WO2012131031A1 - Nouveaux effecteurs allostériques positifs du récepteur nicotinique de l'acétylcholine - Google Patents

Nouveaux effecteurs allostériques positifs du récepteur nicotinique de l'acétylcholine Download PDF

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WO2012131031A1
WO2012131031A1 PCT/EP2012/055775 EP2012055775W WO2012131031A1 WO 2012131031 A1 WO2012131031 A1 WO 2012131031A1 EP 2012055775 W EP2012055775 W EP 2012055775W WO 2012131031 A1 WO2012131031 A1 WO 2012131031A1
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methyl
indol
carboxamide
isoxazole
pyrazole
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PCT/EP2012/055775
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Anette Graven Sams
Jørgen ESKILDSEN
Jesper Frank BASTLUND
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H. Lundbeck A/S
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Publication of WO2012131031A1 publication Critical patent/WO2012131031A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • 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
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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 a7 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, a2 through a 7 and ⁇ 2 through ⁇ 4, prominently exist in the mammalian brain. Many functionally distinct nAChR complexes exist, for example five a7 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, i.e., 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., Behav. Brain Res. 2005, 162: 143-52; Haydar S.N. et al., Curr Top Med Chem.
  • 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
  • NNR ligands include a7 ligands, have also been implicated in weight control, diabetis inflammation, angiogenesis and as potential analgesics (Marrero, M.B. et al., J. Pharmacol Exp Ther. 2010, 332(1): 173-80; Vincler, M., Exp. Opin. Invest.
  • 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 gastro- intestinal 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 activation 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 selec- tively 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).
  • Gen- istein 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 defi- cits 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.
  • NNR PAMs include derivatives of quinuclidine, indole, benzopyrazole, thiazole, and benzoisothiazoles (Hurst, R. S. et al., J. Neurosci. 2005, 25: 4396-4405; Faghih, R., Recent Pat CNS Drug Discov. 2007, 2(2):99-106; Timmermann, D.B., J Pharmacol Exp Ther. 2007 Oct;323(1):294-307; Ng, H.J. et al., Proc Natl Acad Sci U S A. 2007, 104(19): 8059-64; Dinklo, T., J Pharmacol Exp Ther. 2011 , 336(2): 560-74.).
  • WO 01/32619 discloses that compounds of the following core structure possess PAM activity
  • WO 2009/100294 discloses compounds with the core structure
  • ⁇ 7 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.
  • KCNQ channel openers have been associated with a complex range of potential side-effects including but not limited to effects on, the cardiovascular system (Mackie AR, Mol Pharmacol. 2008 74(5) :1 171-9), bladder function (Gopalakrish- nan M, Expert Opin Ther Targets. 2004 8(5):437-58) and hypothermia (Kristensen L, Neuro- sci Lett.
  • KCNQ channel blockers have been suggested to have pro-cognition potential (Gribkoff VK, Expert Opin Ther Targets. 2003, 7(6):737-48), which points to a possible disruptive effect of KCNQ channel openers on cognition.
  • pro-cognition potential Gribkoff VK, Expert Opin Ther Targets. 2003, 7(6):737-48
  • KCNQ channel openers There is therefore a need for new a7 NNR PAMs which show reduced effect as openers of KCNQ channels.
  • Compounds with such improvements are likely to benefit from e.g. reduced side effects, enlarged therapeutic index, improved tolerability and improved compliance.
  • the present invention discloses novel compounds that are PAMs of a7 NNRs.
  • the compounds of the invention furthermore possess improved properties compared to known NNR PAMs.
  • the invention discloses pharmaceutical compositions, methods of preparation and uses of said compounds.
  • furan-2-carboxylic acid (2-methyl-1 H-indol-5-ylmethyl)-amide
  • furan-2-carboxylic acid (1 ,2-dimethyl-1 H-indol-5-ylmethyl)-amide
  • the objective of the present invention is to provide compounds that are positive allos- teric modulators of the nicotinic acetylcholine receptor subtype a7.
  • a further objective of the present invention is to provide compounds which have such activity, and which have improved properties compared to known PAMs of the a7 NNR.
  • R1 represents H, trifluoromethyl, difluoromethyl, Ci -4 alkyl, C 2 . 4 alkenyl or C 2 . 4 alkynyl
  • R2 represents H, Ci -4 alkyl, C 2 _ 4 alkenyl, C 2 . 4 alkynyl, halogen or cyano, wherein said Ci -4 alkyl, C 2 - 4 alkenyl or C 2 . 4 alkynyl is optionally substituted with one or more substituents selected from chlorine and fluorine;
  • R3, R4, R5 and R6 are selected independently from H, Ci -4 alkyl, C 2 _ 4 alkenyl, C 2 . 4 alkynyl, halogen and cyano, wherein said Ci -4 alkyl, C 2 _ 4 alkenyl or C 2 . 4 alkynyl is optionally substituted with one or more substituents selected from chlorine and fluorine;
  • R7 represents H, methyl, trifluoromethyl or hydroxy methyl
  • Q represents a heteroaryl with 5 ring atoms, wherein 1 , 2 or 3 ring atoms are selected inde- pendently from O, N and S, wherein said heteroaryl may be optionally substituted on its carbon atoms with one or more substituents represented by R10, and provided that said heteroaryl cannot be 1 ,2,3 triazolyl or imidazolyl;
  • each R10 is independently selected from Ci -4 alkyl, C 2 _ 4 alkenyl, C 2 . 4 alkynyl, Ci_ 4 alkoxy, Ci. 4 fluoroalkoxy, halogen and oxo, wherein said Ci -4 alkyl, C 2 . 4 alkenyl or C 2 . 4 alkynyl is optionally substituted with one or more substituents selected from fluorine, Ci_ 4 alkoxy and Ci.
