[go: up one dir, main page]

WO2007039782A1 - Derives de tetrazole utilises comme modulateurs de recepteurs metabotropiques du glutamate - Google Patents

Derives de tetrazole utilises comme modulateurs de recepteurs metabotropiques du glutamate Download PDF

Info

Publication number
WO2007039782A1
WO2007039782A1 PCT/HU2006/000088 HU2006000088W WO2007039782A1 WO 2007039782 A1 WO2007039782 A1 WO 2007039782A1 HU 2006000088 W HU2006000088 W HU 2006000088W WO 2007039782 A1 WO2007039782 A1 WO 2007039782A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
group
tetrazol
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
Application number
PCT/HU2006/000088
Other languages
English (en)
Inventor
Krisztina GÁL
Csaba WÉBER
Gábor András WÁGNER
Amrita Ágnes BOBOK
Györgyné NYÉKI
Mónika VASTAG
György KESERÜ
Viktor HÁDA
János KÓTI
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
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 Richter Gedeon Vegyeszeti Gyar RT filed Critical Richter Gedeon Vegyeszeti Gyar RT
Publication of WO2007039782A1 publication Critical patent/WO2007039782A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • C07D405/14—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 three or more hetero rings
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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

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 through mGluR8 Eight distinct mGluR subtypes, termed mGluRl through mGluR8, 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 al., J. Med. Chem.
  • MGluR5-selective compounds such as 2-methyl-6-(phenylethynyl)-pyridine (“MPEP") are effective in animal models of mood disorders, including anxiety and depression (W.PJ.M Spooren et al., Br. J. Pharmacol. Exp. Ther., 295:1267-1275 (2000); E. Tatarczynska et al, Brit. J. Pharmacol., 132:1423-1430 (2001); A.
  • International Patent Application WO 03 029210 claims novel heteroaryl-substituted tetrazoles as modulators of metabotropic glutamate receptor-5 (mGluR5).
  • the specified compound is 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine.
  • International Patent Application WO 03 077918 describes di-aryl substituted tetrazole modulators of mGluR5. It relates to new compounds of 1,3-bisaryltetrazole derivatives, compositions containing them and the method of treating a range of CNS disorders with these compounds, such as pain, including inflammatory pain, anxiety, depression, Parkinson's disease, obesity, bipolar disorders, circadian rhythm disorders and epilepsy.
  • mGluRs metabotropic glutamate receptors
  • Y 1 and Y 2 selected from the group consisting of hydrogen, halogen atom, C 1-4 alkyl, C 1-4 alkoxy or cyano group,
  • X is oxygen or two hydrogen atoms
  • 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 1-3 OC 1-3 alkyl, C 1-4 cyanoalkyl, Q ⁇ CNR ⁇ alkyl, C 1-4 -alkylCOOC 1-4 -alkyl, C 1-4 -alkylOCOC 1-4 -alkyl,
  • C 1-4 -alkylNHCOC 1-4 -alkyl C 2-7 alkenyl, C 2-7 alkynyl, CH 2 O-(CH 2 ) I-3 -OCH 3 ; an optionally substituted C 3-7 cycloalkyl; phenyl; C 3-7 saturated or unsaturated heterocyclyl or heteroaryl group containing 1-4 heteroatom(s);
  • 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.
  • 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 formulations containing a therapeutically effective amount of a compound of formula (I) or diastereomers 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), 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 or cyano group, X is oxygen or two hydrogen atoms; 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 ⁇ hydroxyalkyl, C 1-3 OCi -3 alkyl, C 1-4 cyanoalkyl, Co ⁇ CNR ⁇ alkyl, C 1-4 -alkylCOOC 1-4 -alkyl, C 1-4 -alkylOCOC 1-4 -alkyl, C 1-4 -alkylNHCOC 1-4 -alkyl, C 2-7 alkenyl, C 2-7 alkynyl, CH 2 O-(CH 2 ) L3 -OCH 3 ; an optionally substituted C 3-7 cycloalkyl; phenyl
  • 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, Ci -4 alkyl, C 1-4 alkoxy or cyano group;
  • X is oxygen or two hydrogen atoms
  • 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, Ci -4 haloalkyl, C 1-4 hydroxyalkyl, C 1-3 OCi -3 alkyl, C 1-4 cyanoalkyl, Co ⁇ CNR ⁇ alkyl, C 1-4 -alkylCOOC 1-4 -alkyl, C 1-4 -alkylOCOCi -4 -alkyl, C 1-4 -alkylNHCOC 1-4 -alkyl, C 2-7 alkenyl, C 2-7 alkynyl, CH 2 O-(CH 2 ) 1-3 -OCH 3 ;
  • C 3-7 cycloalkyl which is optionally substituted by one or more substituent(s) selected from the group of C 1-7 alkyl, cyano, acetamido or oxo group,
  • C 3-7 saturated or unsaturated heterocyclyl group which is optionally substituted by one or more substituent(s) selected from C 1-7 alkyl or oxo group, wherein the 1-4 heteroatom is independently selected from the group of N, O, S; phenyl group, which is optionally substituted by one or more substituent(s) selected from the group of Ci -7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl or cyano group; heteroaryl group, which is optionally substituted by one or more substituent(s) selected from halogen atom, C 1-7 alkyl, acetamido, Ci -4 alkoxy, cyano, Ci -4 thioalkyl, or Ci -4 alkanoyl group, wherein the 1-4 heteroatom is independently selected from the group of N, O, S;
  • R 1 and R 2 are independently selected from hydrogen, Ci -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 or cyano group;
  • X is oxygen or two hydrogen atoms;
  • 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 1-3 OC 1-3 alkyl, C 1-4 cyanoalkyl, Co ⁇ CNR ⁇ alkyl, C 1-4 -alkylCOOC 1-4 -alkyl, C 1-4 -alkylOCOC 1-4 -alkyl, C 1-4 -alkylNHCOC 1-4 -alkyl, C 2-7 alkenyl, C 2-7 alkynyl, CH 2 O-(CH 2 )i.
  • C 3-7 cycloalkyl which is optionally substituted by one or more substituent(s) selected from the group consisting of C 1-7 alkyl, cyano, acetamido or oxo group,
