WO2013004617A1 - Pyrazolopyridines utiles dans le traitement de troubles du système nerveux central - Google Patents

Pyrazolopyridines utiles dans le traitement de troubles du système nerveux central Download PDF

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Publication number
WO2013004617A1
WO2013004617A1 PCT/EP2012/062703 EP2012062703W WO2013004617A1 WO 2013004617 A1 WO2013004617 A1 WO 2013004617A1 EP 2012062703 W EP2012062703 W EP 2012062703W WO 2013004617 A1 WO2013004617 A1 WO 2013004617A1
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dimethyl
phenyl
pyridine
pyrazolo
carboxylic acid
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PCT/EP2012/062703
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English (en)
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Jørgen ESKILDSEN
Christian WENZEL TORNØE
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H. Lundbeck A/S
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61P25/28—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

Definitions

  • 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, R.B., 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., 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.
  • AD Alzheimer's disease
  • PD amyotrophic lateral sclerosis
  • Huntington's disease dementia with Lewy bodies
  • diminished CNS function resulting from traumatic brain injury.
  • 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.
  • 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 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 Jan 15;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 IB, 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 ef- fects 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).
  • 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 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.
  • 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 Then 2007, 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. 201 1 336(2):560-74.).
  • WO 01/32619 recites that compounds of the following core structure are 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.
  • the objective of the present invention is to provide compounds that are positive allos- teric modulators (PAMs) of the nicotinic acetylcholine receptor subtype a7.
  • PAMs positive allos- teric modulators
  • the compounds of the present invention are defined by formula [I] below:
  • A4 is C-R4 or N
  • A5 is C-R5 or N
  • A6 is C-R6 or N, provided that at least one of A4, A5 or A6 is N and no more than two of A4, A5 and A6 is N;
  • R1 is phenyl or heteroaryl; wherein said phenyl or heteroaryl is optionally substituted with one or more substituents R1 1 , wherein each R1 1 is individually selected from Ci -6 alkyl, halogen, hydroxy, haloCi -6 alkyl, Ci -6 alkoxy, haloCi -6 alkoxy, cyano, Ci -6 alkylsulfonyl, -S(0) 2 NH 2 and - NR12R13, wherein R12 and R13 independently represent hydrogen or Ci -6 alkyl;
  • R2 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -6 alkoxy, halogen and cyano;
  • R3, R4, R5, R6 and R7 are selected independently of each other from H, Ci -6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, Ci -6 alkoxy, halogen, cyano, and -NR9R10, wherein R9 and R10 inde- pendently represent hydrogen, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloCi -6 alkyl or phenyl;
  • R8 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -6 alkoxy, halogen, cyano and phenyl; and pharmaceutically acceptable salts thereof.
  • the invention relates to a compound according to formula [I], and pharmaceutically acceptable salts thereof, for use as a medicament.
  • 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 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 Hyper
  • 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 spec- trum 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, 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
  • the invention relates to the use of a compound according to for- mula [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 impairment (MCI); age associated memory impairment (AAMI); senile dementia; AIDS demen- tia; 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; Schizoph
  • 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 -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, Ci -6 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- 6 alkyl is intended to indicate such hydrocarbon hav- ing 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.
  • alkenyl is intended to indicate a non-aromatic, straight, branched and/or cyclic hydrocarbon comprising at least one carbon-carbon double bond.
  • C 2 - 6 alkenyl is intended to indicate such hydrocarbon having 2, 3, 4, 5 or 6 carbon atoms.
  • Examples of C 2-6 alkenyl include ethenyl, 1 -propenyl, 2-propenyl, 1 -butenyl, 2-butenyl and 3-butenyl and cyclohexenyl.
  • 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 - 6 alkynyl is intended to indicate such hydrocarbon having 2, 3, 4, 5 or 6 carbon atoms.
  • Examples of C 2- 6 alkynyl include ethynyl, 1 -propynyl, 2-propynyl, 1 -butynyl, 2-butynyl, 3-butynyl and 5-but-1 - en-3-ynyl.
