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WO2007039781A2 - Nouveaux composes - Google Patents

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Publication number
WO2007039781A2
WO2007039781A2 PCT/HU2006/000087 HU2006000087W WO2007039781A2 WO 2007039781 A2 WO2007039781 A2 WO 2007039781A2 HU 2006000087 W HU2006000087 W HU 2006000087W WO 2007039781 A2 WO2007039781 A2 WO 2007039781A2
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WIPO (PCT)
Prior art keywords
group
oxadiazol
alkyl
phenyl
methanone
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
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PCT/HU2006/000087
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WO2007039781A3 (fr
Inventor
Krisztina GÁL
Csaba WÉBER
Gábor András WÁGNER
Attila HORVÁTH
Györgyné NYÉKI
Mónika VASTAG
György KESERÜ
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Richter Gedeon Vegyeszeti Gyar Nyrt
Original Assignee
Richter Gedeon Vegyeszeti Gyar RT
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Publication of WO2007039781A2 publication Critical patent/WO2007039781A2/fr
Anticipated expiration legal-status Critical
Publication of WO2007039781A3 publication Critical patent/WO2007039781A3/fr
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a new class of compounds, the processes for their preparation, the pharmaceutical formulations containing these compounds, as well as the process of treatments with these compounds.
  • a major excitatory neurotransmitter in the mammalian central nervous system is the glutamate molecule, which binds to neurons in the CNS and thereby activating cell surface receptors.
  • These receptors can be divided into two major classes, ionotropic and metabotropic glutamate receptors, based on the structural features of the receptor proteins.
  • Metabotropic glutamate receptors mGluRs are G protein-coupled receptors that activate a variety of intracellular second messenger systems following the binding of glutamate.
  • Activation of mGluRs in intact mammalian neurons elicits one or more of the following responses: activation of phospholipase C; increases in phosphoinositide (PI) hydrolysis; intracellular calcium release; activation of phospholipase D; activation or inhibition of adenyl cyclase; increases or decreases in the formation of cyclic adenosine monophosphate (cAMP); activation of guanylyl cyclase; increases in the formation of cyclic guanosine monophosphate (cGMP); activation of phospholipase A2; increases in arachidonic acid release; and increases or decreases in the activity of voltage- and ligand-gated ion channels.
  • PI phosphoinositide
  • intracellular calcium release activation of phospholipase D
  • activation or inhibition of adenyl cyclase increases or decreases in the formation of cyclic adenosine monophosphate (cAMP
  • mGluRl Eight distinct mGluR subtypes, termed mGluRl through mGluR ⁇ , have been identified by molecular cloning. Nakanishi, Neuron 13:1031 (1994), Pin et al., Neuropharmacology 34: (1995), Knopfel et al., J. Med. Chem. 38:1417 (1995). Further receptor diversity occurs via expression of alternatively spliced forms of certain mGluR subtypes. Pin et al., PNAS 89:10331 (1992), Minakami et al., BBRC 199:1136 (1994), JoIy et al., J. Neurosci. 15:3970 (1995). Metabotropic glutamate receptor subtypes may be subdivided into three groups,
  • Group I, Group II, and Group III mGluRs based on amino acid sequence homology, the second messenger systems utilized by the receptors, and by their pharmacological characteristics.
  • Group I mGluR comprises mGluRl, mGluR5 and their alternatively spliced variants.
  • Metabotropic glutamate receptors have been implicated in a number of normal processes in the mammalian CNS. Activation of mGluRs has been shown to be required for induction of hippocampal long-term potentiation and cerebellar long-term depression. Bashir et al., Nature 363:347 (1993), Bortolotto et al., Nature 368:740 (1994), Aiba et al., Cell 79:365 (1994), Aiba et al., Cell 79:377 (1994). A role for mGluR activation in nociception and analgesia also has been demonstrated. Meller et al., Neuroreport 4: 879 (1993), Bordi and Ugolini, Brain Res. 871:223 (1999).
  • Group I metabotropic glutamate receptors and mGluR5 in particular, have been suggested to play roles in a variety of pathophysiological processes and disorders affecting the CNS. These include stroke, head trauma, anoxic and ischemic injuries, hypoglycemia, epilepsy, neurodegenerative disorders such as Alzheimer's disease and pain (Schoepp et al., Trends Pharmacol. Sci. 14:13 (1993), Cunningham et al., Life Sci. 54:135 (1994), Hollman et al., Ann. Rev. Neurosci. 17:31 (1994), Pin et al., Neuropharmacology 34:1 (1995), Knopfel et ⁇ L, J. Med. Ckem.
  • MGluR5-selective compounds such as 2-methyl-6-(phenylethynyl)- ⁇ yridine (“MPEP") are effective in animal models of mood disorders, including anxiety and depression (W.P.J.M Spooren et al., Br. J. Pharmacol. Exp. Ther., 295:1267-5 1275 (2000); E. Tatarczynska et al Br. J. Pharmacol., 132:1423-1430 (2001); A.
