WO2018079862A1 - Modulateurs de mglur7 - Google Patents

Modulateurs de mglur7 Download PDF

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Publication number
WO2018079862A1
WO2018079862A1 PCT/JP2017/040008 JP2017040008W WO2018079862A1 WO 2018079862 A1 WO2018079862 A1 WO 2018079862A1 JP 2017040008 W JP2017040008 W JP 2017040008W WO 2018079862 A1 WO2018079862 A1 WO 2018079862A1
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Prior art keywords
methyl
oxo
tetrahydroisoquinoline
carboxamide
heterocyclic ring
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PCT/JP2017/040008
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English (en)
Inventor
Martin Teall
Anne STEPHENSON
Kathryn WHITE
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Takeda Pharmaceutical Company Limited
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Publication of WO2018079862A1 publication Critical patent/WO2018079862A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—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
    • C07D405/06—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 carbon chain containing only aliphatic carbon atoms

Definitions

  • the metabotropic glutamate receptors are a family of G protein-coupled receptors that have been divided into three groups on the basis of sequence homology, putative signal transduction mechanisms and pharmacologic properties.
  • Group I includes mGluRl and mGluR5 and these receptors have been shown to activate phospholipase C.
  • Group II includes mGluR2 and mGluR3 whilst
  • Group III includes mGluR4, mGluR6, mGluR7 and mGluR8.
  • Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities.
  • mGluR7 is an inhibitory GPCR expressed pre-synaptically at the synaptic cleft on
  • R 1 independently represents halogen, cyano, hydroxyl, -N(R )2, C1-C6 alkyl, C3- C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, C1-C6 alkylcarbonyl, C3-C6 cycloalkylcarbonyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkoxycarbonyl, a saturated or unsaturated 3- to 7-membered carbocyclic ring or a saturated or unsaturated 4- to 7- membered heterocyclic ring, the heterocyclic ring comprising at least one ring heteroatom independently selected from nitrogen, oxygen and sulphur atoms, wherein each of the alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl and cycloalkoxycarbonyl moieties
  • heterocyclic ring optionally comprising one or two further double bonds
  • the heterocyclic ring comprising at least one ring heteroatom independently selected from nitrogen, oxygen and sulphur atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with at least one substituent
  • R represents C1-C alkyl substituted with at least one substituent independently selected from halogen, cyano, a saturated or unsaturated 3- to 7-membered carbocyclic ring or a saturated or unsaturated 4- to 7-membered heterocyclic ring, the heterocyclic ring comprising at least one ring heteroatom independently selected from nitrogen, oxygen and sulphur atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with at least one substituent independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylamino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and Ci- C3 haloalkoxy; provided that R is not benzyl; and
  • an "alkyl” substituent group or an “alkyl” moiety in a substituent group may be linear or branched.
  • Examples of C1-C6 alkyl groups/moieties include methyl, ethyl, propyl,
  • a “cycloalkyl” substituent group or a “cycloalkyl” moiety in a substituent group refers to a saturated hydrocarbyl ring containing, for example, from 3 to 8 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • a "haloalkyl” or “haloalkoxy" substituent group/moiety comprises at least one halogen atom, e.g. one, two, three, four or five halogen atoms. Examples of such groups/moieties include fluoromethyl, difiuoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,
  • pentafluoroethyl fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy and pentafluoroethoxy.
  • amino refers to a -NH 2 substituent group.
  • methylamino refers to a -NH(CH 3 ) substituent group and the term “dimethylamino” refers to a
  • oxo refers to an oxygen atom doubly bonded to the carbon atom to which it is attached to form the carbonyl of a ketone or aldehyde.
  • a “saturated or unsaturated 4- to 7-membered heterocyclic ring” means a saturated, partially unsaturated or fully unsaturated hydrocarbyl group containing four, five, six or seven ring atoms in which one or more (e.g. one, two, three, four, five or six) ring carbon atoms are replaced by a corresponding number of ring heteroatoms independently selected from nitrogen, oxygen and sulphur, particularly nitrogen and oxygen.
  • a “saturated or unsaturated 3- to 7-membered carbocyclic ring” means a saturated, partially unsaturated or fully unsaturated hydrocarbyl group containing three, four, five, six or seven carbon ring atoms.
  • Examples of such carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl,
  • the 5- to 7-membered carbocyclic or heterocyclic ring comprises at least one double bond and may optionally comprise one or two further double bonds, so that the ring may be partially unsaturated or fully unsaturated.