  • hydroxy is intended to indicate -OH.
  • alkoxy is intended to indicate a moiety of the formula -OR', wherein R' indicates alkyl as defined above.
  • R' indicates alkyl as defined above.
  • Ci -6 alkoxy is intended to indicate such moiety wherein the alkyl part has 1 , 2, 3, 4, 5 or 6 carbon atoms.
  • Examples of “Ci_ 6 alkoxy” include methoxy, ethoxy, n-butoxy and tert-butoxy.
  • halo and halogen are used interchangeably and refer to fluorine, chlorine, bromine or iodine.
  • haloalkyl is intended to indicate an alkyl as defined above substituted with one or more halogens.
  • haloCi- 6 alkyl is intended to indicate a moiety wherein the alkyl part has 1 , 2, 3, 4, 5 or 6 carbon atoms.
  • haloalkyl is trifluoromethyl.
  • haloalkoxy is intended to indicate an alkoxy as defined above substituted with one or more halogens.
  • haloCi -6 alkoxy is intended to indicate a moiety wherein the alkyl part has 1 , 2, 3, 4, 5 or 6 carbon atoms. Particular mention is made of difluoromethoxy and trifluoromethoxy.
  • alkylsulfonyl is intended to indicate -S(0) 2 alkyl
  • Ci -6 alkylsulfonyl is intended to indicate such a moiety wherein the alkyl part has 1 , 2, 3, 4, 5 or 6 carbon atoms. Particular mention is made of methylsulfonyl.
  • cyano indicates the group -C ⁇ N, which consists of a carbon atom triple-bonded to a nitrogen atom.
  • heteroaryl is intended to indicate a 5 or 6 membered aromatic monocyclic ring containing 1 to 5 carbon atoms and one or more heteroatoms selected from oxygen, nitrogen and sulfur.
  • heteroaryls of the present invention include 6- membered heteroaryls such as pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl and 5- membered heteroaryls such as oxathiazolyl, dioxazolyl, dithiazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrrolyl, furanyl and thio- phenyl.
  • An "N-containing heteroaryl” indicates a 5 or 6 membered aromatic system, wherein at least one ring atom is a nitrogen.
  • heteroaryl when a heteroaryl is optionally substituted with one or more substituents it means that said heteroaryl may or may not be substituted on its carbon atoms, and when substituted it is substituted e.g. with 1 , 2 or 3 substituents. In a preferred embodiment an optionally substituted heteroaryl is either not substituted or substituted with one sub- stituent.
  • a phenyl when a phenyl is optionally substituted with one or more substituents it means that said phenyl may or may not be substituted, and when substituted it is substituted e.g. with 1 , 2 or 3 substituents. In a preferred embodiment an optionally substituted phenyl is either not substituted or substituted with one substituent.
  • said substituent when a phenyl is substituted with one substituent said substituent can be located in the ortho, meta or para position of said phenyl.
  • 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.
  • pharmaceutically acceptable salts include pharmaceutical acceptable 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-
  • metal salts examples 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 con- structing 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. Nonetheless, prophylactic (preventive) and therapeutic (curative) treatments are two separate aspects of the present invention.
  • 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 but 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), traumatic brain injury, epi- lepsy, post-traumatic stress, Wernicke-Korsakoff syndrome (W
  • 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 performance impairment" induced by subchronic PCP administration in rats as described by Rodefer; J.S. et al., Eur. J. Neurosci. 21 :1070-1076 (2005).
  • 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 of NNRs may be dosed in combination with other drugs in order to achieve more efficacious treatment in certain patient populations.
  • An a 7 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;1 1 (6):845-50).
  • compounds of the present invention are used for treatment of patients who are already in treatment with another drug selected from the list above. In one embodiment, compounds of the present invention are adapted for administration simultaneous with said other drug. In one embodiment compounds of the present invention are adapted for administration sequentially with said other drug. In one embodiment, compounds of the pre- sent invention are used as the sole medicament in treatment of a patient. In one embodiment, 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.