  • Y 1 and Y 2 selected from the group consisting of hydrogen, halogen atom; C 1-4 alkyl, C 1-4 alkoxy, cyano and trifluoromethyl group, Q is -CH 2 - group or N; X 1 and X 2 are different and are independently selected from N and O; Z is -(CH 2 )n- group or S; n is 1 or 2;
  • R is selected from the group consisting of optionally substituted C 1-7 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 cyanoalkyl, C 1-3 OC 1-3 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, Q ⁇ CNR ⁇ alkyl; an optionally substituted C 3-7 cycloalkyl, aryl, heteroaryl or saturated heterocyclic group; R 1 and R 2 are independently selected from hydrogen, C 1-7 alkyl or C 1-6 alkanoyl group - and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or pharmaceutically acceptable salts thereof formed with acids and bases.
  • Another aspect of the present invention provides processes for the synthesis of compounds of formula (I).
  • a further aspect of the present invention provides pharmaceutical compositions containing a therapeutically effective amount of a compound of formula (I) or enantiomers or racemates or diastereomers or geometric isomers or salts or hydrates or solvates thereof as active ingredient and pharmaceutically acceptable diluents, excipients and/or inert carriers.
  • a further aspect of the present invention provides the use of a compound of formula (I) for the prevention and/or treatment of mgluR5 receptor mediated disorders, particularly neurological disorders, psychiatric disorders, acute and chronic pain and neuromuscular dysfunctions of the lower urinary tract.
  • a further aspect of the present invention provides the use of a compound of formula (I) for the manufacture of a medicament for the prevention and/or treatment of mGluR5 receptor- mediated disorders, particularly neurological disorders, psychiatric disorders, acute and chronic pain and neuromuscular dysfunctions of the lower urinary tract.
  • a further aspect of the present invention provides methods of prevention and/or treatment of mGluR5 receptor-mediated disorders with a compound of formula (I) 5 which means administering to a mammal to be treated - including human - effective amount/amounts of compounds of formula (I) of the present invention as such or as medicament.
  • Y 1 and Y 2 selected from the group consisting of hydrogen, halogen atom; C 1-4 alkyl, C 1-4 alkoxy, cyano and trifiuoromethyl group,
  • Q is -CH 2 - group or N; X 1 and X 2 are different and are independently selected from N and O;
  • Z is -(CH 2 )n- group or S; n is 1 or 2;
  • R is selected from the group consisting of optionally substituted C 1-7 alkyl, C 1-4 haloalkyl, Ci -4 hydroxyalkyl, Ci -4 cyanoalkyl, Ci -3 OC 1-3 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, Co ⁇ CNR ⁇ alkyl; an optionally substituted C 3-7 cycloalkyl, aryl, heteroaryl or saturated heterocyclic group;
  • R 1 and R 2 are independently selected from hydrogen, C 1-7 alkyl or C 1-6 alkanoyl group - and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or pharmaceutically acceptable salts thereof formed with acids and bases.
  • R 1 and R 2 are independently selected from hydrogen, C 1-7 alkyl or C 1-6 alkanoyl group - and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or pharmaceutically acceptable salts thereof formed with acids and bases.
  • Y 1 and Y 2 selected from the group consisting of hydrogen, halogen atom, C 1-4 alkyl,
  • Ci -4 alkoxy, cyano and trifiuoromethyl group is -CH 2 - group or N;
  • X 1 and X 2 are different and are independently selected from N and O;
  • Z is -(CH 2 )n- group or S; n is 1 or 2; R is selected from the group consisting of optionally substituted C 1-7 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 cyanoalkyl, C 1-3 OC 1-3 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, Co ⁇ CNR ⁇ alkyl;
  • C 3-7 cycloalkyl group which is optionally substituted by one or more C 1-7 alkyl or oxo group
  • aryl group which is optionally substituted by one C 1-7 alkyl or C 2-7 alkynyl group
  • R 1 and R 2 are independently selected from hydrogen, C 1-7 alkyl or C 1-6 alkanoyl group - and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or pharmaceutically acceptable salts thereof formed with acids and bases.
  • Y 1 and ⁇ Y 2 selected from the group consisting of hydrogen, halogen atom, C 1-4 alkyl, C 1-4 alkoxy, cyano and trifluoromethyl group;
  • Q is -CH 2 - group or N
  • X 1 and X 2 are different and are independently selected from N and O;
  • Z is -(CH 2 )n- group or S; n is 1 or 2; R is selected from the group consisting of optionally substituted C 1-7 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 cyanoalkyl, C 1-3 OC 1-3 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, Co ⁇ CNR ⁇ alkyl;
  • C 3-7 cycloalkyl group which is optionally substituted by one or more C 1-7 alkyl group; aryl group, which is optionally substituted by one C 1-7 alkyl or C 2-7 alkynyl group; an optionally substituted heteroaryl ring, wherein said heteroaryl ring is selected from the group of furyl, thiophenyl, pyridyl, oxopyrrolyl, oxothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, thiazolyl, thiadiazolyl, izoxazolyl group; 5-6 membered saturated heterocyclyl containing 1-3 heteroatom(s) optionally substituted with Ci_ 6 -alkyl or oxo group;
  • R and R are independently selected from hydrogen, C 1-7 alkyl or C 1-6 alkanoyl group - and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or pharmaceutically acceptable salts thereof formed with acids and bases.
