington's disease
  • E31 The use according to embodiment 30, wherein said disease or disorder is selected from schizophrenia; AD; ADHD; autism spectrum disorders; PD; amyotrophic lateral sclerosis; Huntington's disease; dementia associated with Lewy bodies and pain.
  • said disease or disorder is selected from schizophrenia; AD; ADHD and autism spectrum disorders.
  • E34 The use according to any of embodiments 30-33, wherein said manufacture further comprises the use of a second compound selected from the list consisting of acetylcholinesterase inhibitors; glutamate receptor antagonists; dopamine transport inhibitors; noradrenalin transport inhibitors; D2 antagonists; D2 partial agonists; PDE10 antagonists; 5-HT2A antagonists; 5-HT6 antagonists; KCNQ antagonists; lithium; sodium channel blockers and GABA signaling enhancers.
  • a second compound selected from the list consisting of acetylcholinesterase inhibitors; glutamate receptor antagonists; dopamine transport inhibitors; noradrenalin transport inhibitors; D2 antagonists; D2 partial agonists; PDE10 antagonists; 5-HT2A antagonists; 5-HT6 antagonists; KCNQ antagonists; lithium; sodium channel blockers and GABA signaling enhancers.
  • the compounds of the invention may exist in unsolvated as well as in solvated forms in which the solvent molecules are selected from pharmaceutically acceptable solvents such as water, ethanol and the like. In general, such solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
  • the compounds of the present invention have three asymmetric centers with fixed stereochemistry indicated by the arrows below.
  • the compounds of the present invention are manufactured from two chiral intermedi- ates with one and two asymmetric centers, respectively, as illustrated by the examples below.
  • the intermediate when specifying the enantiomeric form of the intermediate, then the intermediate is in enantiomeric excess, e.g. essentially in a pure, mono- enantiomeric form. Accordingly, the resulting compounds of the invention are having a diastereomeric excess of at least 80%.
  • One embodiment of the invention relates to a compound of the invention having a diastereomeric excess of at least 80% such as at least 85%, such as at least 90%, preferably at least 95% or at least 97% with reference to the three assymetric centers indicated above.
  • the compounds of the present invention may furthermore have one or more additional asymmetric centers. It is intended that any optical isomers (i.e.
  • enantiomers or diastereomers in the form of separated, pure or partially purified optical isomers and any mixtures thereof including racemic mixtures, i.e. a mixture of stereoi- somers, which have emerged because of asymmetric centers in substituent R9, are included within the scope of the invention.
  • Racemic forms can be resolved into the optical antipodes by known methods, for example by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolv- ing racemates into the optical antipodes is based upon chromatography of an optically active matrix. The compounds of the present invention may also be resolved by the formation of diastereomeric derivatives. Additional methods for the resolution of optical isomers, known to those skilled in the art, may be used. Such methods include those discussed by J. Jaques, A. Collet and S. Wilen in "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1981 ). Optically active compounds can also be prepared from optically active starting materials.
  • geometric isomers may be formed. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are in- eluded within the scope of the invention. Likewise, molecules having a bond with restricted rotation may form geometric isomers. These are also intended to be included within the scope of the present invention.
  • the compounds of the present invention may be administered alone as a pure compound or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
  • the pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
  • compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
  • compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings.
  • Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
  • compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use.
  • Suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants, etc.
  • the compound of the present invention is administered in an amount from about 0.001 mg/kg body weight to about 100 mg/kg body weight per day.