  • each R1 1 is independently selected from Ci -4 alkyl and a monocyclic saturated ring moiety having 4-6 ring atoms wherein one of said ring atoms may be O and the rest is C, and wherein said Ci-4 alkyl may be optionally substituted with one or more substituents selected from fluorine, Ci_ 4 alkoxy and Ci_ 4 fluoroalkoxy;
  • two R10 or one R10 and one R1 1 may, when sitting on neighbouring ring atoms and when represented by Ci_ 4 alkyl be linked together by a carbon bond to form a fused ring system; and pharmaceutically acceptable salts thereof;
  • furan-2-carboxylic acid (2-methyl-1 H-indol-5-ylmethyl)-amide
  • furan-2-carboxylic acid (1 ,2-dimethyl-1 H-indol-5-ylmethyl)-amide
  • the invention relates to a compound according to formula [I], and pharmaceutically acceptable salts thereof, for use in therapy.
  • 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 disor- ders, 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); traumatic brain injury; epilepsy; post-traumatic stress; Wernicke-Korsakoff syndrome (WKS); post-traumatic amnesia; cognitive deficits associated with depression; dia- betes, 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
  • 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); 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, 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
  • senile dementia AIDS
  • 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); traumatic brain injury; epilepsy; post-traumatic stress; Wernicke-Korsakoff syndrome (WKS); post-traumatic amnesia; cognitive deficits associated with depression; diabetes, weight control, inflammatory disorders, re- cuted angiogenesis; amyotrophic lateral sclerosis and pain.
  • a disease or disorder selected from Psychosis; Schizophrenia; cognitive disorders; cognitive impairment associated with schizophrenia; Attention Deficit Hyperactivity
  • optionally substituted means that the indicated moiety may or may not be substituted, and when substituted is mono-, di-, or tri-substituted, such as with 1 , 2 or 3 substituents.
  • the substituent is independently selected from the group consisting of Ci -4 alkyl, C 2 . 4 alkenyl, C 2 . 4 alkynyl, phenyl, Ci_ 4 alkoxy, hydroxy, halogen and oxo. It is understood that where no substituents are indicated for an "optionally substituted” moiety, then the position is held by a hydrogen atom.
  • alkyl is intended to indicate a straight, branched and/or cyclic saturated hydrocarbon.
  • Ci -4 alkyl is intended to indicate such hydrocarbon having 1 , 2, 3 or 4 carbon atoms.
  • Examples of Ci_ 4 alkyl include methyl, ethyl, propyl, butyl, cyclo- propyl, cyclobutyl, methylcyclopropyl, 2-methyl-propyl and tert-butyl.
  • alkenyl is intended to indicate a non-aromatic, straight, branched and/or cyclic hydrocarbon comprising at least one carbon-carbon double bond.
  • C 2 - 4 alkenyl is intended to indicate such hydrocarbon having 2, 3 or 4 carbon atoms.
  • Examples of C 2 . 4 alkenyl include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl and 3-butenyl.
  • alkynyl is intended to indicate a non-aromatic, straight, branched and/or cyclic hydrocarbon comprising at least one carbon-carbon triple bond and optionally also one or more carbon-carbon double bonds.
  • C 2 - 4 alkynyl is intended to indicate such hydrocarbon having 2, 3 or 4 carbon atoms. Examples of C 2 . 4 alkynyl include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and 3-butynyl.
  • hydroxy is intended to indicate -OH.
  • alkoxy is intended to indicate a moiety of the formula -OR', wherein R' indicates alkyl as defined above.
  • Ci_ 4 alkoxy is intended to indicate such moiety wherein the alkyl part has 1 , 2, 3 or 4 carbon atoms.
  • Examples of “Ci_ 4 alkoxy” include methoxy, ethoxy, n-butoxy and tert-butoxy.
  • fluoroalkoxy indicates an alkoxy as defined above substituted with one or more fluorine atoms per carbon atom. Examples include trifluoromethoxy and 2,2,2-trifluoroethoxy.
  • halo and halogen are used interchangeably and refer to fluorine, chlorine, bromine or iodine.