  • Y 1 and Y 2 selected from the group consisting of hydrogen, halogen atom, C 1-4 alkyl, C 1-4 alkoxy, cyano and trifluoromethyl group;
  • Q is -CH 2 - group or N;
  • X 1 and X 2 are different and are independently selected from N and O;
  • Z is -(CH 2 )n- group or S; n is 1 or 2;
  • R is selected from the group consisting of C 1-7 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, C 1-3 OC 1- 3 alkyl, C 2-7 alkynyl, C 0 . 2 (NR 1 R 2 )alkyl; an optionally substituted heteroaryl ring, wherein said heteroaryl ring is selected from the group of furyl, thiophenyl, pyridyl, thiazolyl, pyrrolyl group; tetrahydrofuryl or oxotetrahydrofuryl group;
  • R 1 and R 2 are independently selected from hydrogen, C 1-7 alkyl or C 1-6 alkanoyl group - and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or pharmaceutically acceptable salts thereof formed with acids and bases.
  • C 1-6 means a carbon containing linear or branched group having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • alkyl as well as other groups having the prefix “alk” such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like, means carbon chains which may be linear or branched or combinations thereof.
  • alkyl groups examples include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and the like.
  • alkenyl includes both straight and is branched chain alkenyl groups.
  • C 2 - 7 alkenyl refers to an alkenyl group having 2 to 1 carbon atoms and one to three double bonds, and may be, but is not limited to vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, crotyl, pentenyl, isopentenyl or hexenyl.
  • alkynyl includes both straight and branched chain alkynyl groups.
  • C 2-7 alkynyl refers to a group having 2 to 7 carbon atoms and one or two triple bonds, and may be, but is not limited to ethynyl, propargyl, butynyl, isobutynyl, pentynyl, isopentynyl or hexynyl.
  • cycloalkyl refers to an optionally substituted, saturated cyclic hydrocarbon ring system.
  • C 3-7 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • aryl means an aromatic substituent which is a single ring or multiple rings fused together. When formed of multiple rings, at least one of the constituent rings is aromatic.
  • the preferred aryl substituents are phenyl and naphthyl groups.
  • hetero unless specifically stated otherwise includes one or more O, S, or
  • heterocyclyl and heteroaryl include ring systems that contain one or more O, S, or N atoms in the ring, including mixtures of such atoms.
  • the hetero atoms replace ring carbon atoms.
  • heteroaryl rings include pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl.
  • heterocyclyl examples include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrolidin-2-one, piperidin 2-one, and thiomorpholinyl groups.
  • halogen includes fluorine, chlorine, bromine and iodine atoms.
  • halo may be fluoro, chloro, bromo or iodo.
  • haloalkyl means an alkyl group as defined above, wherein at least one or up to all of the hydrogen atoms are replaced with a halogen.
  • C 1-6 haloalkyl may include, but is not limited to fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, bromopropyl.
  • C 1 ⁇ O haloalkyl may include, but is not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy group.
  • optionally substituted is intended to include both substituted and unsubstituted groups.
  • optionally substituted cycloalkyl could represent a methylcyclohexyl or a cyclohexyl ring.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.
  • the salts formed with bases especially important are the salts formed with alkali metals, e.g. sodium, potassium, alkali-earth metals, e.g. calcium and magnesium, as well as with ammonia or organic amines.
  • the latter bases can have further substituents, e.g. hydroxy or amino groups, which can influence e.g. the solubility and the handling of the product.
  • Both organic and inorganic acids can be used for the formation of acid addition salts. Suitable inorganic acids can be e.g. hydrochloric acid, sulfuric acid and phosphoric acid. Representatives of monovalent organic acids can be e.g. formic acid, acetic acid, trifmoroacetic acid, propionic acid, and different butyric acids, valeric acids and capric acids. Representatives of bivalent organic acids can be e.g. oxalic acid, malonic acid, maleic acid, fumaric acid and succinic acid.
  • organic acids can also be used, such as hydroxy acids e.g. citric acid, tartaric acid, or aromatic carboxylic acids e.g. benzoic acid or salicylic acid, as well as aliphatic and aromatic sulfonic acids e.g. methanesulfonic acid and p-toluenesulfonic acid.
  • hydroxy acids e.g. citric acid, tartaric acid
  • aromatic carboxylic acids e.g. benzoic acid or salicylic acid
  • aliphatic and aromatic sulfonic acids e.g. methanesulfonic acid and p-toluenesulfonic acid.
  • aliphatic and aromatic sulfonic acids e.g. methanesulfonic acid and p-toluenesulfonic acid.
  • acid addition salts are pharmaceutically acceptable acid addition salts.
  • activated acid means an activated Boc-protected amino acid, N-acylated amino acid or properly substituted benzoic acid which can be activated as follows: i) as an acid chloride formed from the acid using a suitable reagent such as oxalyl chloride or thionyl chloride; ii) as a mixed anhydride formed with alkyl chloroformate; iii) using traditional methods to activate acids in amide coupling reactions such as CDI, EDC, HBTU.
  • Compounds described herein can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic mixtures and their substantially pure enantiomers.
  • Especially important compounds of formula (I) of the present invention are the following: ⁇ 4-[3-(3-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-thiazolidin-3-yl ⁇ -(5-methyl-thiophen-2-yl)- methanone, ⁇ 2-[3-(3-chloro- ⁇ henyl)-[l,2,4]oxadiazol-5-yl]- ⁇ yrrolidin-l-yl ⁇ -(5-methyl-thio ⁇ hen-2-yl)- methanone,
  • compositions comprising a compound represented by formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof as an active ingredient and one or more pharmaceutically acceptable carrier.
