WO2008036022A1 - Dérivés de tétrahydro-lh-pyrido [3,4 -b] indole ligands du récepteur cb1 - Google Patents

Dérivés de tétrahydro-lh-pyrido [3,4 -b] indole ligands du récepteur cb1 Download PDF

Info

Publication number
WO2008036022A1
WO2008036022A1 PCT/SE2007/000822 SE2007000822W WO2008036022A1 WO 2008036022 A1 WO2008036022 A1 WO 2008036022A1 SE 2007000822 W SE2007000822 W SE 2007000822W WO 2008036022 A1 WO2008036022 A1 WO 2008036022A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
tetrahydro
pyrido
alkyl
oxobutyl
Prior art date
Application number
PCT/SE2007/000822
Other languages
English (en)
Inventor
William Brown
Ziping Liu
Maxime Tremblay
Zhong-Yong Wei
Original Assignee
Astrazeneca Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Publication of WO2008036022A1 publication Critical patent/WO2008036022A1/fr

Links

Classifications

    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention is related to therapeutic compounds, pharmaceutical compositions containing these compounds, manufacturing processes thereof and uses thereof.
  • the present invention is related to compounds that may be effective in treating pain, cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and/or cardiovascular disorders.
  • cannabinoid receptor e.g., CBi receptor, CB 2 receptor
  • CBi receptors e.g., CBi receptor, CB 2 receptor
  • agonists, antagonists and inverse agonists produce relief of pain in a variety of animal models by interacting with CBi and/or CB 2 receptors.
  • CBi receptors are located predominately in the central nervous system
  • CB 2 receptors are located primarily in the periphery and are primarily restricted to the cells and tissues derived from the immune system.
  • CBi receptor agonists such as ⁇ 9 -tetrahydrocannabinol ( ⁇ 9 -THC) and anadamide
  • CNS side-effects e.g., psychoactive side effects, the abuse potential, drug dependence and tolerance, etc.
  • CBi receptors located in CNS There are lines of evidence, however, suggesting that CBi agonists acting at peripheral sites or with limited CNS exposure can manage pain in humans or animals with much improved overall in vivo profile. Therefore, there is a need for new CBi receptor ligands such as agonists that may be useful in managing pain or treating other related symptoms or diseases with reduced or minimal undesirable CNS side-effects.
  • the present invention provides CBi receptor ligands which may be useful in treating pain and/or other related symptoms or diseases.
  • C m . n or "C m . n group” refers to any group having m to n carbon atoms.
  • alkyl refers to a saturated monovalent straight or branched chain hydrocarbon radical comprising 1 to about 12 carbon atoms.
  • alky Is include, but are not limited to, groups, such as methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3 -methyl- 1 -butyl, 2-methyl-3-butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3-methyl-l- ⁇ enryl, 4- methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2- dimethyl-1-butyl, 3,3-dirnethyl-l-butyl, 2-ethyI-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl, and longer alkyl groups, such as heptyl,
  • alkyl can be unsubstituted or substituted with one or two suitable substituents.
  • cycloalkyl refers to a saturated monovalent ring-containing hydrocarbon radical comprising at least 3 up to about 12 carbon atoms.
  • Examples of cycloalkyls include, but are not limited to, C 3 _ 7 cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic and bicyclic terpenes.
  • a cycloalkyl can be unsubstituted or substituted by one or two suitable substituents.
  • the cycloalkyl is a monocyclic ring or bicyclic ring.
  • cycloalkenyl refers to a monovalent ring-containing hydrocarbon radical having at least one carbon-carbon double bond and comprising at least 3 up to about 12 carbon atoms.
  • aryl refers to a monovalent hydrocarbon radical having one or more polyunsaturated carbon rings having aromatic character, (e.g. ⁇ 4n + 2 delocalized electrons) and comprising 5 up to about 14 carbon atoms.
  • heterocyclyc ⁇ e refers to a ring-containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, O, P and S, as a part of the ring structure and including at least 3 and up to about 20 atoms in the ring(s).