  • C 3-7 saturated or unsaturated heterocyclyl which is optionally substituted by one or more substituent(s) selected from C 1-7 alkyl or oxo group, wherein the 1-4 heteroatom is independently selected from the group of N, O, S; phenyl group, which is optionally substituted by one or more substituent(s) selected from the group of C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl or cyano group; a heteroaryl group, which is selected from the group of furyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrazinyl, thiazolyl, thiadiazolyl, izoxazolyl group and is optionally substituted by one or more substituent(s) selected from halogen, C 1-7 alkyl, acetamido, C 1-4 alkoxy, cyano, C 1-4 thioalkyl, or C 1-4 al
  • C 1-7 means a carbon containing linear or branched group having 1, 2, 3, 4, 5, 6 or 7 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 include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and the like.
  • alkenyl includes both straight and branched chain alkenyl groups.
  • C 2-7 alkenyl refers to an alkenyl group having 2 to 7 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 an alkylnyl 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.
  • hetero unless specifically stated otherwise includes one or more O, S, or
  • heterocyclyl and heteroaryl include ring systems that contain one or more C, O, S, or N atoms in the ring, including mixtures of such 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 rings examples include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrrolidin-2-one, ⁇ iperidin-2-one, and thiomorpholinyl groups.
  • halogen includes fluorine, chlorine, bromine and iodine atoms. In this specification, unless stated otherwise, the term “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.
  • OC 1-6 haloalkyl may include, but is not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoro ethoxy, difluoroethoxy group.
  • alkanoyl may include, but is not limited to formyl and acetyl group.
  • optionally substituted is intended to include both substituted and unsubstituted groups.
  • optionally substituted cycloalkyl could represent a methylcyclohexyl or a cyclohexyl ring.
  • 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.
  • 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, trifluoroacetic 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.
  • Other 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.
  • acid addition salts are pharmaceutically acceptable acid addition salts.
  • the reason why acid addition salts, which do not belong to the pharmaceutically acceptable acid addition salts belong to the present invention is, that in given case they can be advantageous in the purification and isolation of the desired compounds.
  • activated acid means a carboxylic acid (RCOOH) which is activated with EDC in the presence of a base such as sodium hydrogen carbonate or TEA.
  • compositions comprising a compound represented by formula (I) and/or enantiomers 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.
  • Compounds of formula (I) and/or enantiomers 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.
  • Pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • Compounds of formula (I) and/or enantiomers 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.
  • Liquid formulations of compounds of formula (I) and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof generally consist of a suspension or solution of a 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, flavoring or coloring 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 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 fo ⁇ n 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 consist of a solution or suspension of the compound of formula (I) and/or enantiomers 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.
  • compositions of the present invention for nasal administration containing a compound of formula (I) and/or enantiomers 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 fluorochlorohydro carbon.
  • the aerosol dosages form can also take the form of 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 enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof for rectal administration are conveniently formulated in the form of suppositories containing a conventional suppository base, such as cocoa butter and other materials commonly used in the art.
  • the suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.
  • compositions of the present invention containing a compound of formula (I) and/or enantiomers 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 enantiomers 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 enantiomers 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 enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts thereof.
  • Physiologically acceptable compounds of formula (I) and/or enantiomers 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.
  • a formulation intended for 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,
  • compounds according to the present invention or salts thereof exhibit a high degree of potency and selectivity for individual metabotropic glutamate receptor (mGluR) subtypes, hi particular there are compounds according to the present invention that are potent and selective for mGluR5 receptor. Accordingly, 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. Compounds maybe used to produce an inhibitory effect of mGluR5, in mammals, including human.
  • 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 rheumatitiod diseases, low back pain, post-operative pain and pain associated with various conditions including angina, in renal or billiary 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 processes for preparing compounds of formula (I) or salts thereof.
  • V a NH(CH 3 )OCH 3 *HCl, DIPEA, DMAP, DCC, dichloromethane, 30 minutes at 0 0 C, 3 hours at 25 0 C, b. LAH, anhydrous THF, 10 minutes at 0 °C, c. p-toluenesulfonhydrazide, ethanol, 30 minutes at 25 °C, d. NaOH, aqueous ethanol, at 0 °C, aqueous solution of compound of formula VH (azide), 30 minutes at O 0 C, 1 hour at 25 °C, e. ethyl acetate saturated with hydrogen chloride gas,