  • A4 is C-R4 or N
  • A5 is C-R5 or N
  • A6 is C-R6 or N, provided that at least one of A4, A5 or A6 is N and no more than two of A4, A5 and A6 is N;
  • R1 is phenyl or heteroaryl; wherein said phenyl or heteroaryl is optionally substituted with one or more substituents R1 1 , wherein each R1 1 is individually selected from Ci -6 alkyl, halogen, hydroxy, haloCi -6 alkyl, Ci -6 alkoxy, haloCi -6 alkoxy, cyano, Ci -6 alkylsulfonyl, -S(0) 2 NH 2 and - NR12R13, wherein R12 and R13 independently represent hydrogen or Ci -6 alkyl;
  • R2 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -6 alkoxy, halogen and cyano
  • R3, R4, R5, R6 and R7 are selected independently of each other from H, Ci -6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, Ci -6 alkoxy, halogen, cyano, and -NR9R10, wherein R9 and R10 independently represent hydrogen, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloCi -6 alkyl or phenyl;
  • R8 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -6 alkoxy, halogen, cyano and phenyl;
  • each R1 1 is individually selected from methyl, trifluoromethyl, fluorine, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, cyano, methylsulfonyl, -S(0) 2 NH 2 and -N(CH 3 ) 2 ;
  • R2 is selected from H, methyl and methoxy
  • R3, R4, R5, R6 and R7 are selected independently of each other from H, methyl, methoxy, cyano and N(CH 3 ) 2 ;
  • R8 is selected from H, methyl and phenyl.
  • E28 The compound according to embodiment 27, wherein R2, R3, R4, R5, R6 and R7 are selected independently of each other from H, methyl and methoxy.
  • E29 The compound according to any of embodiments 1 -28, wherein R2 is methyl.
  • E30 The compound according to any of embodiments 1 -29, wherein at least one of R3 and R7 is selected independently from methyl and methoxy.
  • E32 The compound according to any of embodiments 1 -31 , wherein R4, R5 and R6 are hydrogen.
  • E33. The compound according to any of embodiments 1 -32, wherein R8 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and phenyl.
  • ADHD Attention Deficit Hyperactivity Disorder
  • AD Attention Deficit Hyperactivity Disorder
  • MCI mild cognitive impairment
  • AAMI age associated memory impairment
  • 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.
  • E42 The compound according to embodiment 41 , wherein said disease or disorder is selected from schizophrenia; AD; ADHD and autism spectrum disorders.
  • E43 The compound according to embodiment 42, wherein said disease or disorder is selected from negative and/or cognitive symptoms of schizophrenia.
  • E44 The compound according to any of embodiments 1 -37, for use concomitantly or se- quentially with a therapeutically effective amount of a 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 in the treatment of a disease or disorder accord- ing to any of embodiments 40-43.
  • a pharmaceutical composition comprising a compound according to any of embodiments 1 -37, and one or more pharmaceutically acceptable carrier or excipient.
  • E47 The composition according to embodiment 46, wherein said second compound is an acetylcholinesterase inhibitor.
  • E48. A kit comprising a compound according to any of embodiments 1 -37, together with a second compound selected from the list consisting of acetylcholinesterase inhibitors; gluta- mate 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.
  • E50 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; 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 any of embodiments 1 -37 to a patient in need thereof.
  • ADHD Attention Deficit Hyperactivity Disorder
  • AD Alzheimer's disease
  • E51 The method according to embodiment 50, 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.
  • E53 The method according to embodiment 52, wherein said treatment comprises the treatment of negative and/or cognitive symptoms of schizophrenia.
  • E54 The method according to any of embodiments 50-53, 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.
  • said second compound is an acetylcholinesterase inhibitor.
  • 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; amyotro- phic 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
  • 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.
  • E58 The use according to embodiment 57, wherein said disease or disorder is selected from schizophrenia; AD; ADHD and autism spectrum disorders.
  • said medicament further comprises 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 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 optical isomers i.e. enantiomers or diastereomers
  • any mixtures thereof including race- mic mixtures i.e. a mixture of stereoisomers
  • 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 resolving 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 included 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 contain- ing 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 administra- tion.
