WO2014006117A1 - Nouveaux modulateurs allostériques positifs de récepteur nicotinique à l'acétylcholine - Google Patents

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

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Publication number
WO2014006117A1
WO2014006117A1 PCT/EP2013/064088 EP2013064088W WO2014006117A1 WO 2014006117 A1 WO2014006117 A1 WO 2014006117A1 EP 2013064088 W EP2013064088 W EP 2013064088W WO 2014006117 A1 WO2014006117 A1 WO 2014006117A1
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WO
WIPO (PCT)
Prior art keywords
compound according
disease
antagonists
pharmaceutically acceptable
methoxy
Prior art date
Application number
PCT/EP2013/064088
Other languages
English (en)
Inventor
Jørgen ESKILDSEN
Anette Graven Sams
Ask Püschl
Original Assignee
H. Lundbeck A/S
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/EP2012/063219 external-priority patent/WO2013007621A1/fr
Application filed by H. Lundbeck A/S filed Critical H. Lundbeck A/S
Publication of WO2014006117A1 publication Critical patent/WO2014006117A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6

Definitions

  • 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; do- pamine 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; do- pamine 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.
  • pharmaceutical acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in Berge, S.M. et al., J. Pharm. Sci. 1977,66,2, which is incorporated herein by reference.
  • 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.
  • 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
  • NNRs may be dosed in combination with other drugs in order to achieve more efficacious treatment in certain patient populations.
  • An a7 NNR PAM may act synergis- tically with another drug, this has been described in animals for the combination of compounds affecting nicotinic receptors, including a7 NNRs and D2 antagonism (Wiker, C, Int. J. Neuropsychopharmacol. 2008, 1 1 (6):845-50).
  • E14 The compound according to embodiment 13, 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.
  • E15 The compound according to embodiment 14, wherein said disease or disorder is selected from schizophrenia; AD; ADHD and autism spectrum disorders.
  • a pharmaceutical composition comprising a compound according to any of embodi- ments 1 -10, and one or more pharmaceutically acceptable carrier or excipient.
  • 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.
  • a kit comprising a compound according to any of embodiments 1 -10, 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.
  • 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.
  • ADHD attention deficit hyperactivity disorder
  • MCI mild cognitive impairment
  • AAMI age associated memory impairment
  • senile dementia AIDS dementia
  • Pick's disease dementia associated with Lewy bodies
  • dementia associated with Down's syndrome Huntington's disease
  • Parkinson's disease
  • the compounds of the invention may exist in unsolvated as well as in solvated forms in which the solvent molecules are selected from pharmaceutically acceptable solvents such as water, ethanol and the like. In general, such solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
  • the compounds of the present invention are manufactured from two chiral intermediates with one and two asymmetric centers, respectively, as illustrated by the examples below.
  • the intermediate when specifying the enantiomeric form of the intermediate, then the intermediate is in enantiomeric excess, e.g. essentially in a pure, mono- enantiomeric form. Accordingly, the resulting compounds of the invention are having a dia- stereomeric excess of at least 80%.
  • One embodiment of the invention relates to a compound of the invention having a diastereomeric excess of at least 80% such as at least 85%, such as at least 90%, preferably at least 95% or at least 97% with reference to the three assymetric centers indicated above.
  • the compounds of the present invention may furthermore have one or more additional asymmetric centers. It is intended that any optical isomers (i.e. enantiomers or diastereomers), in the form of separated, pure or partially purified optical isomers and any mixtures thereof including racemic mixtures, i.e. a mixture of stereoisomers, which have emerged because of asymmetric centers in any of substit- uents R7-R12, are included within the scope of the invention.
  • any optical isomers i.e. enantiomers or diastereomers
  • racemic mixtures i.e. a mixture of stereoisomers
  • 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.
  • 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.
  • 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.
  • 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.
  • Formulations of the present invention suitable for oral administration may be present- ed 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.
  • DMEM/F12 Dulbecco's Modified Eagle Medium
  • F12 Nutrient mix
  • FBS Fetal Bovine Serum
  • Pen Penicillin
  • Strep streptomycin
  • G-418 Geneticin
  • HBSS Hanks Balanced Salt Solution
  • HEPES (4-(2-hydroxyethyl)-1 -piperazineethanesulfonic acid)
  • FDSS7000 Functional Drug Screening System from Hamamatso
  • OR2 buffer Oocyte Ringer.
  • the nicotinic acetylcholine receptor a7 is a calcium-permeable ion channel, whose activity can be measured by over expression in mammalian cells or oocytes.
  • the human a7 receptor is stably expressed in the rat GH4C1 cell line.
  • the assay was used to identify positive allosteric modulators (PAMs) of the a7 receptor. Activation of the channel was measured by loading cells with the calcium-sensitive fluorescent dye Calcium-4 (Assay kit from Molecular Devices), and then measuring real-time changes in fluorescence upon treatment with test compounds.
  • the 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 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 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 .
  • Oocytes avoid of the follicle layer are selected and incubated for 24 hours in Modified Barth's Saline buffer (88 mM NaCI, 1 mM KCI, 15 mM HEPES, 2.4 mM NaHC0 3 , 0.41 mM CaCI 2 , 0.82 mM MgS0 4 , 0.3 mM Ca(N0 3 ) 2 ) supplemented with 2 mM sodium pyruvate, 0.1 U/l penicillin and 0.1 ⁇ g/l streptomycin.
  • Modified Barth's Saline buffer 88 mM NaCI, 1 mM KCI, 15 mM HEPES, 2.4 mM NaHC0 3 , 0.41 mM CaCI 2 , 0.82 mM MgS0 4 , 0.3 mM Ca(N0 3 ) 2
  • 2 mM sodium pyruvate 0.1 U/l penicillin and 0.1 ⁇ g/l streptomycin.
  • Stage IV oocytes are identified and injected with 4.2 - 48 nl of nuclease free water containing 0.1 - 1 .2 ng of cRNA coding for human a7 nACh receptors or 3.0 - 32 ng of cRNA coding for rat a7 nACh receptors and incubated at 18°C for 1 - 10 days when they are used for electrophysiological recordings. Electrophysiological recordings of a7 nACh receptors expressed in oocytes.
  • Oocytes are used for electrophysiological recordings 1 - 10 days after injection.
  • doses-response curves can be performed for evaluation of max-fold modulation and EC 50 values for both peak and AUC responses.