  • Heterocycle may be saturated or unsaturated, containing one or more double bonds, and heterocycle may contain more than one ring. When a heterocycle contains more than one ring, the rings may be fused or unfused. Fused rings generally refer to at least two rings share two atoms therebetween.
  • Heterocycle may have aromatic character or may not have aromatic character.
  • heteromatic refers to a ring-containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, O, P and S, as a part of the ring structure and including at least 3 and up to about 20 atoms in the ring(s), wherein the ring-containing structure or molecule has an aromatic character (e.g., 4n + 2 delocalized electrons).
  • heterocyclic group refers to a radical derived from a heterocycle by removing one or more hydrogens therefrom.
  • heterocyclyl refers a monovalent radical derived from a heterocycle by removing one hydrogen therefrom.
  • heterocyclylene refers to a divalent radical derived from a heterocycle by removing two hydrogens therefrom, which serves to links two structures together.
  • heteroaryl refers to a heterocyclyl having aromatic character.
  • heterocycloalkyl refers to a monocyclic or polycyclic ring comprising carbon and hydrogen atoms and at least one heteroatom, preferably, 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and having no unsaturation.
  • heterocycloalkyl groups include pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, and pyranyl.
  • a heterocycloalkyl group can be unsubstituted or substituted with one or two suitable substiruents.
  • the heterocycloalkyl group is a monocyclic or bicyclic ring, more preferably, a monocyclic ring, wherein the ring comprises from 3 to 6 carbon atoms and form 1 to 3 heteroatoms, referred to herein as Cs- ⁇ heterocycloalkyl.
  • ix-membered refers to a group having a ring that contains six ring atoms.
  • five-membered refers to a group having a ring that contains five ring atoms.
  • a five-membered ring heteroaryl is a heteroaryl with a ring having five ring atoms wherein 1, 2 or 3 ring atoms are independently selected from N, O and S.
  • Exemplary five-membered ring heteroaryls are thienyl, fliryl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4- oxadiazolyl.
  • a six-membered ring heteroaryl is a heteroaryl with a ring having six ring atoms
  • Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
  • Heterocyclyl includes, for example, monocyclic heterocyclyls, such as: aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrofuranyl, thiophanyl, piperidinyl, 1,2,3,6-tetrahydro- pyridinyl, piperazinyl, mo ⁇ holinyl, thiomorpholinyl, pyranyl, thiopyranyl, 2,3- dihydropyranyl, tetrahydropyranyl, 1,4-dihydropyridinyl, 1,4-d
  • heterocyclyl includes aromatic heterocyclyls or heteroaryl, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, furazanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3- triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4- thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4 oxadiazolyl.
  • heterocyclyl encompasses polycyclic heterocyclyls (including both aromatic or non-aromatic), for example, indolyl, indolinyl, isoindolinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, 1,4- benzodioxanyl, coumarinyl, dihydrocoumarinyl, benzofuranyl, 2,3- dihydrobenzofuranyl, isobenzofuranyl, chromenyl, chromanyl, isochromanyl, xanthenyl, phenoxathiinyl, thianthrenyl, indolizinyl, isoindolyl, indazolyl, purinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolmyl, pteri
  • heterocyclyl includes polycyclic heterocyclyls wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings.
  • bridged heterocycles include quinuclidinyl, diazabicyclo[2.2.1]heptyl; and 7-oxabicyclo[2.2.1]heptyl.
  • alkoxy refers to radicals of the general formula -O-R, wherein R is selected from a hydrocarbon radical.
  • exemplary alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy, and propargyloxy.
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • RT room temperature
  • an embodiment of the invention provides a compound of Formula I, a pharmaceutically acceptable salt thereof, diastereomers, enantiomers, or mixtures thereof:
  • A is -(CHk) n - optionally substituted with one or more groups selected from methyl, ethyl, phenyl, benzyl and halogen, wherein n is 2, 3 or 4;
  • R 1 is selected from Chalky!, halogenated Ci ⁇ alkyl and Cs ⁇ cycloalkyl;
  • R 9 and R 10 are independently selected from -H, Q-galkyl, Ce-io ⁇ ryl, C ⁇ -ioaryl- C].4alkyl, Cs- ⁇ heterocyclyl, Cs- ⁇ heterocyclyl-C M alkyl, C 2 - 6 alkenyI, C 3-6 cycloalkyl, and C 3-6 cycloalkyl-Ci. 4 alkyl; NjN-diCCi ⁇ alkyOamido-Ci-ealkyl, hydroxy-Ci- ⁇ alkyl and Ci-ealkoxy-Ci- ⁇ alkyl.
  • A is -(CHa) 3 -.
  • A is -(CHa) 2 -.
  • A is -(CH 2 V.
  • A is -CH 2 -CH 2 -CH(-Ph)-.
  • A is -CH 2 -CH 2 -CH(-CH 2 Ph)-.
  • R 1 is selected from methyl, ethyl, 2-fluoroethyl, isopropyl, tert-butyl and cyclopropyl.
  • R 2 is selected from methyl, methylsulfonyl and ethylsulfonyl.
  • R 3 is selected from ethyl, isopropyl, propyl, 2-methy- propyl, 1 -butyl, 1-pentyl, l-acetyl-piperidin-4-yl, tetrahydrothien-3-yl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-tetrahydro-2H-pyranyl, tetrahydro-thiopyran-4-yl, 2-pyrimidinyl, 1- iminoethyl, 2-pyridinyl, 3,4,5,6-teteahydropyrdin-2-yl, 3,4-dihydro-2H-pyrrol-5-yl, 2- pyridinyl-methyl, 3-pyridiny
  • R 3 is selected from ethyl, isopropyl, propyl, 2- methy-propyl, 1-butyl, 1-pentyl, l-acetyl-piperidin-4-yl, tetrahydrothien-3-yl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-tetrahydro-2H-pyranyl, tetrahydro-thiopyran-4-yl, 1-iminoethyl, 3,4,5,6-tetrahydropyrdin-2-yl, 3,4-dihydro-2H-pyrrol-5-yl, tetrahydrofuran-3- yhnethyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, l-methyl-4-piperidinyl, 2- (tetrahydrohydrofuran
  • R 3 is selected from cyclopentyl and 4- tetrahydro-2H-pyranyl.
  • the compounds of the invention may exist in, and be isolated as, enantiomeric or diastereomeric forms, or as a racemic mixture.
  • the present invention includes any possible enantiomers, diastereomers, racemates or mixtures thereof, of a compound of Formula I.
  • the optically active forms of the compound of the invention may be prepared, for example, by chiral chromatographic separation of aracemate, by synthesis from optically active starting materials or by asymmetric synthesis based on the procedures described thereafter.
  • certain compounds of the present invention may exist as geometrical isomers, for example E and Z isomers of alkenes.
  • the present invention includes any geometrical isomer of a compound of Formula I. It will further be understood that the present invention encompasses tautomers of the compounds of the Formula I.
  • salts of the compounds of the Formula I are also salts of the compounds of the Formula I.
  • pharmaceutically acceptable salts of compounds of the present invention may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound, for example an alkyl amine with a suitable acid, for example, HCl or acetic acid, to afford a physiologically acceptable anion.
  • a corresponding alkali metal such as sodium, potassium, or lithium
  • an alkaline earth metal such as a calcium
  • a compound of the present invention having a suitably acidic proton, such as a carboxylic acid or a phenol with one equivalent of an alkali metal or alkaline earth metal hydroxide or alkoxide (such as the ethoxide or methoxide), or a suitably basic organic amine (such as choline or meglumine) in an aqueous medium, followed by conventional purification techniques.
  • a suitably acidic proton such as a carboxylic acid or a phenol
  • an alkali metal or alkaline earth metal hydroxide or alkoxide such as the ethoxide or methoxide
  • a suitably basic organic amine such as choline or meglumine
  • the compound of Formula I above may be converted to a pharmaceutically acceptable salt or solvate thereof, particularly, an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate or/7-toluenesulphonate.
  • an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate or/7-toluenesulphonate.
  • the compounds of the invention exhibit selective activity as agonist of the CBi receptors and are useful in therapy, especially for relief of various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc.