  • 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 sus- pension 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 gela- tine 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, mag- nesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colourings, flavourings, preservatives etc. may be used provided that they are compatible with the active ingredients.
  • the compounds of formula [I] may be prepared by methods described below, together with synthetic methods known in the art of organic chemistry, or modifications that are familiar to those of ordinary skill in the art.
  • the starting materials used herein are available commercially or may be prepared by routine methods known in the art, such as those method described in standard reference books such as "Compendium of Organic Synthetic Methods, Vol. ⁇ - ⁇ (published with Wiley-lnterscience). Preferred methods include, but are not limited to, those described below.
  • Scheme 1 illustrates a method for preparing compounds depicted by formula 1 .6.
  • This method involves the formation of a substituted pyrazole of formula 1 .3.
  • the synthesis of pyra- zoles of formula 1 .3 can as an example be achieved by heating enamines of formula 1 .2 with hydrazines of formula 1 .1 in a solvent such as ethanol, isopropanol, aqueous HCI solution, aqueous acetic acid with or without a base additive such as triethyl amine.
  • a range of other methods have also been described in the literature to give compounds of formula 1 .3 (for example Beilstein J. Org. Chem., 201 1 , 7, 179-197).
  • Substituted pyrazoles of formula 1.3 can react with compounds of formula 1 .4 to give compounds depicted by formula 1.5 by heating a mixture of the compounds in a solvent such as acetic acid.
  • the ester functionality of compounds of formula 1 .5 can be hydrolyzed to provide the corresponding acid derivative of formula 1 .6 for example by treatment with aqueous base such as KOH or LiOH in a solvent such as MeOH or THF.
  • Scheme 2 illustrates a method for preparing compounds depicted by formula 2.3.
  • Nitro compounds depicted by formula 2.2 can be prepared by nitrating compounds depicted by formula 2.1 by treatment under nitrating conditions such as aqueous HN0 3 in H 2 S0 4 , KN0 3 in H 2 S0 4 or methods based on N 2 0 5 ⁇ Synthesis, 1997, 281 -283).
  • Nitro compounds depicted by formula 2.2 can be reduced to compounds depicted by formula 2.3 by reductive methods, such as hydrogenation using Pd/C catalysts in solvents such as EtOH or THF, or treatment with Fe and a proton source such as NH 4 CI in solvents such as EtOH. heme 3.
  • Scheme 3 illustrates methods for preparing compounds of formula I.
  • the carboxylic acid of formula 1 .6 can be coupled to amines of the formula 2.3 using EDC and HOBt or another suitable coupling reagent in the presence of a base such as diisopropyl ethylamine or N-methyl morpholine in a solvent such as DMF or DMAC.
  • Other methods for preparing compounds of formula I includes treating a mixture of a carboxylic acid of formula 1 .6 with an amine of the formula 2.3 with POCI 3 in warm pyridine or treating a preformed salt of carboxylic acid of the formula 1.6 and amine of the formula 2.3 with T3P.
  • Scheme 3 also illustrates a method for preparing compounds of the formula I in which carboxylic esters of formula 1.5, or the corresponding methyl ester, react with a preformed complex between an amine of the formula 2.3 and an alane reagent such as AIMe 3 in a solvent such as toluene or CH 2 CI 2 .
  • HATU 0-(7-Azabenzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
  • HOBt 1 -Hydroxybenzotriazole.
  • HPLC High Performance Liquid Chromatography.
  • T3P 1 -propanephosphonic acid cyclic anhydride.
  • TFA trifluoroacetic acid.
  • THF tetrahy- drofuran.
  • Analytical LCMS was performed using a Waters Acquity 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 Acquity 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 + 0.05 % TFA (A) and acetonitrile + 5% water + 0.035% TFA (B). Gradient: Time, min. %B
  • the title compound is commercially available.
  • a mixture of 4-methyl-2-methoxy-3- nitropyridine (4.5 g, 26.8 mmol), NH 4 CI (7.16 g, 133.9 mmol) and Fe powder (7.5 g, 133.9 mmol) in ethanol (50 mL) was stirred at 25 °C.