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

Abstract

La présente invention porte sur des composés répondant à la formule (I) dans laquelle R1, R2, R3, R4 et R5 représentent H ; R6 représente le groupe méthoxyméthyle ; A7 représente C-R7, A8 représente N et A9 représente C-R9 ; R7, R9, R10 et R11 sont choisis indépendamment les uns des autres parmi H et les groupes alkyle en C1-6, alcényle en C2-6, alcynyle en C2-6, alcoxy en C1-6 et OR12, R12 représentant une fraction cyclique saturée monocyclique ayant 4-6 atomes de cycle, l'un desdits atomes de cycle étant et le reste étant C ; et des sels pharmaceutiquement acceptables de ceux-ci utiles en thérapie, sur des compositions comprenant lesdits composés et sur des procédés de traitement de maladies comprenant l'administration desdits composés. Les composés selon la présente invention sont des modulateurs allostériques positifs (PAM) du récepteur nicotinique à l'acétylcholine α7.
PCT/EP2013/064088 2012-07-06 2013-07-04 Nouveaux modulateurs allostériques positifs de récepteur nicotinique à l'acétylcholine WO2014006117A1 (fr)

Applications Claiming Priority (2)

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

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WO2014006117A1 true WO2014006117A1 (fr) 2014-01-09

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PCT/EP2013/064093 WO2014006120A1 (fr) 2012-07-06 2013-07-04 Nouveaux modulateurs allostériques positifs de récepteur nicotinique à l'acétylcholine

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Cited By (2)

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

Citations (4)

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

Patent Citations (4)

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

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Cited By (3)

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

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AR091678A1 (es) 2015-02-18
AR091679A1 (es) 2015-02-18

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