  • various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc.
  • compounds of the present invention are useful in other disease states in which dysfunction of CBi receptors is present or implicated.
  • the compounds of the invention may be used to treat cancer, multiple sclerosis, Parkinson's disease, Huntington's chorea, Alzheimer's disease, anxiety disorders, obesity, gastrointestinal disorders and cardiovascular disorders. Even furthermore, the compounds of the invention may be useful in enhancing smoking cessation.
  • Compounds of the invention are useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies
  • Compounds of the invention are useful in disease states where degeneration or dysfunction of cannabinoid receptors is present or implicated in that paradigm. This may involve the use of isotopically labelled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).
  • PET positron emission tomography
  • Compounds of the invention are useful for the treatment of diarrhoea, depression, anxiety and stress-related disorders such as post-traumatic stress disorders, panic disorder, generalized anxiety disorder, social phobia, and obsessive compulsive disorder, urinary incontinence, premature ejaculation, various mental illnesses, cough, lung oedema, various gastro-intestinal disorders, e.g. constipation, functional gastrointestinal disorders such as Irritable Bowel Syndrome and Functional Dyspepsia, Parkinson's disease and other motor disorders, traumatic brain injury, stroke, cardioprotection following miocardial infarction, obesity, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension.
  • stress-related disorders such as post-traumatic stress disorders, panic disorder, generalized anxiety disorder, social phobia, and obsessive compulsive disorder, urinary incontinence, premature ejaculation, various mental illnesses, cough, lung oedema
  • Compounds of the invention are useful as an analgesic agent for use during general anaesthesia and monitored anaesthesia care.
  • Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anaesthetic state (e.g. amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anaesthetics, hypnotics, anxiolytics, neuromuscular blockers and opioids.
  • a further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the Formula I above, is administered to a patient in need of such treatment.
  • the invention provides a compound of Formula I or pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
  • the present invention provides the use of a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the term “therapeutic” and “therapeutically” should be contrued accordingly.
  • the term “therapy” within the context of the present invention further encompasses to administer an effective amount of a compound of the present invention, to mitigate either a pre-existing disease state, acute or chronic, or a recurring condition. This definition also encompasses prophylactic therapies for prevention of recurring conditions and continued therapy for chronic disorders.
  • the compounds of the present invention are useful in therapy, especially for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, neuropathic pain, back pain, cancer pain, and visceral pain.
  • the compound of the invention may be administered in the form of a conventional pharmaceutical composition by any route including orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intxathecally, transdermally, intracerebroventricularly and by injection into the joints.
  • the route of administration may be oral, intravenous or intramuscular.
  • the dosage will depend on the route ' of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level at the most appropriate for a particular patient.
  • a solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or table disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid, which is in a mixture with the finely divided compound of the invention, or the active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture in then poured into convenient sized moulds and allowed to cool and solidify.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.