  • the mixture was slowly heated to 90 °C and stirred at this temperature for 2 h.
  • the reaction mixture was filtered through a plug of celite and the celite plug was washed with ethanol (50 mL).
  • the combined filtrates were evaporated to dryness.
  • the remanens was diluted with water (50 mL) and the mixture was extracted with EtOAc (100 mL).
  • IM02 + IM03 Mixture of 4-Methoxy-2-methyl-3-nitro-pyridine and 4-Methoxy-2-methyl-5-nitro- pyridine, IM02+IM03
  • Step 1
  • the intermediate (4-difluoromethoxy-phenyl)-hydrazine was prepared from 4- difluoromethoxy-phenylamine as described in Org. Lett., 2009, 1 1 , 22, 5142-5145.
  • the title compound was obtained as an off-white solid (4.0 g, 58%) sufficiently pure for the next step.
  • the intermediate thiophen-3-yl-hydrazine was prepared as described in Organic Letters 2003, 4129-4131 , followed by Boc deprotection using HCI in dioxane.
  • the title compound was obtained as a solid (7.1 g, 99%).
  • the intermediate pyrimidin-5-yl-hydrazine was prepared as described in Tetrahedron Lett., 51 (2010), 5005-5008, followed by Boc deprotection using HCI in dioxane.
  • the title compound was obtained as a solid (3.85 g, 99%).
  • Step 1
  • IM28 1-(4-Methoxy-phenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester Prepared using IM21. The crude compound was purified by flash chromatography (silica, 10% EtOAc in hexanes) to give the title compound as an off-white solid (3.4 g, 69%).
  • IM32 3, 6-Dimethyl- 1 -(4-trifluoromethoxy-phenyl)- 1 H-pyrazolo[3, 4-b]pyridine-4-carboxylic acid ethyl ester Prepared using IM13. The crude compound was washed with water to give the title compound as a pale, yellow solid (4.0 g, 66%).
  • IM33 1-(4-Difluoromethoxy ⁇ henyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester
  • IM41 3,6-Dimethyl-1-pyrimidin-5-yl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester Prepared using IM20 to give the title compound as a colorless solid (0.25 g, 4%).
  • 1 H NMR (DMSO-d6) ⁇ 9.62 (s, 2 H), 9.12 (s, 1 H), 7.63 (s, 1 H), 4.44 (m, 2 H), 2.71 (s, 3 H), 2.66 (s, 3 H), 1.37 (t, 3 H).
  • IM42 1 -(4-Dimethylamino-phenyl)-3, 6-dimethyl- 1 H-pyrazolo[3, 4-b]pyridine-4-carboxylic acid ethyl ester
  • IM44 1 -(4-Methoxy-phenyl)-3-methyl-6-phenyl- 1 H-pyrazolo[3, 4-b]pyridine-4-carboxylic acid Prepared using IM34 to give the title compound as a yellow solid (2.26 g, 97%) sufficiently pure for the next step.
  • IM45 1-(4-Methanesulfonyl ⁇ henyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid Prepared using IM35 to give the title compound as a solid (1 .61 g, 87%) sufficiently pure for the next step.
  • IM46 3, 6-Dimethyl- 1 -(4-sulfamoyl-phenyl)- 1 H-pyrazolo[3, 4-b]pyridine-4-carboxylic acid
  • IM36 3, 6-Dimethyl- 1 -(4-sulfamoyl-phenyl)- 1 H-pyrazolo[3, 4-b]pyridine-4-carboxylic acid
  • IM47 3, 6-Dimethyl- 1 -(4-trifluoromethyl-phenyl)- 1 H-pyrazolo[3, 4-b]pyridine-4-carboxylic acid Prepared using IM37 to give the title compound as a solid (1.6 g, 85%) sufficiently pure for the next step. The hydrolysis was performed at room temperature.