  • cyano indicates the group -C ⁇ N, which consists of a carbon atom triple-bonded to a nitrogen atom.
  • a "5 membered heteroaryl” is intended to indicate a 5 mem- bered ring wherein 1 , 2 or 3 ring atoms are selected from O, N or S.
  • Examples of 5 membered heteroaryls of the present invention include thiophenyl, pyrrolyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl.
  • a "monocyclic moiety" is intended to indicate a ring formed structure comprising only one ring.
  • a "fused ring system” is intended to indicate a system of monocyclic rings that share their connecting bonds.
  • Said monocyclic rings can be aromatic or non- aromatic and they can comprise one or more atoms selected from N, O and S.
  • One example of a "fused ring system” of the present invention is 5,6-Dihydro-4H-pyrrolo[1 ,2-b]pyrazole.
  • 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.
  • heteroatom means a nitrogen, oxygen or sulfur atom.
  • Examples of 5 membered heteroaromats substituted with an oxo include 2,4-Dihydro-pyrazol-3-one, , 3H-Thiazol-2-one, 4H-lsothiazol-5- one, 3H-Oxazol-2-one, 4H-lsoxazol-5-one.
  • deuterium indicates the atomic isotope of hydrogen consisting of one proton and one neutron in its nucleus, and thus having an approximate weight of two (2).
  • Deuterium is represented as D or 2 H.
  • An example of a substituent labeled with deuterium is trideuteriomethyl (MeD 3 ) wherein the three hydrogens in methyl are the 2 H isotopes.
  • pharmaceutically acceptable salts include pharmaceutical ac- ceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium 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, maleic, 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-bromotheophyl
  • compositions include the pharmaceutically acceptable salts listed in Berge, S.M. et al., J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
  • metal salts include lithium, sodium, potassium, magnesium salts and the like.
  • ammonium and alkylated ammonium salts include ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl-, n-butyl-, sec-butyl-, tert-butyl-, tetrame- thylammonium salts and the like.
  • 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, poly- oxyethylene 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 administration 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 disease 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 disor- der.
  • 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 under- stood 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.
  • the patient to be treated is preferably a mammal, in particular a human being.
  • the term "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 disor- ders, 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 syndrome, 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
  • 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 disorders 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 Sep; 11 (6): 845-50).
  • compounds of the present invention may be useful treatment in the combination with e.g. acetylcholinesterase inhibitors, glutamate receptor antagonists, 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.
  • acetylcholinesterase inhibitors e.g. acetylcholinesterase inhibitors, glutamate receptor antagonists, 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 subjects who are already in treatment with another drug. In one embodiment, compounds of the present invention are used as the sole medicament in treatment of a subject. In one embodiment, compounds of the present invention are used for treatment of subjects who are not already in treatment with another drug. In one embodiment, compounds of the present invention are adapted for administration simultaneous with another drug. In one embodiment com- pounds of the present invention are adapted for administration sequentially with another drug.
  • the first embodiment is denoted E1
  • the second embodiment is denoted E2 and so forth.
  • R1 represents H, trifluoromethyl, difluoromethyl, Ci -4 alkyl, C ⁇ alkenyl or C ⁇ alkynyl
  • R2 represents H, Ci -4 alkyl, C ⁇ alkenyl, C ⁇ alkynyl, halogen or cyano, wherein said Ci -4 alkyl, C 2 - 4 alkenyl or C ⁇ alkynyl is optionally substituted with one or more substituents selected from chlorine and fluorine
  • R3, R4, R5 and R6 are selected independently from H, Ci -4 alkyl, C 2 . 4 alkenyl, C 2 .
  • Ci -4 alkyl, C 2 _ 4 alkenyl or C 2 . 4 alkynyl is optionally substituted with one or more substituents selected from chlorine and fluorine;
  • R7 represents H, methyl, trifluoromethyl or hydroxy methyl
  • Q represents a heteroaryl with 5 ring atoms, wherein 1 , 2 or 3 ring atoms are selected independently from O, N and S, wherein said heteroaryl may be optionally substituted on its carbon atoms with one or more substituents represented by R10, and provided that said heteroaryl cannot be 1 ,2,3 triazolyl or imidazolyl;
  • each R10 is independently selected from Ci -4 alkyl, C 2 _ 4 alkenyl, C 2 . 4 alkynyl, Ci_ 4 alkoxy, Ci. 4 fluoroalkoxy, halogen and oxo, wherein said Ci -4 alkyl, C 2 . 4 alkenyl or C 2 . 4 alkynyl is optionally substituted with one or more substituents selected from fluorine, Ci_ 4 alkoxy and Ci.