  • composition is also intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included.
  • Liquid form compositions include solutions, suspensions, and emulsions.
  • sterile water or water propylene glycol solutions of the active compounds may be liquid preparations suitable for parenteral administration.
  • Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired.
  • Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • the pharmaceutical composition will preferably include from 0.05% to 99%w (per cent by weight), more preferably from 0.10 to 50%w, of the compound of the invention, all percentages by weight being based on total composition.
  • a therapeutically effective amount for the practice of the present invention may be determined, by the use of known criteria including the age, weight and response of the individual patient, and interpreted within the context of the disease which is being treated or which is being prevented, by one of ordinary skills in the art.
  • the use of any compound of Formula I as defined above for the manufacture of a medicament is the use of any compound of Formula I as defined above for the manufacture of a medicament.
  • any compound of Formula I for the manufacture of a medicament for the therapy of pain. Additionally provided is the use of any compound according to Formula I for the manufacture of a medicament for the therapy of various pain conditions including, but not limited to: acute pain, chronic pain, neuropathic pain, back pain, cancer pain, and visceral pain.
  • a further aspect of the invention is a method for therapy of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the Formula I above, is administered to a patient in need of such therapy.
  • a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier for therapy, more particularly for therapy of pain.
  • composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier use in any of the conditions discussed above.
  • IiCB 1 and hCB? receptor binding Human CBi receptor from Receptor Biology (hCBi) or human CB 2 receptor from BioSignal (I1CB 2 ) membranes are thawed at 37 0 C, passed 3 times through a 25- gauge blunt-end needle, diluted in the cannabinoid binding buffer (50 mM Tris, 2.5 mM EDTA, 5 mM MgCl 2 , and 0.5 mg/mL BSA fatty acid free, pH 7.4) and aliquots containing the appropriate amount of protein are distributed in 96-well plates.
  • cannabinoid binding buffer 50 mM Tris, 2.5 mM EDTA, 5 mM MgCl 2 , and 0.5 mg/mL BSA fatty acid free, pH 7.4
  • the IC5 0 of the compounds of the invention at hCBi and I1CB 2 are evaluated from 10-point dose-response curves done with 3 H-CP55,940 at 20000 to 25000 dpm per well (0.17- 0.21 nM) in a final volume of 300 ⁇ l.
  • the total and non-specific binding are determined in the absence and presence of 0.2 ⁇ M of HU210 respectively.
  • the plates are vortexed and incubated for 60 minutes at room temperature, filtered through Unifilters GF/B (presoaked in 0.1% polyethyleneimine) with the Tomtec or Packard harvester using 3 mL of wash buffer (50 mM Tris, 5 mM MgCl 2 , 0.5 mg BSA pH 7.0). The filters are dried for 1 hour at 55 °C.
  • the radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 ⁇ l/well of MS-20 scintillation liquid.
  • Human CBj receptor from Receptor Biology (hCBi) or human CB 2 receptor membranes (BioSignal) are thawed at 37 0 C, passed 3 times through a 25-gauge blunt-end needle and diluted in the GTP ⁇ S binding buffer (50 mM Hepes, 20 mM NaOH, 100 mM NaCl, 1 mM EDTA, 5 mM MgCl 2 , pH 7.4, 0.1% BSA).
  • the EC 50 and E max of the compounds of the invention are evaluated from 10-point dose- response curves done in 300 ⁇ l with the appropriate amount of membrane protein and 100000-130000 dpm of GTPg 35 S per well (0.11 -0.14 nM).
  • the basal and maximal stimulated binding is determined in absence and presence of 1 ⁇ M (hCB 2 ) or 10 ⁇ M (hCBi) Win 55,212-2 respectively.
  • the membranes are pre-incubated for 5 minutes with 56.25 ⁇ M (hCB2) or 112.5 ⁇ M (hCBi) GDP prior to distribution in plates (15 ⁇ M (TiCB 2 ) or 30 ⁇ M (hCBi) GDP final).