  • IM48 1 -(4-Dimethylamino-phenyl)-3, 6-dimethyl- 1 H-pyrazolo[3, 4-b]pyridine-4-carboxylic acid Prepared using IM42 to give the title compound as a solid (0.223 g, 97%) sufficiently pure for the next step.
  • IM51 1-(4-Methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid
  • 1 -(4-methoxy-phenyl)-3,6-dimethyl-1 H- pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester IM23 (16.0 g, 49.2 mmol) in methanol/ water (1 :1 , 600 mL).
  • LiOH hydrate 6.2 g, 147.6 mmol
  • IM53 1-(2-Methoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid
  • the crude compound was prepared from IM25 and subsequently washed with diethyl ether to give the title compound as a pale yellow powder (0.9 g, 83 %).
  • 1 H NMR (DMSO-d6, 400 MHz) ⁇ 13.80 (1 H, br), 7.54-7.5 (1 H, m, ), 7.45 (1 H, s), 7.39-7.37 (1 H, m),7.27-7.25 (1 H, d), 7.12-7.09(1 H, t) 3.69 (3H, s), 2.62 (3H, s), 2.55 (3H, s).
  • IM54 1 -(3-Methoxy-phenyl)-3, 6-dimethyl- 1 H-pyrazolo[3, 4-b]pyridine-4-carboxylic acid
  • the crude compound was prepared from IM26 and subsequently washed with diethyl ether to give the title compound as a pale yellow powder (0.90 g, 62%).
  • 1 H NMR (DMSO-d6, 400 MHz) ⁇ 13.92 (1 H, br s), 7.89-7.84 (2H, m), 7.54 (1 H, s), 7.47-7.43(1 H, m), 6.91 -6.89 (1 H, m), 3.84 (3H, s), 2.69 (3H, s), 2.66 (3H, s).
  • IM55 3, 6-Dimethyl- 1 -( 6-methyl-pyridin-3-yl)- 1 H-pyrazolo[3, 4-b]pyridine-4-carboxylic acid
  • the crude compound was prepared from IM27 and subsequently washed with water to give the title compound as a yellow solid (1.0 g, 74%).
  • 1 H NMR (DMSO-d6, 400 MHz) ⁇ 13.96 (1 H, br s), 9.27-9.28 (1 H, d), 8.48-8.46 (1 H, m), 7.57 (1 H, s), 7.48-7.46 (1 H, m), 2.72 (3H, s), 2.68 (3H, s), 2.56 (3H, s).
  • the crude product was prepared from IM29 and subsequently washed with water followed by diethyl ether to give the title compound as a yellow solid (3.0 g, 65%).
  • the crude product was prepared from IM30 and subsequently washed with water followed by diethyl ether to give the title compound as a yellow solid (1.5 g, 55%).
  • IM59 1 -( 6-Methoxy-pyridin-3-yl)-3, 6-dimethyl- 1 H-pyrazolo[3, 4-b]pyridine-4-carboxylic acid
  • the crude product was prepared from IM31 and subsequently washed with water followed by diethyl ether to give the title compound as a yellow solid (3.0 g, 83%).
  • 1 H NMR (DMSO-d6, 300 MHz) ⁇ 12.0 (1 H, br s), 8.96-8.95 (1 H, d), 8.43-8.40 (1 H, m), 7.21 (1 H, s), 7.01 -6.99 (1 H, m), 3.91 (3H, s), 2.61 (3H, s), 2.60 (3H, s).
  • IM60 3, 6-Dimethyl- 1 -(4-trifluoromethoxy-phenyl)- 1 H-pyrazolo[3, 4-b]pyridine-4-carboxylic acid
  • the crude product was prepared from IM32 and subsequently washed with water followed by diethyl ether to give the title compound as a yellow solid (3.0 g, 65%).
  • 1 H NMR (DMSO-d6, 300 MHz) ⁇ 13.97 (1 H, br s), 8.39-8.35 (2H, m), 7.58-7.56 (3H, m), 2.70 (3H, s), 2.67 (3H, s).
  • IM61 1-(4-Difluoromethoxy-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid
  • the crude product was prepared from IM33 and subsequently washed with water followed by diethyl ether to give the title compound as a yellow solid (1.0 g, 72%).
