WO2007072089A1 - Mglur5 antagonistic carbamoyl-oxime derivatives - Google Patents
Mglur5 antagonistic carbamoyl-oxime derivatives Download PDFInfo
- Publication number
- WO2007072089A1 WO2007072089A1 PCT/HU2006/000117 HU2006000117W WO2007072089A1 WO 2007072089 A1 WO2007072089 A1 WO 2007072089A1 HU 2006000117 W HU2006000117 W HU 2006000117W WO 2007072089 A1 WO2007072089 A1 WO 2007072089A1
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- WIPO (PCT)
- Prior art keywords
- formula
- alkyl
- hydrogen
- oxime
- substituent
- Prior art date
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/60—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups having oxygen atoms of carbamate groups bound to nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/53—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/61—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- the present invention relates to new niGluR5 receptor subtype preferring ligands of formula (I) and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts and/or hydrates and/or solvates thereof, to the processes for their preparation, to pharmaceutical compositions containing these compounds and to their use in therapy and/or prevention of a condition which requires modulation of mGluR5 receptors.
- a major excitatory neurotransmitter in the mammalian central nervous system is the glutamate molecule, which binds to neurons, 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, the means by which the receptors transduce signals into the cell, and pharmacological profiles.
- niGluRs The metabotropic glutamate receptors (niGluRs) 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. (Trends Pharmacol. ScL, 1993, 14, 13; Neuro
- mGluRl Eight distinct mGluR subtypes, termed mGluRl through mGluR8, have been identified by molecular cloning (Neuron, 1994, 13, 1031; Neuropharmacology, 1995, 34, 1; J. Med. Chem., 1995, 38, 1417). Further receptor diversity occurs via expression of alternatively spliced forms of certain mGluR subtypes (PNAS, 1992, 89, 10331; BBRC, 1994, 199, 1136; J. NeuroscL, 1995, 15, 3970).
- Metabotropic glutamate receptor subtypes may be subdivided into three groups, Group I, Group II, and Group III niGluRs, based on amino acid sequence homology, the second messenger systems utilized by the receptors, and by their pharmacological characteristics.
- Group I mGluR comprises niGluRl, 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 (Nature, 1993, 363, 347; Nature, 1994, 368, 740; Cell, 1994, 79, 365; Cell, 1994, 79, 377). A role for mGluR activation in nociception and analgesia also has been demonstrated (Neuroreport, 1993, 4, 879; Brain Res., 1999, 871, 223).
- mGluR5- selective compounds such as 2-methyl-6-(phenylethynyl)- ⁇ yridine (“MPEP") are effective in animal models of mood disorders, including anxiety and depression (J. Pharmacol. Exp. Ther., 2000, 295, 1267; Brit. J. Pharmacol, 2001, 132, 1423; Pol J. Pharmacol, 2001, 132, 1423). Much of the pathology in these conditions is thought to be due to excessive glutamate- induced excitation of CNS neurons. As Group I mGluRs appear to increase glutamate- mediated neuronal excitation via postsynaptic mechanisms and enhanced presynaptic glutamate release, their activation probably contributes to the pathology. Accordingly, selective antagonists of Group I mGluR receptors could be therapeutically beneficial, specifically as neuroprotective agents, analgesics or anticonvulsants.
- MPEP 2-methyl-6-(phenylethynyl)- ⁇ yridine
- O-[[[(un)substituded-phenyl]ammo]carbonyl]-oxime (carbamoyl-oxime) derivatives can be purchased from chemical libraries without known biological activity.
- cyclohexanone carbamoyl oxime derivatives can be purchased from ComGenex International Inc. (Monmouth, NJ, USA), Ambinter (Paris, France), Interchim (Montlucon, France) or Zelinsky Institute of Organic Chemistry (Moscow, Russia); cyclopentanone carbamoyl oxime derivatives from ComGenex International Inc. (Monmouth, NJ, USA) or Interchim (Montlucon, France); 2-butanone carbamoyl oxime derivatives from Interchim (Montlucon, France).
- German Patent DE 1802739 describes biocidal ureas and carbamates (among them cyclohexanone O-[4-(trifluoromethyl)-carbamoyl]oxime) having herbicidal, bactericidal, insecticidal, coccidistatic, anthelmintic, fungicidal and nematocidal properties.
- German (East) Patent DD 32540 relates to O-carbamoyl ketoxime derivatives. These compounds controlled a wide variety of weeds at doses of 2-6 kg/ha.
- the present invention relates to new mGluR.5 receptor subtype preferring ligands of formula (I):
- R 1 and R 2 represent independently a substituent selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl and cyano;
- X is a CHR 6 group or O
- R 3 represents an alkyl substituent
- R 4 and/or R 5 represent hydrogen
- R 6 is hydrogen or alkyl
- Y is an optionally substituted phenyl or heterocyclyl, and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts and/or hydrates • and/or solvates thereof, to the process for producing the same, to pharmaceutical compositions containing the same and to their use in therapy and/or prevention of pathological conditions which require the modulation of mGluR5 receptor such as neurological disorders, psychiatric disorders, acute and chronic pain and neuromuscular dysfunctions of the lower urinary tract.
- the present invention relates to new mGluR5 receptor subtype preferring ligands of formula (I):
- R 1 and R 2 represent independently a substituent selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl and cyano;
- X is a CHR 6 group or O
- R 3 represents an alkyl substituent
- R 4 and/or R 5 represent hydrogen
- R 6 is hydrogen or alkyl
- Y is an optionally substituted phenyl or heterocyclyl, and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts and/or hydrates and/or solvates thereof.