  • the plates are vortexed and incubated for 60 minutes at room temperature, filtered on Unifilters GFfB (presoaked in water) with the Tomtec or Packard harvester using 3 ml of wash buffer (50 mM Tris, 5 mM MgCl 2 , 50 mM NaCl, pH 7.0). The filters are dried for 1 hour at 55 0 C. The radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 ⁇ l/well of MS-20 scintillation liquid.
  • wash buffer 50 mM Tris, 5 mM MgCl 2 , 50 mM NaCl, pH 7.0.
  • IC 50 is the concentration of the compound of the invention at which 50% displacement has been observed
  • [rad] is a standard or reference radioactive ligand concentration at that moment; and Kd is the dissociation constant of the radioactive ligand towards the particular receptor.
  • the compounds of the invention are found to be active towards human CBi receptors.
  • Step A ⁇ ir -[4-(Cyclopropylamino)-4-oxobutyl]-iV,5-dimethyl-2-(tetrahydro-2J3 r - pyran-4-yI)-2,3,4,5-tetrahydro-lH-pyrido[4,3-6]indoIe-8-carboxamide
  • HATU(146 mg, 0.38 mmol) was added portionwise into a mixture of 5-methyl-2- (tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-lH-pyrido[4,3- ⁇ ]indole-8-carboxylic acid (100 mg, 0.32 mmol) (see following steps B, C, D, E, F, G, and ⁇ for its preparation), 4-(methylamino) butyric acid hydrochloride (50 mg, 0.32 mmol) and NN-diisopropylethylamine (0.3 uL, 1.3 mmol) in dry DMF (5 mL) at 0 0 C.
  • the carboxylic acid (87.7 g) was mixed with methanol in a 3L round bottom flask and cooled in an ice bath. Acetyl chloride (100 mL) was slowly added and the ice bath was removed. The mixture was heated at reflux for 3.5 hours. After cooling at room temperature, the mixture was concentrated by evaporation of methanol and the solid was collected by filtration to provide final product (87.3 g, 111 % for two steps, still containing ammonium chloride).
  • Step E 2-fert-Butyl 8-methyl 5-methyl-l,3,4,5-tetrahydro-2H-pyrido[4,3- ⁇ ]indole-2,8-dicarboxyIate
  • Step F Methyl 5-methyl-2,3,4,5-tetrahydro-lia r -pyrido[4,3-6]indole-8- carboxylate
  • Step G Methyl 5-methyl-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-lH- pyrido [4,3-6] indole-8-carboxylate
  • Step H 5-Methyl-2-(tetrahydro-2fr-pyran-4-yl)-2,3,4,5-tetrahydro-lJ3 r - pyrido [4,3-6]indole-8-carboxylic acid
  • HATU (0.21 g, 0.56 mmol) was added to a solution of 4-[ ⁇ [2-cyclopentyl-5- (methylsulfonyl)-2,3,4,5-tetrahydro-lH-pyrido[4,3- ⁇ ]indol-8- yl]carbonyl ⁇ (methyl)amino]butanoic acid (0.20 g, 0.43 mmol), DIPEA (0.18 roL, 1.0 mmol) and methylamine (2M in T ⁇ F, 0.25 mL, 0.52 mmol) in DMF (15 mL). The reaction mixture was stirred for 3 hrs. and was then concentrated.
  • Step E 2-(4-Tetrahydropyranyl)-5-raetliylsulfone-2,3,4,5-tetrahydro-li ⁇ - pyrido[4-3b]indole-8-carboxylic acid
  • the crude methyl ester was diluted in hot denatured ethanol (350 mL) and 1,2 M lithium hydroxide solution (60 mL) was added. The mixture was heated at reflux for 4 hours. After cooling to room temperature, ethanol was evaporated and water (60 mL) was added. Acetic acid was slowly added to obtain a pH of 5-6. Then the product precipitated as a thick solid that gave to the mixture a creamy texture. After filtration under vacuum, the final product was obtained as a beige solid (free amine).
  • Step F Methyl 4-[ ⁇ [2-cyclopentyl-5-(methylsuIfonyl)-2,3,4,5-tetrahydro-lH- pyrido[4,3-AJindol-8-yl]carbonyl ⁇ (methyl)amino]butanoate
  • the reaction mixture was slowly added to a mixture OfNaHCO 3 (0.40 g, 4.8 mmol) and MeOH (80 mL) at -78°C. The resulting mixture was allowed to warm to ambient temperature and the solvent was concentrated. CH 2 CI 2 (20 mL) was added and the precipitated salts were filtered. The filtrate was concentrated and the product was purified by preparative reverse-phase HPLC to provide the TFA salt of the title compound as a white solid (60 mg, 20 %).
  • Step G 2-Cyclopentyl- ⁇ '-[4-(cyclopropylamino)-4-oxobutyl]-iV-methyl-2,3,4,5- tetrahydro ⁇ lH-pyrido[4,3-Z>]indole-8-carboxamide
  • Step A iV-[4-(Cyclopropylamino)-4-oxobutyl]-5-(ethyIsulfonyl)-iV-methyl-2- (tetrahydro-2J3 r -pyran-4-yl)-2,3,4,5-tetrahydro-lH-pyrido[4,3-6]indole-8- carboxamide
  • Step D Methyl 5-(ethylsulfonyl)-2-(tetrahydro-2H-pyraa-4-yl)-2,3,4,5- tetrahydro-lH-pyrido [4,3-b]indoIe-8-carboxylate