  • Compound of formula (III) can be prepared using synthetic chemical methods well known in the art (Martinez, J. et al. J. Med. Chem., 1985, 28, 1874-1879; Joyeau, R. et al. Eur. J. Med. Chem. Chim.Ther., 2000, 35, 257-266).
  • Aldehydes of formula (III) can be prepared by reduction of Weinreb amide in anhydrous THF at 0 °C with LAH for 10- 15 minutes. (Balboni, G. et al. Eur. J. Med. Chem. Chim.Ther., 2000, 35, 979-988).
  • Weinreb amid can be prepared by reacting a Boc-protected amino acid with N 5 O- dimethylhydroxylamine hydrochloride in the presence of DIPEA, DCC and DMAP.
  • Hydrazone of formula (IV) can be prepared by reacting an aldehyde of formula (III) with p-toluenesulfonhydrazide in ethanol (Chandrasekhar, S. et al., Tetrahedron Lett., 2000, 41, 10131-10134).
  • 2,5-Disubstituted tetrazoles of formula (V) can be prepared by reacting a phenylsulfonylhydrazones of formula (IV) with an appropriate aryldiazonium salt, compound of formula (VII) according to the process well known in the art (Ito, S. et al., Bull. Chem. Soc. Jpn., 1976, 49, 1920-1923; Shavali, A.S. J. Heterocyclic Chem., 1979, 16, 123-128).
  • An aqueous solution of compound of formula (VII) can be prepared from the hydrochloric acid solution of a suitable substituted aniline of formula (VI) and sodium nitrite at 0 °C.
  • Compound of formula (V) can be prepared by reacting a solution of hydrazon of formula (IV) with a solution of diazonium salt of formula (VII) in a mixture of sodium hydroxide and ethanol at 0-5 0 C.
  • Compound of formula (V) can be obtained by acidic hydrolysis with a solvent such as ethyl acetate or dioxane saturated with hydrogen chloride gas.
  • the present invention provides processes for the synthesis of compounds of formula (I),
  • V with an activated acid of formula RCOOH, wherein R is as defined in claim 1.
  • Acylation of compound of formula (V) can be accomplished with an acid (RCOOH) as reagent, which is activated with EDC in the presence of a base such as sodium hydrogen carbonate or TEA for 1 hour at 25 0 C.
  • the acylation can be carried out with an appropriate amino- carbamoyl-chloride or appropriate isocyanides.
  • Reductive alkylation of compound of formula (V) can be accomplished with an aldehyde (RCHO) and sodium triacetoxy-borohydride (Abdel-Magid, A.F. et al. Tetrahedron Lett. 1990, 31, 5595-5598 ).
  • the final product, compound (I) can be obtained in appropriate purity therefore after concentration of the solution biological experiments can be carried out without further purification.
  • 3-Chloroaniline (1.5 ml, 14 mmol) was suspended in 6 N aqueous hydrochloric acid (9 ml), the stirred suspension was cooled to 0 °C and a solution of sodium nitrite (1.1 g, 16 mmol) in water (7 ml) was added at 0-5 0 C, then the mixture was stirred at this temperature for 15 minutes.
  • the title compound was prepared from Boc-nipecotic acid according to the method described in Example 1 for Intermediate A.
  • the compound was purified by column chromatography to yield (96 %) an oily product.
  • the title compound was prepared from D-Boc-pipecolinic acid according to the method described in Example 1 for Intermediate A.
  • the compound was purified by column chromatography to yield (92 %) an oily product.
  • the reaction mixture was diluted with dichloromethane (4 ml), washed twice with aqueous hydrochloric acid (6 ml, 1% (m/m), twice with aqueous sodium carbonate solution (6 ml, 2 % m/m) and once with ion exchanged water (6 ml).
  • the reaction mixture was diluted with dichloromethane (4 ml), washed twice with aqueous hydrochloric acid (6 ml, 1% m/m), twice with aqueous sodium carbonate solution (6 ml, 2 % m/m) and once with ion exchanged water (6 ml).
  • the organic layer was passed through a column filled with 400 mg isoluteOsorbent and the resulting dry dichloromethane solution was concentrated to dryness (Addition of reagents and extractions were carried out with Tecan Combitec synthesizer, the samples were concentrated with Savant centrifugal evaporator.)
  • 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.
  • 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 admim ' stration.
  • MGluR5 receptor binding was determined according to Gasparini et.al. (Bioorg. Med. Chem. Lett. 2000, 12:407-409) with modifications. Based on the high homology between the human and rat mGluR5 receptors, 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. As radioligand [ 3 H]-M-MPEP (2 nM) was used. The nonspecific binding was determined in the presence of 10 ⁇ M M-MPEP.
  • CHO cells stably expressing recombinant human mGluR5a (CH0-mGluR5a, purchased from Euroscreen) receptors were cultured in F 12 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 °C in a humidified incubator in an atmosphere of 5% CO 2 /95% air and were passaged three times a week.
  • Cells were plated at 2.5-3.5xlO 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 2+ Ji ) were carried out on primary neocortical cultures, and on CHO-mGluR5a cells stably expressing human mGluR5a receptors.
  • assay buffer 145 mM NaCl, 5 mM KCl, 2 mM MgCl 2 , 2 mM CaCl 2 , 10 mM HEPES, 20 mM D-glucos
  • the assay buffer also contained TTX (0.5 ⁇ M, to suppress spontaneous oscillations of [Ca 2+ ]j).
  • TTX 0.5 ⁇ M, to suppress spontaneous oscillations of [Ca 2+ ]j.
  • baseline and agonist-evoked changes of [Ca 2+ ]i 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+ ]i-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.
  • concentration was 20 ⁇ M for the neocortical cultures.
  • ECgo-values were derived from daily determined dose-response curves. Fluorescence data were expressed as ⁇ F/F (fluorescence change normalized to baseline).