  • a "5- to 7-membered carbocyclic or heterocyclic ring” means a hydrocarbyl group containing five, six or seven ring atoms in which one or more (e.g. one, two, three, four, five or six) ring carbon atoms are optionally replaced by a corresponding number of ring heteroatoms independently selected from nitrogen, oxygen and sulphur, particularly nitrogen and oxygen.
  • cycloalkoxycarbonyl methylamino, dimethylamino, haloalkyl or haloalkoxy, the last mentioned moiety contains the atom by which the group is attached to the rest of the molecule.
  • R 1 independently represents halogen, cyano, hydroxyl, -N(R )2, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, C1-C6 alkylcarbonyl, C3-C6 cycloalkylcarbonyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkoxycarbonyl, a saturated or unsaturated 3- to 7-membered carbocyclic ring or a saturated or unsaturated 4- to 7- membered heterocyclic ring, the heterocyclic ring comprising at least one ring heteroatom (e.g.
  • R 1 independently represents halogen, C1-C6 alkyl, C1-C6 alkoxy, or a saturated or unsaturated 4- to 7-membered heterocyclic ring, the heterocyclic ring comprising at least one ring heteroatom (e.g. one, two, three, four, five or six ring heteroatoms) independently selected from nitrogen and oxygen atoms, wherein each of the alkyl and alkoxy moieties and the heterocyclic ring is independently
  • X is -NH-, -O- or -S-, preferably -NH- or -0-, and wherein any suitable heterocyclic ring atom is attached to the rest of the molecule.
  • R represents hydrogen, fluorine, chlorine, bromine, cyano, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl or C1-C4 haloalkoxy.
  • R represents hydrogen, fluorine, chlorine, hydroxyl, C1-C3 alkyl, C 1-C3 alkoxy, C1-C3 haloalkyl or C1-C3 haloalkoxy.
  • R represents hydrogen, fluorine, chlorine, hydroxyl or C1-C3 alkyl.
  • R represents hydrogen
  • substituents independently selected from halogen, cyano, hydroxyl, oxo, amino, methylamino, dimethylamino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy.
  • R represents C1-C5 alkyl substituted with at least one substituent (e.g. one, two, three, four, five, six or seven substituents) independently selected from halogen, a saturated or unsaturated 3- to 6-membered carbocyclic ring or a saturated or unsaturated 5- or 6-membered heterocyclic ring, the heterocyclic ring comprising one, two or three ring heteroatoms independently selected from nitrogen and oxygen atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with one, two or three substituents independently selected from halogen, hydroxyl, amino, methylamino, dimethylamino, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy.
  • substituent e.g. one, two, three, four, five, six or seven substituents
  • substituents e.g. one, two, three,
  • R represents C1-C4 alkyl substituted with one, two, three, four or five substituents independently selected from fluorine or chlorine; or R represents Ci alkyl substituted with one substituent selected from a saturated or unsaturated 3- to 6-membered carbocyclic ring or a saturated or unsaturated 5- or 6- membered heterocyclic ring, the heterocyclic ring comprising one or two ring heteroatoms independently selected from nitrogen and oxygen atoms, wherein the carbocyclic or heterocyclic ring is unsubstituted or substituted with one or two substituents independently selected from fluorine, chlorine and C1-C3 alkyl.
  • R represents Ci alkyl substituted with an optionally substituted saturated or unsaturated 5-membered heterocyclic ring selected from:
  • X is -NH-, -O- or -S-, preferably -NH- or -0-, and wherein any suitable heterocyclic ring atom is attached to the Ci alkyl of R "
  • X is -NH-, -O- or -S-, preferably -NH- or -0-, and wherein any suitable heterocyclic ring atom is attached to the Ci alkyl of R .
  • the present invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above which comprises reacting a compound of formula (II) or a salt (e.g. hydrochloride salt) thereof
  • R 2 and R 3 are as defined in formula (I) above, with a compound of formula (III) or a salt (e.g. hydrochloride s
  • the above process may conveniently be carried out by combining the carboxylic acid of formula (II) with the amine of formula (III) in the presence of a coupling reagent such as:
  • EDC.HC1 N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • HO At (1 -hydroxy- 7-azabenzotriazole) with triethylamine in a solvent such as
  • T3P (1-propylphosphonic anhydride) with triethylamine in a solvent such as dichloromethane at room temperature to 60°C;
  • COMU (( 1 -cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino- carbenium hexafluorophosphate) with 2,2,6,6-tetramethylpiperidine in a solvent such as dichloromethane at room temperature to 60°C;
  • the compounds of formula (I) above may be converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a formate, hemi-formate,
  • hydrochloride hydrobromide
  • benzenesulphonate besylate
  • saccharin e.g.
  • the compounds of formula (I) are in the form of a hydrochloride salt.
  • compounds of formula (I) may bear one or more radiolabels.
  • radiolabels may be introduced by using radiolabel-containing reagents in the synthesis of the compounds of formula (I), or may be introduced by coupling the
  • radiolabeled versions of the compounds may be used, for example, in diagnostic imaging studies.
  • any atom specified herein may also be an isotope of said atom.
  • hydrogen encompasses ! H, 2 H and 3 H.
  • carbon atoms are to be understood to include 12 C, 13 C and 14 C