  • the compounds of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof may be administered by any convenient method, for example by oral, parenteral (including subcutaneous, intramuscular, and intravenous), buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • the compounds of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation of the compounds of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof generally consist of a suspension or solution of the compound of formula (I) or physiologically acceptable salts thereof in a suitable liquid carrier(s) for example an aqueous solvent, such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • a suitable liquid carrier(s) for example an aqueous solvent, such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • the formulation may also contain a suspending agent, preservative, flavouring or colouring agent.
  • a composition in the solid form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carrier(s) include lactose, terra alba, sucrose, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid etc.
  • tablets may be coated by standard aqueous or nonaqueous techniques.
  • a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent.
  • a composition in the solid form of a capsule can be prepared using routine encapsulation procedures.
  • pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatine capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatine capsule.
  • Typical parenteral compositions consising of a solution or suspension of the compound of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • compositions of the present invention for nasal administration containing a compound of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof may conveniently be formulated as aerosols, drops, gels and powders.
  • Aerosol formulations of the present invention typically comprise a solution or fine suspension of the compound of formula (I) in a physiologically acceptable aqueous or nonaqueous solvent and are usually presented in a single or multidose quantities in sterile form is a sealed container, which can take the form of a cartridge or refill for use with an atomizing device.
  • the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted.
  • the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas, such as compressed air or an organic propellant, such as a fluorochlorohydrocarbon.
  • the aerosol dosages form can also take the form af a pump- atomiser.
  • compositions of the present invention containing a compound of formula (I) are suitable for buccal or sublingual administration including tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier, such as sugar and acacia, tragacanth, or gelatine, glycerin etc.
  • a carrier such as sugar and acacia, tragacanth, or gelatine, glycerin etc.
  • Compositions of the present invention containing a compound of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter and other materials commonly used in the art.
  • compositions of the present invention containing a compound of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof for transdermal administration include ointments, gels and patches.
  • compositions of the present invention containing a compound of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof is preferably in the unit dose form, such as tablet, capsule or ampoule.
  • Each dosage unit of the present invention for oral administration contains preferably from 0.1 to 500 mg of a compound of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof.
  • Each dosage unit of the present invention for parenteral administration contains preferably from 0.1 to 500 mg of a compound of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof.
  • physiologically acceptable compounds of formula (I) and/or enentiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof can be administered in a daily dosage regimen.
  • mGluR5 mediated disorders such as schizophrenia, anxiety, depression, panic, bipolar disorders, and circadian disorders or chronic and acute pain disorders
  • the dosage levels from about 0,01 mg/kg to about 140 mg/kg of body weight per day are useful or alternatively about 0.5 mg to about 7 g per patient per day.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration to humans may conveniently contain from about 0.5 mg to about 5 g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Unit dosage forms will generally contain between from about 1 mg to about 1000 mg of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 25-300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.
  • the compounds of formula (I) of the present invention have been found to exhibit biological activity at mGluR5 receptors and are expected to be useful in the treatment of mGluR5 mediated disorders.
  • the compounds according to the present invention or salts thereof exhibit a high degree of potency and selectivity for individual metabotropic glutamate receptor (mGluR) subtypes.
  • mGluR metabotropic glutamate receptor
  • the compounds according to the present invention that are potent and selective for mGluR5 receptor.
  • the compounds of the present invention are expected to be useful in the prevention and/or treatment of conditions associated with excitatory activation of an mGluR5 receptor and for inhibiting neuronal damage caused by excitatory activation of an mGluR5 receptor.
  • the compounds may be used to produce an inhibitory effect of mGluR5, in mammals, including man.
  • the compounds of the invention are well suited for the prevention and/or treatment of mGluR5 receptor-mediated disorders such as acute and chronic neurological and psychiatric disorders, chronic and acute pain disorders and neuromuscular dysfunctions of the lower urinary tract.
  • the dose required for the therapeutic or preventive treatment of a particular disorder will necessarily be varied depending on the host treated and the route of administration.
  • the invention relates to compounds of formula (I) as defined hereinbefore, for use in therapy.
  • the invention relates to compounds of formula (I) as defined hereinbefore, for use in prevention and/or treatment of mGluR5 receptor-mediated disorders.
  • the invention relates to compounds of formula (I) as defined hereinbefore, for use in prevention and/or treatment of neurological disorders.
  • the invention relates to compounds of formula (I) as defined hereinbefore, for use in prevention and/or treatment of psychiatric disorders.
  • the invention relates to compounds of formula (I) as defined hereinbefore, for use in prevention and/or treatment of chronic and acute pain disorders.
  • the invention relates to compounds of formula (I) as defined hereinbefore, for use in prevention and/or treatment of neuromuscular dysfunctions of the lower urinary tract.
  • the invention relates to compounds of formula (I) as defined hereinbefore, for use in prevention and/or treatment of pain related to migraine, inflammatory pain, neuropathic pain disorders such as diabetic neuropathies, arthritis and rheumatoid diseases, low back pain, post-operative pain and pain associated with various conditions including angina, in renal or biliary colic, menstruation, migraine and gout.