Abstract

La présente invention concerne des dérivés de tétrahydro-lH-pyrido [3, 4- b] indole, des procédés de préparation de ceux-ci, des compositions pharmaceutiques les contenant et leur utilisation thérapeutique. Ces composés sont des ligands du récepteur des cannabinoïdes (CB1) et peuvent ainsi être utilisés dans le traitement de la douleur, du cancer, de la sclérose en plaques, de la maladie de Parkinson, de la chorée de Huntington, de la maladie d'Alzheimer, des troubles de l'anxiété, des troubles gastro-intestinaux et/ou des troubles cardiovasculaires.
PCT/SE2007/000822 2006-09-20 2007-09-19 Dérivés de tétrahydro-lh-pyrido [3,4 -b] indole ligands du récepteur cb1 WO2008036022A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US82625006P 2006-09-20 2006-09-20
US60/826,250 2006-09-20

Publications (1)

Publication Number Publication Date
WO2008036022A1 true WO2008036022A1 (fr) 2008-03-27

Family

ID=39200762

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2007/000822 WO2008036022A1 (fr) 2006-09-20 2007-09-19 Dérivés de tétrahydro-lh-pyrido [3,4 -b] indole ligands du récepteur cb1

Country Status (1)

Country Link
WO (1) WO2008036022A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1863810A1 (fr) * 2005-03-22 2007-12-12 AstraZeneca AB NOUVEAUX DERIVES DE TETRAHYDRO-1H-PYRIDO [4,3-b] INDOLE UTILISES COMME LIGANDS DU RECEPTEUR CB1'
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040023947A1 (en) * 2002-05-24 2004-02-05 X-Ceptor Therapeutics Inc. Azepinoindole and pyridoindole derivatives as pharmaceutical agents
JP2005162657A (ja) * 2003-12-02 2005-06-23 Takeda Chem Ind Ltd カンナビノイド受容体調節剤
WO2006101434A1 (fr) * 2005-03-22 2006-09-28 Astrazeneca Ab Nouveaux derives de tetrahydro-1h-pyrido [4,3-b]indole utilises comme ligands du recepteur cb1'

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040023947A1 (en) * 2002-05-24 2004-02-05 X-Ceptor Therapeutics Inc. Azepinoindole and pyridoindole derivatives as pharmaceutical agents
JP2005162657A (ja) * 2003-12-02 2005-06-23 Takeda Chem Ind Ltd カンナビノイド受容体調節剤
WO2006101434A1 (fr) * 2005-03-22 2006-09-28 Astrazeneca Ab Nouveaux derives de tetrahydro-1h-pyrido [4,3-b]indole utilises comme ligands du recepteur cb1'

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1863810A1 (fr) * 2005-03-22 2007-12-12 AstraZeneca AB NOUVEAUX DERIVES DE TETRAHYDRO-1H-PYRIDO [4,3-b] INDOLE UTILISES COMME LIGANDS DU RECEPTEUR CB1'
EP1863810A4 (fr) * 2005-03-22 2010-03-31 Astrazeneca Ab NOUVEAUX DERIVES DE TETRAHYDRO-1H-PYRIDO [4,3-b] INDOLE UTILISES COMME LIGANDS DU RECEPTEUR CB1'
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments

Similar Documents

Publication Publication Date Title
US20100113502A1 (en) Novel Tetrahydro-1H-Pyrido[4,3-b] Indole Derivatives as CB1 Receptor Ligands
US7615642B2 (en) Therapeutic compounds
JP2008519833A (ja) インダゾールスルホンアミド誘導体
US20090062251A1 (en) Novel Compounds 002
RU2346938C2 (ru) Производные бензимидазола, содержащие их композиции, их получение и применение
US7501447B2 (en) Benzimidazole derivatives, compositions containing them, preparation thereof and uses thereof
ES2285409T3 (es) Derivados pirrol(2,3-b)piridina sustituidos con heteroarilo como antagonistas del receptor de crf.
HUT62573A (en) Process for producing piperidine derivatives and pharmaceutical compositions comprising such compounds
EP1615922A1 (fr) Derives azaindole, preparations de ces derives azaindole et compositions contenant ces derniers
MXPA05003901A (es) Nuevos compuestos.
US20070072853A1 (en) Benzimidazole derivatives compositions containing them, preparation thereof and uses thereof
JP2006527247A (ja) ベンゾイミダゾール誘導体、それらを含む組成物、それらの製造及びそれらの使用
EP1670790B1 (fr) Derives de benzimidazole, compositions contenant ces derives, preparation et utilisations
WO2008036021A1 (fr) Dérivés de tétrahydro-lh-pyrido [3,4 -b] indole ligands du récepteur cbl
AU2005287429A1 (en) Compounds, compositions containing them, preparations thereof and uses thereof II
EP1670770B1 (fr) Derives de benzimidazole, compositions contenant ces derives, preparation et utilisations de ceux-ci
US20070161619A1 (en) Pyrroloquinoline and piperidoquinoline derivatives, preparation thereof, compositions containing them and uses thereof
WO2008036022A1 (fr) Dérivés de tétrahydro-lh-pyrido [3,4 -b] indole ligands du récepteur cb1
SK8542002A3 (en) Substituted homopiperidinyl benzimidazole analogues as fundic relaxants
US20110086853A1 (en) Therapeutic Compounds
JP2008534641A (ja) 二環式化合物の調製方法
MXPA06008941A (en) Pyrroloquinoline and piperidoquinoline derivatives, preparation thereof, compositions containing them and uses thereof
KR20070057856A (ko) 화합물, 그를 함유하는 조성물, 그의 제조 방법 및 그의용도

Legal Events

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

Ref document number: 07808831

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07808831

Country of ref document: EP

Kind code of ref document: A1