  • nitrogen atoms are to be understood to include 14 N and 15 N
  • oxygen atoms are to be understood to include 16 0, 17 0 and 18 0.
  • compounds of formula (I) may be isotopically labelled.
  • an “isotopically labelled" compound is one in which the abundance of a particular nuclide at a particular atomic position within the molecule is increased above the level at which it occurs in nature.
  • Compounds of formula (I) and their salts may be in the form of hydrates or solvates which form an aspect of the present invention.
  • Such solvates may be formed with common organic solvents, including but not limited to, alcoholic solvents e.g. methanol, ethanol or isopropanol.
  • Compounds of formula (I) and their salts may be amorphous or in a polymorphic form or a mixture of any of these, each of which forms an aspect of the present invention.
  • the compounds of formula (I) and their pharmaceutically acceptable salts have activity as pharmaceuticals and may be used in treating conditions or disorders associated with changes in one or both of the glutamatergic and GABAergic signalling pathways regulated in full or in part by metabotropic glutamate receptor 7.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined for use in therapy, in particular for the treatment of conditions associated with metabotropic glutamate receptor 7.
  • the present invention also provides the use of a compound of formula (I) or a
  • the present invention still further provides a method of treating a condition associated with metabotropic glutamate receptor 7 which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a
  • Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disorder or condition in question.
  • Persons at risk of developing a particular disorder or condition generally include those having a family history of the disorder or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disorder or condition or those in the prodromal phase of a disorder.
  • treat include improvement of the conditions described herein.
  • the terms “treat”, “treatment” and “treating” include all processes providing slowing, interrupting, arresting, controlling, or stopping of the state or progression of the conditions described herein, but does not necessarily indicate a total elimination of all symptoms or a cure of the condition.
  • the terms “treat”, “treatment” and “treating” are intended to include therapeutic as well as prophylactic treatment of such conditions.
  • condition As used herein the terms “condition”, “disorder” and “disease” relate to any unhealthy or abnormal state.
  • the term “conditions associated with metabotropic glutamate receptor 7” includes conditions, disorders and diseases in which the modulation of mGluR.7 may provide a therapeutic benefit, examples of which include:
  • Nervous system disorders Parkinson's disease, including dementia associated with Parkinson's disease; Alzheimer's disease; Huntington's Chorea; amyotrophic lateral sclerosis; multiple sclerosis; bipolar disorder; and psychiatric disorders such as
  • schizophrenia, post-traumatic stress disorder, anxiety disorders and depression e.g. major depressive disorder
  • Hearing disorders hearing loss and/or tinnitus caused by age, noise or trauma;
  • Schizophrenia is a debilitating psychiatric disorder characterised by a combination of negative symptoms (such as social withdrawal, anhedonia, avolition and apathy) and positive symptoms (including hallucinations, delusions and paranoia) as well as marked cognitive deficits (such as impairment of executive function).
  • the executive function (EF) has been defined as "a set of abilities, which allows us to invoke voluntary control of our behavioral responses. These functions enable human beings to develop and carry out plans, make up analogies, obey social rules, solve problems, adapt to unexpected circumstances, do many tasks simultaneously, and locate episodes in time and place.
  • EF includes divided attention and sustained attention, working memory (WM), set-shifting, flexibility, planning, and the regulation of goal directed behavior and can be defined as a brain function underlying the human faculty to act or think not only in reaction to external events but also in relation with internal goals and states" (Orellana G. and Slachevsky A., 2013. Executive Functioning in Schizophrenia. Front. Psychiatry, 4, 35). Accordingly, the present invention also provides a method of treating a negative symptom, a positive symptom and/or a cognitive deficit associated with a psychiatric disorder, especially schizophrenia, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.
  • the daily dosage of the compound of the invention if inhaled, may be in the range from 0.05 micrograms per kilogram body weight ⁇ g/kg) to 100 micrograms per kilogram body weight ⁇ g/kg).
  • the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ⁇ g/kg) to 100 milligrams per kilogram body weight (mg/kg).
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the invention still further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • compositions of the invention are those conventionally employed in the field of pharmaceutical formulation, and include, but are not limited to, sugars, sugar alcohols, starches, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulphate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol
  • carboxymethylcellulose polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • compositions of the present invention may be administered orally, parenterally, by inhalation spray, rectally, nasally, buccally, vaginally or via an implanted reservoir. Oral administration is preferred.
  • the pharmaceutical compositions of the invention may contain any conventional non-toxic pharmaceutically acceptable adjuvants, diluents or carriers.
  • parenteral as used herein includes subcutaneous,
  • the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
  • the suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • suitable diluents and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycendes.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long- chain alcohol diluent or dispersant.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, powders, granules, and aqueous suspensions and solutions. These dosage forms are prepared according to techniques well-known in the art of pharmaceutical formulation. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavouring and/or colouring agents may be added.
  • compositions of the invention may also be administered in the form of suppositories for rectal administration.
  • These compositions can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active ingredient.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (percent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
  • the compounds of the invention that is, compounds of formula (I) and pharmaceutically acceptable salts thereof
  • the invention therefore further relates to combination therapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention is administered with another therapeutic agent or agents for the treatment of one or more of the conditions previously indicated.
  • therapeutic agents may be selected from the following:
  • anti-addiction drugs including, for example, acamprosate, disulfiram, naltrexone and nalmefene for alcohol dependency, and gabapentin, modafinil, topiramate, vigabatrin and baclofen for drug, particularly cocaine, addiction;
  • antidepressants such as amitriptyline, amoxapine, bupropion, citalopram,
  • clomipramine desipramine, doxepin duloxetine, elzasonan, escitalopram, fluvoxamine, fluoxetine, gepirone, imipramine, ipsapirone, maprotiline, nortriptyline, nefazodone, paroxetine, phenelzine, protriptyline, reboxetine, robaizotan, sertraline, sibutramine, tianeptine, thionisoxetine, tranylcypromaine, trazodone, trimipramine, venlafaxine, vortioxetine and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
  • antipsychotics including, for example, amisulpride, aripiprazole, asenapine, benzisoxidil, bifeprunox, brexpiprazole, carbamazepine, cariprazine, clozapine, chlorpromazine, debenzapine, divalproex, duloxetine, eszopiclone, fluphenazine, haloperidol, iloperidone, lamotrigine, loxapine, lurasidone, mesoridazine, olanzapine, paliperidone, perlapine, perphenazine, phenothiazine, phenylbutlypiperidine, pimozide, prochlorperazine, quetiapine, risperidone, sertindole, sulpiride, suproclone, suriclone, thioridazine, trifluoperazine, trim
  • anxiolytics including, for example, alnespirone, azapirones, benzodiazepines, barbiturates, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof.
  • Example anxiolytics include adinazolam, alprazolam, balezepam, bentazepam, bromazepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, cyprazepam, diazepam, diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam, prazosin, quazepam, reclazepam, tracazo
  • anticonvulsants including, for example, carbamazepine, valproate, lamotrigine, levetiracetam and gabapentin, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
  • Alzheimer's therapies including, for example, donepezil, galantamine, memantine, rivastigmine, tacrine, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
  • Parkinson's therapies including, for example, L-dopa, ropinirole, pramipexole, monoamine oxidase type B (MAO-B) inhibitors such as deprenyl, selegiline and rasagiline, catechol- O-methyl transferase (COMT) inhibitors such as entacapone or tolcapone, adenosine A-2 inhibitors, dopamine re-uptake inhibitors, NMD A antagonists, Nicotine agonists, and Dopamine agonists and inhibitors of neuronal nitric oxide synthase, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
  • MAO-B monoamine oxidase type B
  • COMP catechol- O-methyl transferase
  • entacapone or tolcapone adenosine A-2 inhibitors
  • dopamine re-uptake inhibitors NMD A antagonists
  • Nicotine agonists and Dopamine
  • migraine therapies including, for example, almotriptan, amantadine, botulinum toxin A, bromocriptine, butalbital, cabergoline, dichloralphenazone, dihydroergotamine, eletriptan, frovatriptan, lisuride, naratriptan, pergolide, pramipexole, rizatriptan, ropinirole, sumatriptan, topiramate, zolmitriptan, and zomitriptan, and equivalents and
  • (ix) stroke therapies including, for example, abciximab, activase, citicoline, desmoteplase, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
  • urinary incontinence therapies including, for example, darafenacin, duloxetine, falvoxate, mirabegron, oxybutynin, propiverine, robalzotan, solifenacin, and tolterodine, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
  • nociceptive pain therapies such as celecoxib, etoricoxib, lumiracoxib, rofecoxib, valdecoxib, diclofenac, loxoprofen, naproxen, and paracetamol, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