Landscapes

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

Abstract

L'invention concerne de nouveaux composés de formule (I) dans laquelle Y1 et Y2 sont sélectionnés dans le groupe constitué par hydrogène, un atome halogène, C1-4 alkyle, C1-4 alkoxy ou cyano, X représente l'oxygène ou deux atomes hydrogène; 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, C1-3OC1-3 alkyle, C1-4 cyanoalkyle, C0-2(NR1R2)alkyle, C1-4-alkylCOOC1-4-alkyle, C1-4-alkylOCOC1-4-alkyle, C1-4-alkylNHCOC1-4-alkyle, C2-7 alcényle, C2-7 alkynyle, CH2O-(CH2)1-3-OCH3 éventuellement substitués ; par un cycloalkyle en C3-7 éventuellement substitué; phényle; hétérocyclyle saturé ou insaturé en C3-7 ou par un groupe hétéroaryle contenant 1 à 4 hétéroatomes; R1 et R2 sont sélectionnés indépendamment dans le groupe constitué par hydrogène ou C1-7 alkyle ou C1-6 alkanoyle; et/ou 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 porte également sur 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/HU2006/000088 2005-10-05 2006-10-05 Derives de tetrazole utilises comme modulateurs de recepteurs metabotropiques du glutamate Ceased WO2007039782A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HUP0500921 2005-10-05
HU0500921A HUP0500921A2 (en) 2005-10-05 2005-10-05 Tetrazole derivatives, process for their preparation and their use