  • each R1 1 is independently selected from Ci -4 alkyl and a monocyclic saturated ring moiety having 4-6 ring atoms wherein one of said ring atoms may be O and the rest is C, and wherein said Ci -4 alkyl may be optionally substituted with one or more substituents selected from fluorine, Ci -4 alkoxy and Ci -4 fluoroalkoxy;
  • two R10 or one R10 and one R1 1 may, when sitting on neighbouring ring atoms and when represented by Ci -4 alkyl be linked together by a carbon bond to form a fused ring system; and pharmaceutically acceptable salts thereof;
  • furan-2-carboxylic acid (2-methyl-1 H-indol-5-ylmethyl)-amide
  • furan-2-carboxylic acid (1 ,2-dimethyl-1 H-indol-5-ylmethyl)-amide
  • R2 represents H, Ci -2 alkyl or cyano, wherein said Ci -2 alkyl is optionally substituted with one or more fluorine;
  • R3, R4, R5 and R6 are selected independently from H, methyl and fluorine;
  • R7 represents H, methyl or trifluoromethyl;
  • Q represents a heteroaryl with 5 ring atoms, wherein 1 , 2 or 3 ring atoms are selected independently from O, N and S, wherein said heteroaryl may be optionally substituted on its carbon atoms with one or more substituents represented by R10 and provided that said het- eroaryl cannot be 1 ,2,3 triazolyl or imidazolyl;
  • each R10 is independently selected from Ci_ 4 alkyl, Ci_ 2 alkoxy, halogen and oxo, wherein said Ci_ 4 alkyl is optionally substituted with one or more substituents selected from fluorine and Ci. 2 alkoxy;
  • each R1 1 is independently selected from Ci_ 4 alkyl and a monocyclic saturated ring moiety having 4-6 ring atoms, wherein one of said ring atoms may be O and the rest is C, and wherein said Ci_ 4 alkyl may be optionally substituted with one or more substituents selected from fluorine and Ci_ 2 alkoxy;
  • two R10 or one R10 and one R1 1 may, when sitting on neighbouring ring atoms and when both are represented by Ci_ 4 alkyl be linked together by a carbon bond to form a fused ring system.
  • E5. The compound according to embodiment 4, wherein R1 is H.
  • E6. The compound according to any of embodiments 1-5, wherein four or more of R2, R3, R4, R5 and R6 are H.
  • each R10 is independently selected from Ci -4 alkyl, d. 2 alkoxy, halogen and oxo, wherein said Ci -4 alkyl is optionally substituted with one or more substituents selected from fluorine and Ci_ 2 alkoxy.
  • each R10 is independently selected from methyl, isopropyl, methoxy and oxo.
  • each R11 is independently selected from Ci -4 alkyl and a monocyclic saturated ring moiety having 4-6 ring at- oms wherein one of said ring atoms may be O and the rest is C, and wherein said Ci -4 alkyl may be optionally substituted with one or more substituents selected from fluorine and Ci. 2 alkoxy.
  • each R11 is independently se- lected from methyl, trifluoromethyl and [2,2,2]trifluoroethyl.
  • a compound according to any of embodiments 1-31 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); traumatic brain injury; epilepsy; post-traumatic stress; Wernicke-Korsakoff syndrome (WKS); post-traumatic amnesia; cognitive deficits as- sociated with depression; diabetes, weight control, inflammatory disorders, reduced angio- genesis; 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'
  • E34 The compound according to embodiment 33, wherein said 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.
  • E35 The compound according to embodiment 34, wherein said disease or disorder is selected from schizophrenia; AD; ADHD and autism spectrum disorders.
  • E36 The compound according to embodiment 35, wherein said disease or disorder is selected from negative and/or cognitive symptoms of schizophrenia.
  • E37 The compound according to any of embodiments 33-35, wherein the treatment further comprises treatment with a second compound selected from the list consisting of acetylcholi- nesterase 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 pharmaceutical composition comprising a compound according to any of embodi- ments 1-31 , and one or more pharmaceutically acceptable carrier or excipient.
  • composition according to embodiment 39 which composition additionally comprises a second compound selected from the list consisting of acetylcholinesterase inhibitors; glutamate receptor antagonists; dopamine transport inhibitors; noradrenalin transport inhibi- tors; 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 inhibi- tors
  • 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 40 wherein said second compound is an acetylcholinesterase inhibitor.
  • a kit comprising a compound according to any of embodiments 1-31 , 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.
  • E45 The method according to embodiment 44, 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.
  • disease or disorder is selected from schizophrenia; AD; ADHD and autism spectrum disorders.
  • E48 Use of a compound according to any of embodiments 1-31 , 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 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); 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's disease (AD
  • 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.
  • disease or disorder is selected from schizophrenia; AD; ADHD and autism spectrum disorders.
  • E51 The use according to embodiment 50, wherein said disease is the positive, negative and/or cognitive symptoms of schizophrenia.
  • 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.
  • isotopically labeled compounds which are identical to those claimed in formula [I], wherein one or more atoms are represented by an atom of the same element having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (e.g., 2 H, 3 H, 11 C, 13 C, 15 N, 18 F and the like).
  • the compounds of the present invention may have one or more asymmetric centres and 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 race- mic mixtures, i.e. a mixture of stereoisomers, are included within the scope of the invention.