  • daily dosages may be in the range of 0.01 mg/kg body weight to about 50 mg/kg body weight per day. The exact dosages will depend upon the frequency and mode of administration, the sex, the age the weight, and the general condition of the subject to be treated, the nature and the severity of the condition to be treated, any concomitant diseases to be treated, the desired effect of the treatment and other factors known to those skilled in the art.
  • a typical oral dosage for adults will be in the range of 0.1 -1000 mg/day of a compound of the present invention, such as 1 -500 mg/day, such as 1 -100 mg/day or 1 -50 mg/day.
  • the compounds of the invention are administered in a unit dosage form containing said compounds in an amount of about 0.1 to 500 mg, such as 10 mg, 50 mg 100 mg, 150 mg, 200 mg or 250 mg of a compound of the present invention.
  • solutions of the compound of the invention in sterile aqueous solution aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are par- ticularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
  • solid carriers are lactose, terra alba, su- crose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose.
  • liquid carriers are syrup, peanut oil, olive oil, phospho lipids, fatty acids, fatty acid amines, polyoxyethylene and water.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient.
  • the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.
  • the preparation may be tablet, e.g. placed in a hard gelatine capsule in powder or pellet form or in the form of a troche or lozenge.
  • the amount of solid carrier may vary but will usually be from about 25 mg to about 1 g.
  • the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • Tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents followed by the compression of the mixture in a conventional tabletting machine.
  • adjuvants or diluents comprise: Corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants or additives usual- ly used for such purposes such as colourings, flavourings, preservatives etc. may be used provided that they are compatible with the active ingredients.
  • the nicotinic acetylcholine receptor a7 is a calcium-permeable ion channel, whose activity can be measured by over expression in mammalian cells or oocytes. These two individ- ual assays are described in Example 1 and 2, respectively.
  • DMEM/F12 Dulbecco's Modified Eagle Medium
  • F12 Nutrient mix
  • FBS Fetal Bovine Serum
  • Pen Penicillin
  • Strep streptomycin
  • G-418 Geneticin
  • HBSS Hanks Balanced Salt Solution
  • HEPES (4-(2-hydroxyethyl)-1 -piperazineethanesulfonic acid)
  • FDSS7000 Functional Drug Screening System from Hamamatso
  • OR2 buffer Oocyte Ringer.
  • the nicotinic acetylcholine receptor a7 is a calcium-permeable ion channel, whose ac- tivity can be measured by over expression in mammalian cells or oocytes.
  • the human a7 receptor is stably expressed in the rat GH4C1 cell line.
  • the assay was used to identify positive allosteric modulators (PAMs) of the a7 receptor. Activation of the channel was measured by loading cells with the calcium-sensitive fluorescent dye Calcium-4 (Assay kit from Molecular Devices), and then measuring real-time changes in fluorescence upon treatment with test compounds.
  • the cell line ChanClone GH4C1 -nAChRalpha7 from Genionics was seeded from frozen stock in 384-well plates in culture media 2-3 days before experiment to form an approximately 80% confluent layer on the day of experiment.
  • the cell culture were split into "22.5cm x 22.5cm"-plates with approximately 100x10 3 cells/cm 2 . After four days incubation in a humidified incubator at 37°C and 5% C0 2 , it had grown to an 80-90% confluent layer, and the cells were harvested.
  • Culture media :
  • the media was poured off and the plate washed with PBS and left to drain. 5 mL Trypsin was added, cells were washed and incubated (at room temperature) for about 10 seconds. Trypsin was poured of quickly and the cells were incubated for 2 minutes at 37°C (if the cells were not already detached). Cells were resuspended in 10 mL culture media and transfered to 50 mL tubes.
  • the cell suspension was counted (NucleoCounter, total cell count) from the first plates to estimate the total cell number of the whole batch.
  • the cells were seeded in 384 well plates with 30 [ ⁇ Uwe ⁇ (30000 cells/well) while stirring the cell suspension or otherwise preventing the cells from precipitating.
  • the plates were incubated at room temperature for 30-45 minutes.
  • the plates were placed in incubator for two days (37°C and 5% C0 2 ).
  • the loading buffer was 5% v/v Calcium-4 Kit and 2.5 mM Probenecid in assay buffer.
  • the assay buffer was HBSS with 20 mM HEPES, pH 7.4 and 3 mM CaCI 2 .