Publications (1)

Publication Number Publication Date
WO2007039782A1 true WO2007039782A1 (fr) 2007-04-12

Family

ID=89986318

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/HU2006/000088 Ceased WO2007039782A1 (fr) 2005-10-05 2006-10-05 Derives de tetrazole utilises comme modulateurs de recepteurs metabotropiques du glutamate

Country Status (2)

Country Link
HU (1) HUP0500921A2 (fr)
WO (1) WO2007039782A1 (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007130821A3 (fr) * 2006-05-05 2007-12-27 Astrazeneca Ab Modulateurs des récepteurs de mglur5 ii
WO2007130822A3 (fr) * 2006-05-05 2008-01-03 Astrazeneca Ab Modulateurs des récepteurs mglur5 iii
WO2010084050A2 (fr) 2009-01-13 2010-07-29 Novartis Ag Dérivés de quinazolinone utiles comme antagonistes vanilloïdes
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
WO2012052489A1 (fr) 2010-10-21 2012-04-26 Bayer Cropscience Ag 1-(carbonyl hétérocyclique)pipéridines
JP2013536851A (ja) * 2010-09-02 2013-09-26 モンサント テクノロジー エルエルシー 線虫を防除する新規組成物および方法
US9173401B2 (en) 2013-03-15 2015-11-03 Monsanto Technology Llc N-,C-disubstituted azoles and compositions and methods for controlling nematode pests
WO2017002083A1 (fr) 2015-07-02 2017-01-05 Wockhardt Limited Composés bicycliques contenant de l'azote et leur utilisation dans le traitement d'infections bactériennes
CN107108492A (zh) * 2014-12-24 2017-08-29 北京生命科学研究所 细胞坏死抑制剂
JP2022552401A (ja) * 2019-10-17 2022-12-15 ジボダン エス エー Ｔｒｍｐ８モジュレーターとしての置換アザシル
JP7778688B2 (ja) 2019-10-17 2025-12-02 ジボダン エス エー Ｔｒｍｐ８モジュレーターとしての置換アザシル

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003029210A2 (fr) * 2001-10-04 2003-04-10 Merck & Co. Inc. Composes de tetrazole substitues par heteroaryle, modulateurs du recepteur-5 metabotropique du glutamate
WO2005080356A1 (fr) * 2004-02-18 2005-09-01 Astrazeneca Ab Composes de tetrazole et leur utilisation comme antagonistes de recepteurs de glutamate metabotropiques
WO2005080386A1 (fr) * 2004-02-18 2005-09-01 Astrazeneca Ab Composes polyheterocycliques et utilisation de ceux-ci comme antagonistes du recepteur metabotropique du glutamate
WO2006048771A1 (fr) * 2004-11-04 2006-05-11 Addex Pharmaceuticals Sa Nouveaux derives de tetrazole utilises comme modulateurs allosteriques positifs des recepteurs de glutamate metabotropiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003029210A2 (fr) * 2001-10-04 2003-04-10 Merck & Co. Inc. Composes de tetrazole substitues par heteroaryle, modulateurs du recepteur-5 metabotropique du glutamate
WO2005080356A1 (fr) * 2004-02-18 2005-09-01 Astrazeneca Ab Composes de tetrazole et leur utilisation comme antagonistes de recepteurs de glutamate metabotropiques
WO2005080386A1 (fr) * 2004-02-18 2005-09-01 Astrazeneca Ab Composes polyheterocycliques et utilisation de ceux-ci comme antagonistes du recepteur metabotropique du glutamate
WO2006048771A1 (fr) * 2004-11-04 2006-05-11 Addex Pharmaceuticals Sa Nouveaux derives de tetrazole utilises comme modulateurs allosteriques positifs des recepteurs de glutamate metabotropiques