  • the invention relates to compounds of formula (I) as defined hereinbefore, for use in prevention and/or treatment of Alzheimer's disease senile dementia, AIDS-induced dementia Parkinson's disease, amyotrophic lateral sclerosis, Huntington's Chorea, migraine, epilepsy, schizophrenia, depression, anxiety, acute anxiety, obsessive compulsive disorder, ophthalmological disorders such as retinopathies, diabetic retinopathies, glaucoma, auditory neuropathic disorders such as tinnitus, chemotherapy induced neuropathies, post-herpetic neuralgia and trigeminal neuralgia, tolerance, dependency, Fragile X, autism, mental retardation, schizophrenia and Down's Syndrome.
  • the invention relates to compounds of formula (I) as defined hereinbefore, for use in prevention and/or treatment of stroke, head trauma, anoxic and ischemic injuries, hypoglycemia, cardiovascular diseases and epilepsy.
  • the compounds are also well suited for the treatment of neuromuscular dysfunction of the lower urinary tract, such as urinary urgency, overactive bladder, greater urinary frequency, reduced urinary compliance, cystitis, incontinence, enuresis and dysuria.
  • the present invention relates also to the use of a compound of formula (I) as defined hereinbefore, in the manufacture of a medicament for the prevention and/or treatment of mGluR5 receptor-mediated disorders and any disorder listed above.
  • the invention also provides a method of treatment and/or prevention of mGluR5 receptor mediated disorders and any disorder listed above, in a patient suffering from, or at risk of, said condition, which comprises administering to the patient an effective amount of a compound of formula (I), as hereinbefore defined.
  • the term “therapy” includes treatment as well as prevention, unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly.
  • the term “antagonist” means a compound that by any means, partly or completely blocks the transduction pathway leading to the production of a response by the ligand.
  • disorder means any condition and disease associated with metabotropic glutamate receptor activity.
  • the pharmacological properties of the compounds of the invention were analyzed by determining binding affinity of the compounds to a binding site on mGluR5 receptors and by fluorimetric assays of intracellular calcium concentration to determine functional activity.
  • Another aspect of the present invention provides a process for preparing a compound of formula (I) or salt thereof.
  • R 5 R 3 or R 4 ' independently
  • Amidoximes, compounds of formula (III) can be prepared using synthetic chemical methods well known in the art (see C. Ainsworth et al., J. Med. Chem., 1967, 10, 208-211) by reacting suitable nitriles and hydroxylamine hydrochloride in refluxing methanol or ethanol in the presence of an appropriate base, for example an alkali metal carbonate, such as potassium carbonate or an alkali such as sodium hydroxide.
  • an alkali metal carbonate such as potassium carbonate
  • alkali such as sodium hydroxide
  • Pyridine-2-aldoxime and pyridine-3-aldoxime are commercially available.
  • Boc protected piperidine and pyrrolidine-aldoximes can be prepared by the above mentioned procedure using commercially available nitriles.
  • Boc protected or N-acylated piperidine and pyrrolidine-nitriles can be prepared from carboxamides under mild conditions (pi. S.N. Banerjee et al. Int. J. Peptid Protein Res. 1979, 14, 234-246).
  • the acid (R 5 COOH) can be activated as follows: i) as an acid chloride formed from the acid using a suitable reagent such as oxalyl chloride or thionyl chloride; ii) as a mixed anhydride formed with alkyl chloroformate; iii) using traditional methods to activate acids in amide coupling reactions such as CDI, EDC, HBTU.
  • Compounds of formula (V), 3,5-disubstituted-[l,2,4]oxadiazoles can be prepared by cyclocondensation of a compound of formula (IV).
  • Preparation of compounds of formula (V) can be carried out by cyclocondensation of O-acylamidoximes (IV) in ether type solvent (preferable THF) in the presence of tetra- butylammonium salt catalyst (TBAF) at room temperature or by heating as it is known from the literature (see: A.R. Gangloff et.al, Tetrahedron Lett., 2001, 42, 1441-43), or in the presence of a catalyst (e.g. CDI) in dimethylformamide (Deegan TX. et al. Bioorg. Med. Chem. Lett., 1999, 9, 209-212).
  • a catalyst e.g. CDI
  • Compounds of formula (VII) can be obtained by deprotecting compound of formula (VI) by acidic hydrolysis in an appropriate solvent such as ethyl acetate or dioxane saturated with hydrogen chloride gas.
  • Compounds of formula (I) can be prepared by acylation (RCOOH) of the secondary amines of general formula (VII).
  • Acylation of compounds of formula (VII) can be accomplished with an acid (RCOOH) as a reagent, which is activated by the above mentioned methods, preferably by EDC in the presence of a base such as sodium hydrogencarbonate or TEA.
  • the acylation can be carried out with a proper aminocarbamoyl chloride or isocyanide.
  • Compounds of general formula (I) can also be prepared by the following method: compounds of formula (Ha) can be prepared from N-acylated amino acids according to the above mentioned procedure. Amidoximes, compounds of formula (Ilia), can be prepared from nitriles of formula (Ila) according to the method described above. Compounds of formula (IVa) can be prepared from compounds of formula (Ilia) by acylation with a properly substituted benzoic acid (R 3 COOH). Cyclocondensation of the above mentioned O- acylamidoximes (FVa) results in compounds of general formula (Ia).
  • compounds of general formula (I) can also be prepared by the following method: compounds of formula (IVb) can be prepared by reacting a compound of formula (HIb) and an N-acylated amino acid (R 4 COOH). Cyclocondensation of the above mentioned O- acylamidoximes (IVb) results in compounds of general formula (Ib).