  • any optical isomers i.e. enantiomers or diastereomers
  • any mixtures thereof including race- mic mixtures i.e. a mixture of stereoisomers
  • the compounds of the present invention may have an asymmetric centre at C-R7 indicated with an arrow below.
  • the compounds of the invention are manufactured from a chiral intermediate e.g. (+)-1-(2-Methyl-1 H-indol-5-yl)- ethylamine (IM9) with the stereochemistry around R7 as indicated by the arrow below.
  • one embodiment of the invention relates to a compound of the invention having an enantiomeric excess of at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 96%, preferably at least 98%.
  • 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 inventors have found that a broad selection of the compounds of the invention- possesses improved aqueous solubility compared to prior art compounds.
  • the choice of the substituents R1-R5 has an impact on the solubility of the compounds.
  • Especially compounds of the invention wherein R2 is not trifluoromethyl have shown to possess im- proved aqueous solubility compared to prior art compounds which are PAMs of the NNRs.
  • 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.
  • 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 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 particularly 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, sucrose, 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 pre- sented 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 usu- ally used for such purposes such as colourings, flavourings, preservatives etc. may be used provided that they are compatible with the active ingredients.
  • TMS was used as internal reference for 1 H and the solvent was used as internal reference for 13 C.
  • DMSO-d 6 or CDCI 3 was used as solvent.
  • LC-MS were run on a Sciex API 150EX equipped with APPI-source operating in positive ion mode.
  • the HPLC consisted of Shimadzu LC10-ADvp LC pumps, SPD-M20A PDA detector (operating at 254 nM) and SCL-10A system controller.
  • Autosampler was Gilson 215, Colomn oven was a Jones Chromatography 7990R and ELS detector was a Sedere Sedex 85.
  • LC-conditions The column was a Waters Symmetry C-18, 4.6 x 30 mm, 3.5 ⁇ operating at 60 °C with 3.0 ml/min of a binary gradient consisting of water + 0.05 % TFA (A) and methanol + 0.05 % TFA (B).
  • LC-MS were run on Waters Aquity UPLC-MS consisting of Waters Aquity including column manager, binary solvent manager, sample organizer, PDA detector (operating at 254 nM), ELS detector and SQ-MS equipped with APPI-source operating in positive ion mode (ESI- source, APCI-source positive ion mode, negative ion mode).
  • Waters Aquity UPLC-MS consisting of Waters Aquity including column manager, binary solvent manager, sample organizer, PDA detector (operating at 254 nM), ELS detector and SQ-MS equipped with APPI-source operating in positive ion mode (ESI- source, APCI-source positive ion mode, negative ion mode).
  • LC-conditions The column was a Acquity UPLC BEH C18 1.7 ⁇ ; 2.1x50mm operating at 60 °C with 1.2 ml/min of a binary gradient consisting of water + 0.01 % formic acid (A) and ace- tonitrile + 5% water + 0.1 % formic acid (B). Gradient: Time, min. %B
  • the column was a Acquity UPLC BEH C18 1.7 ⁇ ; 2.1x50mm operating at 60 °C with 1.2 ml/min of a binary gradient consisting of water + 0.05 % TFA (A) and acetonitrile + 5% water + 0.035% TFA (B).
  • Preparative supercritical fluid chromatography was performed on a Berger Multigram II operating at 50 ml/min at 35 °C and 100 bar backpressure using stacked injections.
  • the column was a Phenomenex Lux 5 ⁇ Cellulose-1 (250*21.2 mm).
  • the eluent was CO 2 (70 %) and methanol + 0.5 % diethylamine (30%).
  • Method F Preparative supercritical fluid chromatography (SFC) was performed on a Thar SFC-80 system operating at 80g/min and 80 bar backpressure. The column was a Chiralcel OJ-H (250X30)mm, 5 ⁇ . Co Solvent: 20% of 0.5% Isopropyl amine in Isopropanol; Diluent: Metha- nol+lsopropanol (50+50).
  • Preparative HPLC was performed on a Shimadzu LC-8A instrument fitted with a Phenomenex Gemini C18 250*21.2 ⁇ ⁇ *5 ⁇ column using water and acetonitrile as the eluents.
  • Mobile phase A water (containing 0.05% ammonia, v/v)
  • mobile phase B acetonitrile.
  • Gradient B from 25% to 55% in 25min.
  • Preparative HPLC was performed on a Shimadzu FRC-10A instrument fitted with a Synergi C18 column (250mm*50mm, 10 ⁇ ), using water and acetonitrile as the eluents.
  • Mobile phase A water (containing 0.1 % TFA, v/v)
  • mobile phase B acetonitrile.
  • Gradient 10-40% B, 0-22min; 40-70% B, 23-35 min.
  • Preparative HPLC was performed on a Gilson-GX-821 Autosampler (Pumps-333 &334 De- tector-UV) instrument fitted with a Chiralpak-IA column (250*30*5 ⁇ ) using N-Hexane and Ethanol as the eluents.