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007130821A3 (fr) * 2006-05-05 2007-12-27 Astrazeneca Ab Modulateurs des récepteurs de mglur5 ii
WO2007130822A3 (fr) * 2006-05-05 2008-01-03 Astrazeneca Ab Modulateurs des récepteurs mglur5 iii
WO2010084050A2 (fr) 2009-01-13 2010-07-29 Novartis Ag Dérivés de quinazolinone utiles comme antagonistes vanilloïdes
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
US9907306B2 (en) 2010-09-02 2018-03-06 Monsanto Technology Llc Compositions and methods for controlling nematode pests
US9339035B2 (en) 2010-09-02 2016-05-17 Monsanto Technology Llc Compositions and methods for controlling nematode pests
JP2013536851A (ja) * 2010-09-02 2013-09-26 モンサント テクノロジー エルエルシー 線虫を防除する新規組成物および方法
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
WO2012052489A1 (fr) 2010-10-21 2012-04-26 Bayer Cropscience Ag 1-(carbonyl hétérocyclique)pipéridines
CN103313977A (zh) * 2010-10-21 2013-09-18 拜耳知识产权有限责任公司 1-(杂环羰基)哌啶
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
US9402397B2 (en) 2013-03-15 2016-08-02 Monsanto Technology Llc N-,C-disubstituted azoles and compositions and methods for controlling nematode pests
US9763449B2 (en) 2013-03-15 2017-09-19 Monsanto Technology Llc N-,C-disubstituted azoles and compositions and methods for controlling nematode pests
US9173401B2 (en) 2013-03-15 2015-11-03 Monsanto Technology Llc N-,C-disubstituted azoles and compositions and methods for controlling nematode pests
US10398144B2 (en) 2013-03-15 2019-09-03 Monsanto Technology Llc N-,C-disubstituted azoles and compositions and methods for controlling nematode pests
CN107108492A (zh) * 2014-12-24 2017-08-29 北京生命科学研究所 细胞坏死抑制剂
JP2018504393A (ja) * 2014-12-24 2018-02-15 ナショナル・インスティチュート・オブ・バイオロジカル・サイエンシズ，ベイジン ネクローシス阻害薬
WO2017002083A1 (fr) 2015-07-02 2017-01-05 Wockhardt Limited Composés bicycliques contenant de l'azote et leur utilisation dans le traitement d'infections bactériennes
JP2022552401A (ja) * 2019-10-17 2022-12-15 ジボダン エス エー Ｔｒｍｐ８モジュレーターとしての置換アザシル
JP7778688B2 (ja) 2019-10-17 2025-12-02 ジボダン エス エー Ｔｒｍｐ８モジュレーターとしての置換アザシル

Also Published As

Publication number Publication date
HUP0500921A2 (en) 2007-07-30
HU0500921D0 (en) 2005-12-28

Similar Documents

Publication Publication Date Title
CN101903372B (zh) 作为食欲肽受体拮抗剂的杂芳基衍生物
SG175867A1 (en) Isoxazole-pyridine derivatives
WO2007039781A2 (fr) Nouveaux composes
CA2750678C (fr) Derives d'isoxazole
JP2009536211A (ja) Ｍｇｌｕｒ５モジュレーターｉｉｉ
US20040162278A1 (en) Triazole compounds useful in therapy
TW200811156A (en) mGluR5 modulators IV
US7825256B2 (en) Inducible nitric oxide synthase dimerization inhibitors
EP1716135B1 (fr) Piperidinyl-carbonyl-pyrrolidines et leur utilisation en tant que agonistes de la melanocortine
WO2007039782A1 (fr) Derives de tetrazole utilises comme modulateurs de recepteurs metabotropiques du glutamate
EP1638944A1 (fr) Antagonistes du recepteur tachykinine
US20090048303A1 (en) Indole-2-carboxamidine derivatives as nmda receptor antago
US7649002B2 (en) (3,5-dimethylpiperidin-1yl)(4-phenylpyrrolidin-3-yl)methanone derivatives as MCR4 agonists
US20080306055A1 (en) Heterocyclic Mchr1 Antagonists And Their Use In Therapy
MX2007001049A (es) Nuevos derivados de amida de acido carboxilico heterociclicos.
ZA200700322B (en) New benzoyl urea derivatives
AU2005266162A1 (en) Kynurenic acid amide derivatives as NR2B receptor antagonists
KR101174980B1 (ko) Ｎｋ３ 수용체 길항제로서의 피페리딘 유도체
EP1708718A1 (fr) Derives de triazole inhibant l'activite antagoniste de vasopressine
US20090149495A1 (en) Compounds
US20110184014A1 (en) New compounds
US20090326001A1 (en) Thienopyridine derivatives as modulators of metabotropic glutamate receptors

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06795046

Country of ref document: EP

Kind code of ref document: A1