  • insomnia therapies including, for example, allobarbital, alonimid, amobarbital, benzoctamine, butabarbital, capuride, chloral, cloperidone, clorethate, dexclamol, ethchlorvynol, eszopiclone, etomidate, glutethimide, halazepam, hydroxyzine, lorediplon, mecloqualone, melatonin, mephobarbital, methaqualone, midaflur, nisobamate, pentobarbital, phenobarbital, propofol, ralmeteon, roletamide, suvorexant, triclofos, secobarbital, zaleplon, and Zolpidem, zopiclone and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
  • mood stabilizers including, for example, carbamazepine, divalproex, gabapentin, lamotrigine, lithium, olanzapine, quetiapine, valproate, valproic acid, and verapamil, and equivalents and pharmaceutically active isomer(s) and/or metabolite(s) thereof;
  • alpha 7 nicotinic agonists such as, for example, compounds disclosed in
  • Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 300 MHz as stated and at 300.3K, 298.2K or 293K unless otherwise stated; the chemical shifts ( ⁇ ) are reported in parts per million.
  • Spectra were recorded using a Bruker (trade mark) 400 AVANCE instrument fitted with a 5mm BBFO probe with instrument controlled by Bruker TopSpin 2.1 software, or by a Bruker 400 AVANCE-III HD instrument fitted with a 5mm BBFO smart probe or a 5mm BBFO probe with instrument controlled by Bruker TopSpin 3.2 software, or by a Bruker 400 AVANCE-III instrument fitted with a 5mm BBFO probe with instrument controlled by Bruker Topspin 3.0 software or by a Bruker 300MHz AVANCE II instrument fitted with a 5mm DUL probe with instrument controlled by Bruker TopSpin 1.3 software, or 5mm BBFO probe controlled by Bruker Topspin 3.2 software, or by a JEOL 400 Lambd
  • Preparative HPLC was performed using Agilent Technologies (trade mark) 1 100 Series system or a Waters autopurification LC/MS system or a Shimadzu semi prep HPLC system, typically using Waters 19 mm id x 250 mm long CI 8 columns such as XBridge (trade mark) or SunFire (trade mark) 5 ⁇ materials at room temperature.
  • Mobile phases typically consisted of acetonitrile mixed with water containing either 0.1 % formic acid or 0.1%) ammonia, unless otherwise stated.
  • Super Critical Fluid Chromatography (SFC) chiral separations were performed on a Waters prep30/MS system, using a flow rate of 30 mL/min, temperature of 40 °C and a pressure of 100 bar or on a Sepiatec prep 100 system, using a flow rate of 60 mL/min, temperature of 40 °C and pressure of 100 bar.
  • Mobile phases typically consisted of supercritical C0 2 and a polar solvent such as methanol, ethanol or isopropanol. Column type and eluent are detailed for individual examples.
  • 'Room temperature' as used in the present specification, means a temperature in the range from about 18 °C to about 25 °C.
  • COMU ( 1 -Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-mo holino- carbenium hexafluorophosphate
  • NBS N-bromosuccinimide
  • Example 1 7V-[(3-chlorophenyl)methyI]-2-(cycIopropyImethyl)-3-oxo-l,2,3,4- tetrahydroisoquinoline-l-carboxamide
  • T3P (0.617 mL, 1.037 mmol) was added to a stirred solution of TEA (0.211 mL, 1.555 mmol), 2-[(oxan-4-yl)methyl]-3-oxo-l,2,3,4-tetrahydroisoquinoline-l-carboxylic acid (Intermediate 3, 150 mg, 0.518 mmol) and (3-chlorophenyl)methanamine (73 mg, 0.518 mmol) in DCM (5 mL) and stirred for 30 minutes. The reaction mixture was washed with sodium bicarbonate solution and purified by column chromatography on silica, eluted with 0 - 100% EtO Ac/petroleum ether to afford the title compound.
  • Example 8 N- [(4-fluorophenyl)methyl] -2- [(oxan-4-yl)methyl] -3-oxo-l ,2,3,4- tetrahydroisoquinoline-l-carboxamide
  • Example 25 N- ⁇ [4-chloro-3-(trifluoromethyl)phenyl]methyl ⁇ -2-[(oxan-4-yl)methyl]-3- oxo-1 ,2,3 i 4-tetrahydroisoquinoline-l -carboxamide
  • test compounds were assessed in a CRE- directed luciferase reporter gene assay, using a stable CHO cell line expressing the CRE- luc reporter and human mGluR7 genes. In this cell line, production of cAMP stimulated the transcription of the luciferase gene and luciferase activity was then measured in a luminescent enzyme assay (Steady Glo assay; Promega E2550). Activation of mGluR7 decreased the forskolin stimulated luminescence signal.
  • Forskolin (Sigma F3917) was then added to the wells (5 ⁇ of 2.5 ⁇ ) and the plate was incubated for five hours (37 °C). During this incubation, the Steady Glo Substrate reagent was warmed to 37 °C. Aliquots (1 lml; stored at -20 °C) of this reagent were prepared by dissolving the contents of 1 vial of lyophilised substrate in 100 ml Steady-Glo buffer. A 25 ⁇ addition of the substrate was made to all wells and the plate was incubated for thirty minutes at RT, on a plate shaker (300 rpm; in the dark). Luminescence was then measured using the EnVision Multilabel Reader (Perkin Elmer).
  • Luminescence values were normalised to 'maximum' (forskolin alone) and 'minimum' (forskolin in the presence of tool mGluR7 agonist) controls.
  • EC 50 values were derived from this data using non-linear regression and a four parameter curve fit. The EC50 values for the compounds of the Examples are shown in Table 1.
  • Metabotropic glutamate 7 receptor subtype modulates motor symptoms in rodent models of Parkinson's disease. J Pharmacol Exp Ther., 332 (3), 1064-71.