  • Mobile phase A N-Hexane (85%)
  • mobile phase B Ethanol (15%).
  • Method Isocratic with runtime 30min.
  • API 150EX single qaudrupole mass spectrometer and atmospheric pressure photo ionisation (APPI) ion source Gilson 333/334 pumps, Gilson UV/VIS 155 detector, and Gilson GX 281 sampler/fraction collector.
  • Step 1
  • 5-bromo-2-methylindole (6.00g, 28.6 mmol) was dissolved in quinoline (50 mL). Copper cyanide (7.46 g, 83.3 mmol) was added. The mixture was refluxed for 1 hour.
  • LiAIH 4 (9.70g, 255 mmol) was suspended in THF (400 mL) and the resulting suspension was cooled in a ice/water bath.
  • Step 1 A round-bottomed flask was charged with 3-methyl-4-nitrobenzyl alcohol (30.0 g, 179 mmol) in methylene chloride (200 mL). To this solution was added triethylamine (40.0 mL, 287 mmol) and 4-dimethylaminopyridine (2.20 g, 18.0 mmol). The solution was cooled to 0 °C. A solution of te/f-butyldimethylsilyl chloride (29.8 g, 197 mmol) dissolved in methylene chloride (50 mL) was added dropwise over 10 minutes keeping the internal temperature at 4-11 °C . The mixture was then stirred at room temperature over night.
  • Step-4 A round-bottomed flask was charged with (7-methyl-1 H-indol-5-yl)-methanol (3.44 g, 18.1 mmol) in THF (125 mL). To this solution was added phthalimide (3.34 g, 22.7 mmol) and triphenylphosphine (7.61 g, 29.0 mmol. The mixture was stirred for 10 minutes and then cooled in an ice-water bath. A solution of diethyl azodicarboxylate in toluene (0.225M, 141 mL) was added dropwise over 10 minutes keeping the internal temperature at 10-25 °C. The mixture was then stirred for 2 hours at room temperature. The mixture was concentrated to a volume of approx.
  • the compound was prepared as described in WO2009/127678A1.
  • the compound was purchased from Chembridge, Catalog No 4102139.
  • the compound was purchased from Enamine, Catalog No. EN300-55879.
  • IM9 (+)-R- 1-(2-Methyl- 1H-indol-5-yl)-ethylamii 0.170 g isolated (Method E). Optical rotation + 24.7 0 (0.5% in CH 3 OH). A crystal of a salt of amine IM9 with /V-Ac-L-phenyl-alanine (S)-configuration) shows that the absolute configuration of IM9 is (R).
  • Step 1
  • Step 5 To a solution of (S)-2-methyl-propane-2-sulfinic acid [(S)-2,2,2-trifluoro-1-(2-methyl-1 H-indol- 5-yl)-ethyl]-amide (6.3 g, 19.0 mmol) in diethyl ether (64 mL) at 0 °C was added 2M HCI in diethyl ether (32 mL). The reaction mixture was subsequently stirred at 25 °C for 4 h. The reaction mixture was then filtered and the remanence washed with EtOAc and dried under vac- uum. The crude salt was dissolved in water (120 mL) and basified with 1 M NaOH. The resulting mixture was filtered and the remanence was washed with water (60 mL) to give the title compound IM10 as a pale brown powder (3.5g, 81 %).
  • Step 1
  • the compound was purchased from Sigma-Aldrich, Catalog No 655864.
  • Step 1
  • Step 1
  • Step 2 To a solution of LDA (1.8 M, 10 ml_, 19.7 mmol) in THF (30 ml_) at -78 °C under an atmosphere of nitrogen was added a solution of 1-benzenesulfonyl-1 H-indole-5-carbonitrile (4.0g, 14.1 mmol) in THF (15 ml_). The mixture was stirred for 30 min, the temperature of the solution was slowly raised to -40 °C and after 30 min the mixture was re-cooled to -78 °C. To this solution was added dropwise a solution of Mel (4.42g, 31.1 mmol) in THF (15 ml_). The reaction temperature was maintained at -78 °C for 2 h.
  • Step 1
  • Step 1
  • IM18 was prepared in a sequence of steps similar to IM17 and IM16 as outlined above. IM18 was isolated from HCI in isopropylacetate to give the HCI salt of the title compound as colorless crystals.
  • Step 1
  • Step 1
  • Step 1
  • IM22 (-)-1-(2-Trifluoromethyl-1H-indol-5-yl)-ethylamine
  • the (-)-1-(1-benzyl-2-trifluoromethyl-1 H-indol-5-yl)-ethylamine isomer was taken the same step as described for IM21 to give (-)1-(2-Trifluoromethyl-1 H-indol-5-yl)-ethylamine.
  • Step l
  • the 5-bromo-6-fluoro-1 H-indole was taken through steps 2 to 8 as described for IM28.
  • the methylation step 3 gave two methylated isomers with 2-methyl being major and 7-methyl be- ing minor. This binary mixture was used without further purification to make amides 102 and 103.