  • the agonist acetylcholine was added to a final concentration of 20 ⁇ (-EC100).
  • the Ex480-Em540 was measured with 1 second intervals.
  • the baseline was made of 5 frames before addition of test compounds, and 95 frames more were made before addition of acetylcholine.
  • the measurement stopped 30 frames after the 2 nd addition.
  • Results were calculated as % modulation of test compound compared to the reference PNU-120596 set to 100%. From these data EC 50 curves were generated giving EC 50 , hill and maximum stimulation.
  • the compounds of the invention were shown to be PAMs of the ol receptor.
  • the compounds of the present invention characterized in the flux assay generally possess EC 50 values below 20.000 nM or less such as below 10.000 nM. Many compounds, in fact have EC 50 values below 5.000 nM. Table 2 shows EC 50 values for exemplified compounds of the invention.
  • Oocytes are surgically removed from mature female Xenepus laevis anaesthetized in 0.4% MS-222 for 10 - 15 min. The oocytes are then digested at room temperature for 2-3 hours with 0.5 mg/mL collagenase (type IA Sigma-Aldrich) in OR2 buffer (82.5 mM NaCI, 2.0 mM KCI, 1 .0 mM MgCI 2 and 5.0 mM HEPES, pH 7.6).
  • Oocytes avoid of the follicle layer are selected and incubated for 24 hours in Modified Barth's Saline buffer (88 mM NaCI, 1 mM KCI, 15 mM HEPES, 2.4 mM NaHC0 3 , 0.41 mM CaCI 2 , 0.82 mM MgS0 4 , 0.3 mM Ca(N0 3 ) 2 ) supplemented with 2 mM sodium pyruvate, 0.1 U/l penicillin and 0.1 ⁇ g/l streptomycin.
  • Modified Barth's Saline buffer 88 mM NaCI, 1 mM KCI, 15 mM HEPES, 2.4 mM NaHC0 3 , 0.41 mM CaCI 2 , 0.82 mM MgS0 4 , 0.3 mM Ca(N0 3 ) 2
  • 2 mM sodium pyruvate 0.1 U/l penicillin and 0.1 ⁇ g/l streptomycin.
  • Stage IV oocytes are identified and injected with 4.2 - 48 nl of nuclease free water containing 0.1 - 1 .2 ng of cRNA coding for human a7 nACh receptors or 3.0 - 32 ng of cRNA coding for rat a7 nACh receptors and incubated at 18°C for 1 - 10 days when they are used for electrophysiological recordings. Electrophysiological recordings of a7 nACh receptors expressed in oocytes.
  • Oocytes are used for electrophysiological recordings 1 - 10 days after injection.
  • Oocytes are placed in a 1 mL bath and perfused with Ringer buffer (1 15 mM NaCI, 2.5 mM KCI, 10 mM HEPES, 1.8 mM CaCI 2 , 0.1 mM MgCI 2 , pH 7.5). Cells are impaled with agar plugged 0.2 - 1 ⁇ electrodes containing 3 M KCI and voltage clamped at -90 mV by a GeneClamp 500B amplifier. The experiments are performed at room temperature. Oocytes are continuously perfused with Ringer buffer and the drugs are applied in the perfusate. ACh (30 ⁇ ) applied for 30 sec are used as the standard agonist for activation of the a7 nACh receptors.
  • the new test compound (10 ⁇ or 30 ⁇ ) are applied for 1 min of pre-application allowing for evaluation of agonistic activity followed by 30 sec of co-application with ACh (30 ⁇ ) allowing for evaluation of PAM activity.
  • the response of co-application was compared to the agonistic response obtained with ACh alone.
  • the drug induced effects on both the peak response and the total charge (AUC) response are calculated thus giving the effect of drug induced PAM activity as fold modulation of the control response.
  • doses-response curves can be performed for evaluation of max-fold modulation and EC 50 values for both peak and AUC responses.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (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)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention porte sur des composés répondant à la formule (I) dans laquelle R1, R2, R3, R4 et R5 représentent H; R6 est choisi entre un groupe méthyle et un groupe hydroxyméthyle; A7 représente C-R7, A8 représente N et A9 représente C-R9; R7, R10 et R11 représentent H; R9 représente OR12, R12 représentant une fraction cyclique saturée monocyclique ayant 4-6 atomes de cycle, l'un desdits atomes de cycle étant O et le reste étant C; et des sels pharmaceutiquement acceptables de ceux-ci utiles en thérapie, sur des compositions comprenant lesdits composés et sur des procédés de traitement de maladies comprenant l'administration desdits composés. Les composés selon l'invention sont des modulateurs allostériques positifs (PAM) du récepteur nicotinique à l'acétylcholine α7.
PCT/EP2013/064093 2012-07-06 2013-07-04 Nouveaux modulateurs allostériques positifs de récepteur nicotinique à l'acétylcholine WO2014006120A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/EP2012/063219 WO2013007621A1 (fr) 2011-07-08 2012-07-06 Modulateurs allostériques positifs des récepteurs nicotiniques d'acétylcholine
EPPCT/EP2012/063219 2012-07-06