  • the final product, compound (I) can be obtained in appropriate purity therefore after concentration of the solution the biological experiments can be carried out without further purification.
  • Optical purities of the enantiomers were controlled by HPLC, using DAICEL Chiracel ODH chiral column.
  • Eluent a mixture of n-hexane/2-propanol/methanol (90: 5: 5 v/v) containing 0.05 % diethylamine.
  • Flow rate 1 ml/min, detection: at 220 nm.
  • 1 H NMR spectra were recorded on a Varian Unity Inova 300 or on a Varian Unity Inova 500 spectrometer. Chemical shifts are reported in parts per million relative to TMS as internal standard.
  • the reaction mixture was diluted with dichloromethane (10 ml), washed with 1 N aqueous hydrochloric acid (10 ml), water (10 ml) and 5% aqueous sodium hydrogencarbonate solution (10 ml). The organic layer was dried, filtered and concentrated to yield 0.188 g (82 %) of the title compound as oil.
  • Boc-thioproline (1.4 g, 6 mmol) was dissolved in dry THF (12 ml), CDI (1.07 g, 6.6 mmol) was added, and the mixture was stirred at 25 0 C for 30 minutes.
  • 3-Chloro-N-hydroxy- benzamidine (1.05 g, 6.15 mmol) was added (example 1, intermediate A), the reaction mixture was stirred for 1.5 hours and concentrated. The residue was dissolved in dichloromethane, washed with 1 N aqueous hydrochloric acid and brine. After drying and concentration the isolated O-acylated amidoxime was dissolved in dry THF and TBAF (1.575 g, 6 mmol) was added.
  • N-(Furan-2-carbonyl)-pyrrolidine-2-carboxylic acid (0.31 g, 1.5 mmol) (Laduree, D.et al, J.Med.Chem.,1989, 32, 456-461) was dissolved in DMF (3 ml), CDI (0.3 g, 1.65 mmol) was added, and the reaction mixture was stirred at 25 °C for 30 minutes, then 3-chloro- N-hydroxy-benzamidine (0.28 g, 1.65 mmol; Example 1, Intermediate A) was added.
  • Boc-D-proline (0.645 g, 3 mmol) was dissolved in 6 ml dry THF and CDI (0.535 g,
  • NMM 22 ml, 2 mmol
  • isobutyl chloroformate (0.26 ml, 2 mmol) were added at 0 0 C and the reaction mixture was stirred at 0 0 C for half an hour.
  • a solution of l-(tert- butoxycarbonyl)-N-hydroxy ⁇ piperidine-2-carboxamidine (Intermediate C; 0.5 g, 2 mmol) in dry DMF was added, and the reaction mixture was stirred for 1 hour, during this time the temperature reached 25 °C.
  • TBAF 0.1 g, 0.4 mmol
  • nipasol 0.005-0.02 % of nipasol, 0.01-0.5 % of carbopol (polyacrilic acid), 0.1-5 % of 96 % ethanol,
  • flavoring agent 20-70 % of sorbitol (70 % aqueous solution) and 30-50 % of distilled water.
  • suppositories For each suppository 0.01-15% of active ingredient of formula (I) and 1-20% of lactose were thoroughly mixed, then 50-95% of adeps pro suppository (for example Witepsol 4) was melted, cooled to 35 °C and the mixture of active ingredient and lactose was mixed in it with homogenizator. The obtained mixture was mould in cooled forms.
  • adeps pro suppository for example Witepsol 4
  • Lyophilized powder ampoule compositions A 5 % solution of mannitol or lactose was made with bidistilled water for injection use, and the solution was filtered so as to have sterile solution.
  • a 0.01-5 % solution of the active ingredient of formula (I) was also made with bidistilled water for injection use, and this solution was filtered so as to have sterile solution. These two solutions were mixed under aseptic conditions, filled in 1 ml portions into ampoules, the content of the ampoules was lyophilized, and the ampoules were sealed under nitrogen. The contents of the ampoules were dissolved in sterile water or 0.9 % (physiological) sterile aqueous sodium chloride solution before administration.
  • MGluR5 receptor binding was determined according to Gasparini et.al. (Bioorg.
  • rat cerebro-cortical membrane preparation was used to determine the binding characteristics of reference compounds and novel compounds to the rat mGluR5.
  • the Al 8 cell line expressing hmGluR5a (purchased from Euroscreen) was used to determine binding characteristics of the chemical compounds to the human mGluR5a receptor.
  • radioligand [ 3 H]-M-MPEP (2 nM) was used. The nonspecific binding was determined in the presence of 10 ⁇ M M-MPEP. Assessment of functional activity
  • Chinese hamster ovary (CHO) cells stably expressing recombinant human mGluR5a (CH0-mGluR5a, purchased from Euroscreen) receptors were cultured in F12 medium containing 10% FCS, 1% antibiotic antimycotic solution, 400 ⁇ g/ml G418, 250 ⁇ g/ml zeocin, 5 ⁇ g/ml puromycin.
  • Cells were kept at 37 0 C in a humidified incubator in an atmosphere of 5% C ⁇ 2 /95% air and were passaged three times a week.
  • Cells were plated at 2.5-3.5x 10 4 cell/well on standard 96-well microplates, receptor expression was induced by adding 600 ng/ml doxycycline on the next day. The calcium measurements were carried out 16-24 hours after the addition of the inducing agent.