  • Step 1
  • Step 6 To a solution of 2-(2,2,2-trifluoro-ethyl)-1 H-indole-5-carbonitrile (110 mg, 0.491 mmol) in methanol (3 mL) was added Raney Ni (20 mg) followed by 5 M ammonia in methanol (2 mL). The reaction solution was hydrogenated at 60 psi for 4 h at room temperature. The reaction mixture was filtered through a plug of celite. The filtrate was concentrated under vacuo and the resulting crystals were washed with diethyl ether to give the title compound IM25 as colorless crystals (0.11g, 98%).
  • Step 1
  • Step 1
  • 2,6-lutidine (1.2 g, 10.9 mmol) was added to a mixture of 4-fluoro-2-methyl-1 H-indol-5-ol (1.4g, 9.1 mmol) in methylene chloride (70 mL) at 0 °C.
  • Tf 2 0 (3.0g, 10.9 mmol) dropwise and the mixture was stirred at room temperature overnight.
  • Water was added and the mixture was extracted with methylene chloride (1500 mL). The organic layer was washed with water, brine, dried over Na 2 S0 4 and evaporated to dryness.
  • Step 1
  • Step 3 A solution of LDA in THF (2.0M, 35.1 mL, 68.8 mmol) added to THF (120 mL) and the mixture was cooled to -78 °C. A solution of 1-benzenesulfonyl-5-bromo-7-fluoro-1 H-indole (13.5 g, 38.2 mmol) in THF (90 mL) added dropwise. After 30 min the mixture was allowed to reach - 30 °C and stirred at this temperature for 30 min before being re-cooled to -78 °C. lo- domethane (5.4 mL, 84.04 mmol) in THF (50 mL) was added dropwise and the mixture was allowed to slowly reach room temperature overnight.
  • Step 6 To a solution of (S)-2-methyl-propane-2-sulfinic acid [1-(1-benzenesulfonyl-7-fluoro-2-methyl- 1 H-indol-5-yl)-ethylidene]-amide (1.3 g, 2.99 mmol) in THF (30 mL) was slowly added L- selectride (1.0M in THF, 3.89 mL, 3.89 mmol) at -78 °C. The reaction mixture was stirred at this temperature for 2 h. The mixture was quenched with saturated, aqueous NH 4 CI solution and extracted with ethyl acetate (2 x 30 mL).
  • the compound can be prepared as described in WO2009010871A2.
  • the compound was prepared as described for IM31 using 2-methoxy-1-bromoethane to give the title compound IM30 as a colorless solid.
  • Step 1
  • Step 2 To a solution of 1-(2-fluoro-ethyl)-1 H-pyrazole-4-carboxylic acid ethyl ester (4.0 g, 21.48 mmol) in THF: CH 3 OH: water (20:60:20 mL) was added LiOH (1.8 g, 42.96 mmol) and the mixture was stirred at room temperature for 6 h. The volume was concentrated under reduced pressure and pH was adjusted to 2-3 using 1 N HCI. The mixture was extracted with EtOAc (3 x 50 mL) and the combined organic layers were washed with water (2 x 30 mL), dried over Na 2 S0 4 and evaporated to dryness to give the title compound IM31 as a colorless solid (2.3g, 67%).
  • Step l
  • Step 1
  • Step 3 To a solution of 4-iodo-1-(tetrahydro-furan-3-yl)-1 H-pyrazole (7.00 g, 26.8 mmol) in THF (100 mL) was added i-PrMgCI (2M in THF, 106.0 mL) dropwise at 0 °C. The mixture was then stirred at 25 °C for 30 min. DMF (9.69 g, 132.5 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with saturated, aqueous NH 4 CI (200 mL) and then evaporated to dryness. Flash chromatography (silica,
  • Step 1
  • Step 1
  • the compound was prepared as described for IM36 using 2-methoxy-1-bromoethane to give the title compound IM37 as a colorless solid.
  • Step 1
  • Step 1
  • Example 1 Compounds of the invention

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Abstract

La présente invention concerne des composés utiles en thérapie, des compositions comprenant lesdits composés, et des procédés permettant de traiter des maladies et impliquant l'administration desdits composés. Les composés de l'invention sont des effecteurs allostériques positifs ou "PAM" (Positive Allosteric Modulators) du récepteur nicotinique de l'acétylcholine α7.