Publications (1)

Publication Number Publication Date
WO2014006120A1 true WO2014006120A1 (fr) 2014-01-09

Family

ID=48745970

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/EP2013/064093 WO2014006120A1 (fr) 2012-07-06 2013-07-04 Nouveaux modulateurs allostériques positifs de récepteur nicotinique à l'acétylcholine
PCT/EP2013/064088 WO2014006117A1 (fr) 2012-07-06 2013-07-04 Nouveaux modulateurs allostériques positifs de récepteur nicotinique à l'acétylcholine

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/EP2013/064088 WO2014006117A1 (fr) 2012-07-06 2013-07-04 Nouveaux modulateurs allostériques positifs de récepteur nicotinique à l'acétylcholine

Country Status (2)

Country Link
AR (2) AR091679A1 (fr)
WO (2) WO2014006120A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9840481B2 (en) 2016-03-22 2017-12-12 Merck Sharp & Dohme Corp. Allosteric modulators of nicotinic acetylcholine receptors
US11332463B2 (en) 2018-05-01 2022-05-17 Merck Sharp & Dohme Corp. Spiropiperidine allosteric modulators of nicotinic acetylcholine receptors

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009043784A1 (fr) 2007-10-04 2009-04-09 F. Hoffmann-La Roche Ag Dérivés de cyclopropyl aryl amides et leurs utilisations
WO2010137351A1 (fr) 2009-05-29 2010-12-02 Raqualia Pharma Inc. Dérivés de carboxamide substitués par aryle comme inhibiteurs des canaux calciques ou sodiques
WO2011044195A1 (fr) * 2009-10-07 2011-04-14 Bristol-Myers Squibb Company Modulateurs du récepteur 88 couplé à une protéine g
WO2013007621A1 (fr) 2011-07-08 2013-01-17 H. Lundbeck A/S Modulateurs allostériques positifs des récepteurs nicotiniques d'acétylcholine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009043784A1 (fr) 2007-10-04 2009-04-09 F. Hoffmann-La Roche Ag Dérivés de cyclopropyl aryl amides et leurs utilisations
WO2010137351A1 (fr) 2009-05-29 2010-12-02 Raqualia Pharma Inc. Dérivés de carboxamide substitués par aryle comme inhibiteurs des canaux calciques ou sodiques
WO2011044195A1 (fr) * 2009-10-07 2011-04-14 Bristol-Myers Squibb Company Modulateurs du récepteur 88 couplé à une protéine g
WO2013007621A1 (fr) 2011-07-08 2013-01-17 H. Lundbeck A/S Modulateurs allostériques positifs des récepteurs nicotiniques d'acétylcholine