  • cytosolic calcium concentration [Ca ]j ) were carried out on primary neocortical cultures, and on CH0-mGluR5a cells stably expressing human mGluR5a receptors.
  • assay buffer 145 niM NaCl, 5 niM KCl, 2 mM MgCl 2 , 2 mM CaCl 2 , 10 mM HEPES, 20 mM D
  • the assay buffer also contained TTX (0.5 ⁇ M, to suppress spontaneous oscillations of [Ca 2+ ]O- After incubation at 37 °C for 10-20 min. baseline and agonist-evoked changes of [Ca 2+ ]* were measured column by column with a plate reader fluorimeter (FlexStation II, Molecular Devices). Excitation and detection of emission was carried out from the bottom of the plate. The whole measurement process was performed at 37 0 C and was controlled by custom software. Inhibitory potency of the test compounds was assessed by measuring the reduction in the agonist-evoked [Ca 2+ ]j-elevation in the presence of different concentrations of the compounds.
  • DHPG was used as agonist for both cultures, the concentration was 20 ⁇ M for the neocortical cultures.
  • the EC 8 o-values were derived from daily determined dose-response curves. Fluorescence data were expressed as ⁇ F/F (fluorescence change normalized to baseline).

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Abstract

L'invention concerne de nouveaux composés de formule (I) dans laquelle Y1 et Y2 sont sélectionnés dans le groupe constitué par hydrogène, atome halogène ; C1-4 alkyle, C1-4 alkoxy, cyano et un groupe trifluorométhyle, Q représente le groupe -CH- ou N; X1 et X2 sont différents et sont sélectionnés indépendamment dans le groupe N et O; Z désigne le groupe -(CH2)n- ou S; n est égal à 1 ou à 2; R est sélectionné dans le groupe constitué par C1-7 alkyle, C1-4 haloalkyle, C1-4 hydroxyalkyle, C1-4 cyanoalkyle, C1-3 OC1-3 alkyle, C2-7 alcényle, C2-7 alkynyle, C0-2(NR1R2)alkyle éventuellement substitués; par un cycloalkyle éventuellement substitué en C3-7, aryle, hétéroaryle ou hétérocyclyle saturés; R1 et R2 sont sélectionnés indépendamment dans le groupe constitué par hydrogène, C1-7 alkyle ou C1-6 alkanoyle ; par des énantiomères et/ou des racémates et/ou des diastéréoisomères et/ou des isomères géométriques et/ou des sels pharmaceutiquement acceptables formés d'acides et de bases ; l'invention concerne également des procédés de production desdits composés, des compositions pharmaceutiques renfermant lesdits composés et leur utilisation dans la prévention et/ou le traitement de troubles induits par le récepteur de mGluR5.
PCT/HU2006/000087 2005-10-05 2006-10-05 Nouveaux composes Ceased WO2007039781A2 (fr)

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US7834039B2 (en) 2006-12-15 2010-11-16 Abbott Laboratories Oxadiazole compounds
WO2011082010A1 (fr) * 2009-12-29 2011-07-07 Eli Lilly And Company Composés de tétrahydrotriazolopyridine en tant que potentialisateurs sélectifs de récepteur mglu5 utiles pour le traitement de la schizophrénie
WO2011092293A2 (fr) 2010-02-01 2011-08-04 Novartis Ag Dérivés de cyclohexylamide utilisés en tant qu'antagonistes du récepteur du crf
WO2011092290A1 (fr) 2010-02-01 2011-08-04 Novartis Ag Dérivés de pyrazolo[5,1-b] utilisés en tant qu'antagonistes du récepteur de crf-1
WO2011095450A1 (fr) 2010-02-02 2011-08-11 Novartis Ag Dérivés de cyclohexylamide à titre d'antagonistes du récepteur crf
WO2012052489A1 (fr) 2010-10-21 2012-04-26 Bayer Cropscience Ag 1-(carbonyl hétérocyclique)pipéridines
EP2421370A4 (fr) * 2009-04-23 2012-12-12 Merck Sharp & Dohme Modulateurs du récepteur mglur5 fourrés de 2-alkyl pipéridines
WO2014057435A1 (fr) 2012-10-10 2014-04-17 Actelion Pharmaceuticals Ltd Antagonistes des récepteurs de l'orexine, qui sont des dérivés [ortho bi (hetero )aryl]-[2-(meta bi (hetero )aryl)-pyrrolidin-1-yl]-methanone
US9403813B2 (en) 2013-03-12 2016-08-02 Actelion Pharmaceuticals Ltd. Azetidine amide derivatives as orexin receptor antagonists
US9421177B2 (en) 2009-08-14 2016-08-23 University Of Virginia Patent Foundation Imidamide sphingosine kinase inhibitors
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US10329287B2 (en) 2012-06-04 2019-06-25 Idorsia Pharmaceuticals Ltd Benzimidazole-proline derivatives