  • 1 H NMR (DMSO-d6, 400 MHz) ⁇ 13.09 (1 H, br s), 8.26-8.24 (2H, m), 7.51 (1 H, s), 7.46-7.09 (3H, m), 2.68 (3H, s), 2.65 (3H, s).
  • IM62 3-Methoxy- 1 -(4-methoxy-phenyl)-6-methyl- 1 H-pyrazolo[3, 4-b]pyridine-4-carboxylic acid Prepared from IM39 to give a solid (0.16 g, 89%) sufficiently pure for the next step. The hydrolysis was performed at room temperature.
  • Step 1
  • 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 individual assays are described in Examples 2 and 3, respectively.
  • 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 ol receptor is stably expressed in the rat GH4C1 cell line.
  • the assay was used to identify positive allosteric modulators (PAMs) of the ol 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. Cell plating and dye loading
  • 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.
  • Greiner bio-one (781946, CELLCOAT, Poly-D-Lysine, black, ⁇ C ⁇ ear). 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 a7 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 1 shows EC 50 values for exemplified compounds of the invention.
  • Oocytes were surgically removed from mature female Xenepus laevis anaesthetized in 0.4 % MS-222 for 10-15 min. The oocytes were 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).
  • 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 were 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 were 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 were used for electrophysiological recordings.
  • Electrophysiological recordings of a7 nACh receptors expressed in oocytes Electrophysiological recordings of a7 nACh receptors expressed in oocytes.
  • Oocytes were used for electrophysiological recordings 1-10 days after injection. Oocytes were 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 were impaled with agar plugged 0.2 - 1 ⁇ electrodes containing 3 M KCI and voltage clamped at -90 mV by a Ge- neClamp 500B amplifier. The experiments were performed at room temperature. Oocytes were continuously perfused with Ringer buffer and the drugs were applied in the perfusate.
  • 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 were impaled with agar plugged 0.2 - 1 ⁇ electrodes containing 3 M KCI and voltage clampe
  • ACh (30 ⁇ ) applied for 30 sec were used as the standard agonist for activation of the a7 nACh receptors.
  • the new test compound (10 ⁇ or 30 ⁇ ) were 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 were calculated thus giving the effect of drug induced PAM activity as fold modulation of the control response.
  • Table 2 indicates fold modulation of compounds No. 21 , 22, 24, 34, 35 and 36 at determined at 10 ⁇ .

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  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des composés utiles en thérapie, des compositions comprenant lesdits composés, et des méthodes de traitement de maladies comprenant l'administration desdits composés. Les composés mentionnés ici sont des modulateurs allostériques positifs (PAM) du récepteur nicotinique de l'acétylcholine α7.
PCT/EP2012/062703 2011-07-01 2012-06-29 Pyrazolopyridines utiles dans le traitement de troubles du système nerveux central WO2013004617A1 (fr)

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WO2017030171A1 (fr) * 2015-08-19 2017-02-23 アステラス製薬株式会社 Composé tétrahydrooxépinopyridine
WO2017082377A1 (fr) * 2015-11-13 2017-05-18 国立大学法人大阪大学 Dérivé pyrazolopyridine et utilisation de ce dernier

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017030171A1 (fr) * 2015-08-19 2017-02-23 アステラス製薬株式会社 Composé tétrahydrooxépinopyridine
KR20180037983A (ko) * 2015-08-19 2018-04-13 아스텔라스세이야쿠 가부시키가이샤 테트라히드로옥세피노피리딘 화합물
EA034794B1 (ru) * 2015-08-19 2020-03-23 Астеллас Фарма Инк. Соединение тетрагидрооксепинопиридина
KR102614279B1 (ko) 2015-08-19 2023-12-18 아스텔라스세이야쿠 가부시키가이샤 테트라히드로옥세피노피리딘 화합물
WO2017082377A1 (fr) * 2015-11-13 2017-05-18 国立大学法人大阪大学 Dérivé pyrazolopyridine et utilisation de ce dernier

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