Non-Patent Citations (38)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 1995, MACK PUB- LISHING CO.
ARIAS, H.R., INT. J. BIOCHEM. CELL BIOI., vol. 41, no. 7, 2009, pages 1441 - 51
BERGE, S.M. ET AL., J. PHARM. SCI., vol. 66, 1977, pages 2
BITNER, R.S., J PHARMACOL EXP THER., vol. 334, no. 3, January 2010 (2010-01-01), pages 875 - 86
BROAD, L. M. ET AL., DRUGS OF THE FUTURE, vol. 32, no. 2, 2007, pages 161 - 170
DEUTSCH, S.I., CLIN NEUROPHAR- MACOL., vol. 33, no. 3, 2010, pages 114 - 20
DINKLO, T., J. PHARMACOL. EXP. THER., vol. 336, no. 2, 2011, pages 560 - 74
FAGHIH, R., RECENT PAT CNS DRUG DISCOV, vol. 2, no. 2, 2007, pages 99 - 106
FAGHIH, R., RECENT PAT CNS DRUG DISCOV., vol. 2, no. 2, 2007, pages 99 - 106
FEUERBACH, D., NEUROPHARMACOLOGY, vol. 56, no. 1, 2009, pages 254 - 63
FREEDMAN, R. ET AL., AM J PSYCHIATRY., vol. 165, no. 8, 2008, pages 1040 - 7
GOTTI, C. ET AL., BIOCHEMICAL PHARMACOLOGY, vol. 78, 2009, pages 703 - 711
GOTTI, C. ET AL., PROG. NEUROBIOL., vol. 74, 2004, pages 363 - 396
HAJOS, M. ET AL., J. PHARMACOL EXP THER., vol. 312, 2005, pages 1213 - 22
HAYDAR, S.N. ET AL., CURR TOP MED CHEM., vol. 10, no. 2, 2010, pages 144 - 52
HEVERS, W. ET AL., MOL. NEUROBIOL., vol. 18, 1998, pages 35 - 86
HURST ET AL., NEUROSCI, vol. 25, no. 17, 2005, pages 4396 - 405
HURST, R. S. ET AL., J. NEUROSCI., vol. 25, 2005, pages 4396 - 4405
J. JAQUES; A. COLLET; S. WILEN: "Enantiomers, Racemates, and Resolutions", 1981, JOHN WILEY AND SONS
JONNALA, R. B. ET AL., J. NEUROSCI. RES., vol. 66, 2001, pages 565 - 572
KARACONJI, I.B. ET AL., ARH HIG RADA TOKSIKOL., vol. 56, no. 4, 2005, pages 363 - 71
KELLER, J. J. ET AL., BE- HAV. BRAIN RES., vol. 162, 2005, pages 143 - 52
LIU, Q.-S. ET AL., PNAS, vol. 98, 2001, pages 4734 - 4739
MARRERO, M.B. ET AL., J. PHARMACOL. EXP. THER., vol. 332, no. 1, 2010, pages 173 - 80
NG, H.J. ET AL., PROC. NATL. ACAD. SCI. USA., vol. 104, no. 19, August 2007 (2007-08-01), pages 8059 - 64
OLINCY, A. ET AL., ARCH GEN PSYCHIATRY., vol. 63, no. 6, 2006, pages 630 - 8
PAPKE, R.L. ET AL., J PHARMACOL EXP THER., vol. 329, no. 2, 2009, pages 791 - 807
PICHAT, P. ET AL., NEUROPSYCHOPHARMACOLOGY., vol. 32, no. 1, 2007, pages 17 - 34
POORTHUIS RB, BIOCHEM PHARMACOL, vol. 78, no. 7, January 2009 (2009-01-01), pages 668 - 76
RODEFER, J.S. ET AL., EUR. J. NEUROSCI., vol. 21, 2005, pages 1070 - 1076
ROSAS-BALLINA, M., J. INTERN MED., vol. 265, no. 6, 2009, pages 663 - 79
SHIMO- HAMA, S., BIOL PHARM BULL., vol. 32, no. 3, 2009, pages 332 - 6
SHIMOHAMA, S., BRAIN RES., vol. 779, 1998, pages 359 - 363
THOMSEN, M.S. ET AL., CURR PHARM DES., vol. 16, no. 3, January 2010 (2010-01-01), pages 323 - 43
TIMMERMANN, D.B., J. PHARMACOL. EXP. THER., vol. 323, no. 1, 2007, pages 294 - 307
TIZABI, Y., BIOL PSYCHIATRY., vol. 51, no. 2, 2002, pages 164 - 71
VINCLER, M., EXP. OPIN.LNVEST. DRUGS, vol. 14, no. 10, 2005, pages 1191 - 1 198
WIKER, C., INT. J. NEUROPSYCHOPHARMACOL, vol. 11, no. 6, 2008, pages 845 - 50

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9840481B2 (en) 2016-03-22 2017-12-12 Merck Sharp & Dohme Corp. Allosteric modulators of nicotinic acetylcholine receptors
US9926285B2 (en) 2016-03-22 2018-03-27 Merck Sharp & Dohme Corp. Allosteric modulators of nicotinic acetylcholine receptors
US11332463B2 (en) 2018-05-01 2022-05-17 Merck Sharp & Dohme Corp. Spiropiperidine allosteric modulators of nicotinic acetylcholine receptors

Also Published As

Publication number Publication date
WO2014006117A1 (fr) 2014-01-09
AR091678A1 (es) 2015-02-18
AR091679A1 (es) 2015-02-18

Similar Documents

Publication Publication Date Title
US9023870B2 (en) Positive allosteric modulators of nicotinic acetylcholine receptor
AU2017203014B2 (en) Positive allosteric modulators of nicotinic acetylcholine receptor
WO2014006120A1 (fr) Nouveaux modulateurs allostériques positifs de récepteur nicotinique à l'acétylcholine
US20150315130A1 (en) New positive allosteric modulators of nicotinic acetylcholine receptor
WO2013004617A1 (fr) Pyrazolopyridines utiles dans le traitement de troubles du système nerveux central
OA17441A (en) Positive allosteric modulators of nicotinic acetylcholine receptor.
OA19541A (en) Positive Allosteric Modulators of Nicotinic Acetylcholine Receptor.

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: 13734071

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: 13734071

Country of ref document: EP

Kind code of ref document: A1