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Abstract

La présente invention concerne des composés de formule (I), ainsi que leurs sels pharmaceutiquement acceptables. Dans la formule (I), R1, R2, R3 et n sont tels que définis dans la spécification. L'invention concerne également des procédés de préparation de ces composés, des compositions pharmaceutiques les contenant et leur utilisation thérapeutique en tant que modulateurs du récepteur 7 métabotropique du glutamate (mGluR7).
PCT/JP2017/040008 2016-10-31 2017-10-31 Modulateurs de mglur7 WO2018079862A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024105018A1 (fr) * 2022-11-14 2024-05-23 Addex Pharma S.A. Nouveaux dérivés de pyrrolo[1,2-d][1,2,4]triazinone en tant qu'effecteurs allostériques négatifs des récepteurs mglur7
WO2024105016A1 (fr) * 2022-11-14 2024-05-23 Addex Pharma S.A. Nouveaux dérivés bicycliques de [1,2,4]triazolone servant de modulateurs allostériques négatifs des récepteurs mglu7
WO2024105021A1 (fr) * 2022-11-14 2024-05-23 Addex Pharma S.A. Nouveaux dérivés de pyrrolo[1,2-d][1,2,4]triazin-1-one servant de modulateurs allostériques négatifs des récepteurs mglu7

Citations (1)

* Cited by examiner, † Cited by third party
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US20110245247A1 (en) * 2010-03-30 2011-10-06 Abbott Gmbh & Co. Kg Novel small molecule potentiators of metabotropic glutamate receptors

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110245247A1 (en) * 2010-03-30 2011-10-06 Abbott Gmbh & Co. Kg Novel small molecule potentiators of metabotropic glutamate receptors

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024105018A1 (fr) * 2022-11-14 2024-05-23 Addex Pharma S.A. Nouveaux dérivés de pyrrolo[1,2-d][1,2,4]triazinone en tant qu'effecteurs allostériques négatifs des récepteurs mglur7
WO2024105016A1 (fr) * 2022-11-14 2024-05-23 Addex Pharma S.A. Nouveaux dérivés bicycliques de [1,2,4]triazolone servant de modulateurs allostériques négatifs des récepteurs mglu7
WO2024105021A1 (fr) * 2022-11-14 2024-05-23 Addex Pharma S.A. Nouveaux dérivés de pyrrolo[1,2-d][1,2,4]triazin-1-one servant de modulateurs allostériques négatifs des récepteurs mglu7

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