PCT/EP2012/055775 2011-04-01 2012-03-30 Nouveaux effecteurs allostériques positifs du récepteur nicotinique de l'acétylcholine WO2012131031A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014049133A1 (fr) * 2012-09-28 2014-04-03 H. Lundbeck A/S Nouveaux effecteurs allostériques positifs du récepteur nicotinique de l'acétylcholine

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000024739A1 (fr) 1998-10-23 2000-05-04 Dow Agrosciences Llc Composes 3-(substitues phenyle)-5-(substitues heterocyclyle)-1,2, 4-triazole
WO2001032619A1 (fr) 1999-11-03 2001-05-10 Astrazeneca Ab Modulateurs positifs des agonistes du recepteur nicotinique
WO2004104006A2 (fr) 2003-05-16 2004-12-02 Wyeth Holdings Corporation Procede de synthese d'intermediaires d'inhibiteurs de beta-lactamase
WO2009010871A2 (fr) 2007-07-13 2009-01-22 Addex Pharma S.A. Nouveaux dérivés hétéroaryle servant d'antagonistes du récepteur a3 de l'adénosine
WO2009100294A2 (fr) 2008-02-07 2009-08-13 Abbott Laboratories Dérivés d'amide en tant que modulateurs allostériques positifs et procédés d'utilisation associés
WO2009127679A1 (fr) 2008-04-17 2009-10-22 Glaxo Group Limited Indoles utilisés en tant que modulateurs du sous-type alpha-7 du récepteur nicotinique de l'acétylcholine
WO2009153307A1 (fr) 2008-06-20 2009-12-23 Glaxo Group Limited Composés
WO2010119078A1 (fr) 2009-04-16 2010-10-21 Glaxo Group Limited Dérivés indoles modulateurs de l'alpha 7 nachr

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000024739A1 (fr) 1998-10-23 2000-05-04 Dow Agrosciences Llc Composes 3-(substitues phenyle)-5-(substitues heterocyclyle)-1,2, 4-triazole
WO2001032619A1 (fr) 1999-11-03 2001-05-10 Astrazeneca Ab Modulateurs positifs des agonistes du recepteur nicotinique
WO2004104006A2 (fr) 2003-05-16 2004-12-02 Wyeth Holdings Corporation Procede de synthese d'intermediaires d'inhibiteurs de beta-lactamase
WO2009010871A2 (fr) 2007-07-13 2009-01-22 Addex Pharma S.A. Nouveaux dérivés hétéroaryle servant d'antagonistes du récepteur a3 de l'adénosine
WO2009100294A2 (fr) 2008-02-07 2009-08-13 Abbott Laboratories Dérivés d'amide en tant que modulateurs allostériques positifs et procédés d'utilisation associés
WO2009127679A1 (fr) 2008-04-17 2009-10-22 Glaxo Group Limited Indoles utilisés en tant que modulateurs du sous-type alpha-7 du récepteur nicotinique de l'acétylcholine
WO2009127678A1 (fr) 2008-04-17 2009-10-22 Glaxo Group Limited Indoles utilisés en tant que modulateurs du sous-type alpha-71 du récepteur nicotinique de l'acétylcholine
WO2009153307A1 (fr) 2008-06-20 2009-12-23 Glaxo Group Limited Composés
WO2010119078A1 (fr) 2009-04-16 2010-10-21 Glaxo Group Limited Dérivés indoles modulateurs de l'alpha 7 nachr

Non-Patent Citations (38)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 1995, MACK PUBLISHING CO.
ARIAS, H.R., INT. J. BIOCHEM CELL BIOL., vol. 41, no. 7, 2009, pages 1441 - 51
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 NEUROPHARMACOL., 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
GOPALAKRISH- NAN M, EXPERT OPIN THER TARGETS, vol. 8, no. 5, 2004, pages 437 - 58
GOTTI, C. ET AL., BIOCHEMICAL PHARMACOLOGY, vol. 78, 2009, pages 703 - 711
GOTTI, C. ET AL., PROG. NEUROBIOL., vol. 74, 2004, pages 363 - 396
GRIBKOFF VK, EXPERT OPIN THER TARGETS, vol. 7, no. 6, 2003, pages 737 - 48
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, 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., BEHAV. BRAIN RES., vol. 162, 2005, pages 143 - 52
KRISTENSEN L, NEUROSCI LETT., vol. 488, no. 2, pages 178 - 82
LIU, Q.-S. ET AL., PNAS, vol. 98, 2001, pages 4734 - 4739
MACKIE AR, MOL PHARMACOL., vol. 74, no. 5, 2008, pages 1171 - 9
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 U S A., vol. 104, no. 19, 2007, pages 8059 - 64
OLAH, G. ET AL., ANGEW. CHEM. INT. ED., vol. 40, no. 3, 2001, pages 589 - 590
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
ROSAS-BALLINA, M., J. INTERN MED., vol. 265, no. 6, 2009, pages 663 - 79
SHIMOHAMA, 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, October 2007 (2007-10-01), pages 294 - 307
VINCLER, M., EXP. OPIN.LNVEST. DRUGS, vol. 14, no. 10, 2005, pages 1191 - 1 198
WIKER, C., INT J NEUROPSYCHOPHARMACOL., vol. 11, no. 6, September 2008 (2008-09-01), pages 845 - 50

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014049133A1 (fr) * 2012-09-28 2014-04-03 H. Lundbeck A/S Nouveaux effecteurs allostériques positifs du récepteur nicotinique de l'acétylcholine

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