WO2020154431A1 (fr) * 2019-01-25 2020-07-30 Lynch Kevin R Inhibiteurs de l'homologue 2 de spinster (spns2) destinés à être utilisés en thérapie
WO2022056042A1 (fr) * 2020-09-09 2022-03-17 University Of Virginia Patent Foundation Inhibiteurs de l'homologue de spinster 2 (spns2) à utiliser en thérapie
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US6596731B2 (en) * 2001-03-27 2003-07-22 Hoffmann-La Roche Inc. Substituted imidazo[1,2-A] pyridine derivatives
JP2006502134A (ja) * 2002-08-09 2006-01-19 アストラゼネカ アクチボラグ 代謝調節型グルタミン酸受容体において活性を有する化合物
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EP2421370A4 (fr) * 2009-04-23 2012-12-12 Merck Sharp & Dohme Modulateurs du récepteur mglur5 fourrés de 2-alkyl pipéridines
US9421177B2 (en) 2009-08-14 2016-08-23 University Of Virginia Patent Foundation Imidamide sphingosine kinase inhibitors
US9908849B2 (en) 2009-08-14 2018-03-06 University Of Virginia Patent Foundation Imidamide sphingosine kinase inhibitors
JP2013515777A (ja) * 2009-12-29 2013-05-09 イーライ リリー アンド カンパニー 統合失調症の処置に有用な選択的ｍＧｌｕ５受容体増強因子としてのテトラヒドロトリアゾロピリジン化合物
WO2011082010A1 (fr) * 2009-12-29 2011-07-07 Eli Lilly And Company Composés de tétrahydrotriazolopyridine en tant que potentialisateurs sélectifs de récepteur mglu5 utiles pour le traitement de la schizophrénie
US8592590B2 (en) 2009-12-29 2013-11-26 Eli Lilly And Company Tetrahydrotriazolopyridine compounds as selective MGLU5 receptor potentiators useful for the treatment of schizophrenia
WO2011092290A1 (fr) 2010-02-01 2011-08-04 Novartis Ag Dérivés de pyrazolo[5,1-b] utilisés en tant qu'antagonistes du récepteur de crf-1
WO2011092293A2 (fr) 2010-02-01 2011-08-04 Novartis Ag Dérivés de cyclohexylamide utilisés en tant qu'antagonistes du récepteur du crf
WO2011095450A1 (fr) 2010-02-02 2011-08-11 Novartis Ag Dérivés de cyclohexylamide à titre d'antagonistes du récepteur crf
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JP2013541553A (ja) * 2010-10-21 2013-11-14 バイエル・インテレクチユアル・プロパテイー・ゲー・エム・ベー・ハー １−（ヘテロ環式カルボニル）ピペリジン類
WO2012052489A1 (fr) 2010-10-21 2012-04-26 Bayer Cropscience Ag 1-(carbonyl hétérocyclique)pipéridines
CN103313977B (zh) * 2010-10-21 2015-06-03 拜耳知识产权有限责任公司 1-(杂环羰基)哌啶
US9545105B2 (en) 2010-10-21 2017-01-17 Bayer Intellectual Property Gmbh 1-(heterocyclic carbonyl) piperidines
US11040966B2 (en) 2012-06-04 2021-06-22 Idorsia Pharmaceuticals Ltd Benzimidazole-proline derivatives
US10329287B2 (en) 2012-06-04 2019-06-25 Idorsia Pharmaceuticals Ltd Benzimidazole-proline derivatives
CN104703980A (zh) * 2012-10-10 2015-06-10 埃科特莱茵药品有限公司 属于[邻双(杂)芳基]-[2-(间双(杂)芳基)吡咯啶-1-基]甲酮衍生物的食欲素受体拮抗剂
US9493446B2 (en) 2012-10-10 2016-11-15 Actelion Pharmaceuticals Ltd. Orexin receptor antagonists which are [ortho bi-(hetero-)aryl]-[2-(meta bi-(hetero-)aryl)-pyrrolidin-1-yl]-methanone derivatives
JP2015533157A (ja) * 2012-10-10 2015-11-19 アクテリオン ファーマシューティカルズ リミテッドＡｃｔｅｌｉｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｌｔｄ ［オルトビ−（ヘテロ−）アリール］−［２−（メタビ−（ヘテロ−）アリール）−ピロリジン−１−イル］−メタノン誘導体であるオレキシン受容体アンタゴニスト
WO2014057435A1 (fr) 2012-10-10 2014-04-17 Actelion Pharmaceuticals Ltd Antagonistes des récepteurs de l'orexine, qui sont des dérivés [ortho bi (hetero )aryl]-[2-(meta bi (hetero )aryl)-pyrrolidin-1-yl]-methanone
US9403813B2 (en) 2013-03-12 2016-08-02 Actelion Pharmaceuticals Ltd. Azetidine amide derivatives as orexin receptor antagonists
US9914721B2 (en) 2013-12-04 2018-03-13 Idorsia Pharmaceuticals Ltd Use of benzimidazole-proline derivatives
WO2020154431A1 (fr) * 2019-01-25 2020-07-30 Lynch Kevin R Inhibiteurs de l'homologue 2 de spinster (spns2) destinés à être utilisés en thérapie
US20240132487A1 (en) * 2019-10-17 2024-04-25 Givaudan Sa Substituted azacyles as trmp8 modulators
US20230277427A1 (en) * 2020-08-05 2023-09-07 Givaudan Sa Cooling sensation compositions
WO2022056042A1 (fr) * 2020-09-09 2022-03-17 University Of Virginia Patent Foundation Inhibiteurs de l'homologue de spinster 2 (spns2) à utiliser en thérapie

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