- R 1 and/or R 2 and/or R 3 and/or R 6 represent alkyl
- the alkyl group contains 1 to 4 carbon atom(s) with straight or branched chain.
- R 1 and/or R 2 represent alkoxy and/or haloalkyl group
- the alkyl moiety inside the group contains 1 to 4 carbon atom(s) with straight or branched chain.
- the phenyl group may be optionally substituted with one or more substituent(s) selected from halogen, hydroxy, cyano, C 1-4 alkylamino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl.
- the heterocyclyl group may be a saturated or unsaturated monocyclic or bicyclic ring, which contains 1-4 heteroatom(s) selected from O, N or S, and which may be optionally substituted with one or more substituent(s) selected from halogen, hydroxy, cyano, C 1-4 alkylamino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl.
- 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 and up to all of the hydrogen atoms are replaced with a halogen.
- Certain compounds of formula (I) contain basic function(s) so may form salts with acids.
- the invention relates also to the salts of compounds of formula (I) formed with acids, especially the salts formed with pharmaceutically acceptable acids.
- the meaning of compound of formula (I) is either the free base or the salt even if it is not referred separately.
- Both organic and inorganic acids can be used for the formation of acid addition salts.
- Suitable inorganic acids can be for example hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.
- Representatives of monovalent organic acids can be for example formic acid, acetic acid, propionic acid, and different butyric acids, valeric acids and capric acids.
- Representatives of bivalent organic acids can be for example oxalic acid, malonic acid, maleic acid, fumaric acid and succinic acid.
- organic acids can also be used, such as hydroxy acids for example citric acid, tartaric acid, or aromatic carboxylic acids for example benzoic acid or salicylic acid, as well as aliphatic and aromatic sulfonic acids for example methanesulfonic acid, naphthalenesulfonic acid and p-toluenesulfonic acid.
- hydroxy acids for example citric acid, tartaric acid, or aromatic carboxylic acids for example benzoic acid or salicylic acid
- aliphatic and aromatic sulfonic acids for example methanesulfonic acid, naphthalenesulfonic acid and p-toluenesulfonic acid.
- 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.
- the compounds of formula (I) exist in the form of ,,E" or ,,Z" isomers with respect of the configuration of the oxime moiety. These and their mixtures are likewise within the scope of the present invention.
- the compounds of the invention are preferably in ,,E" configuration.
- the compounds of formula (I) exist in the form of ,,E" or ,,Z" isomers with respect of the configuration of the so obtained double bond. These and their mixtures are likewise within the scope of the present invention.
- the compounds of the invention are preferably in ,,E" configuration.
- Certain compounds of formula (I) can exist as enantiomers and racemates and diastereomers, too. These and the mixtures thereof are likewise within the scope of the present invention.
- Preferred compounds of the invention are those compounds of formula (I), wherein
- R 1 and R 2 represent independently a substituent selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, Cj -4 haloalkyl and cyano;
- X is a CHR 6 group
- R 3 represents a C 1-4 alkyl substituent
- R 4 and/or R 5 represent hydrogen
- R 6 is hydrogen or C 1-4 alkyl
- Y is phenyl optionally substituted with one or more substituent(s) selected from halogen, hydroxy, cyano, C 1-4 alkylamino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, or unsaturated heterocyclyl optionally substituted with one or more substituent(s) selected from halogen, hydroxy, cyano, C 1-4 alkylamino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts and/or hydrates and/or solvates thereof.
- substituent(s) selected from halogen, hydroxy, cyano, C 1-4 alkylamino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and/or enantiomers and/or racemates and/or diastereomers
- Particulary preferred compounds of the invention are those compounds of formula (I), wherein
- R 1 and R 2 represent independently a substituent selected from hydrogen, halogen, methyl, methoxy, trifluoromethyl and cyano;
- X is a CHR 6 group
- R 3 represents a C 1-4 alkyl substituent
- R 4 and/or R 5 represent hydrogen
- R 6 is hydrogen
- Y is phenyl optionally substituted with halogen, or pyridyl, thiophenyl, pyrrolyl, furanyl, imidazolyl optionally substituted with one or two methyl substituent(s), and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts and/or hydrates and/or solvates thereof.
- the invention also relates to the pharmaceutical compositions containing the compounds of formula (I) and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof as active ingredient and one or more physiologically acceptable carriers.
- the compounds of formula (I) and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or hydrates and/or solvates 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 compounds of formula (I) and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or hydrates and/or solvates 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 enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof generally consist of a suspension or solution of the compound of formula (I) and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof in a suitable liquid carrier(s) for example an aqueous solvent, such as water and 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 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 these are 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 is filled into a soft gelatine capsule.
- Aerosol formulations of the present invention typically comprise a solution or fine suspension of the compound of formula (I) and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or hydrates and/or solvates in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in a single or multidose quantities in sterile form in 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.
- 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 physiologically acceptable salts and/or hydrates and/or solvates 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 physiologically acceptable salts and/or hydrates and/or solvates 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.
- 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.
- 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 physiologically acceptable salts and/or hydrates and/or solvates thereof calculated as a free base.
- the compounds of formula (I) and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof can normally 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, 250-300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.
- 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) and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof 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 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 Miliary 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 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 present invention provides a process for preparing compounds of formula (I):
- X is a CHR 6 group or O
- R 3 represents an alkyl substituent
- R 4 and/or R 5 represent hydrogen
- R 6 is hydrogen or alkyl
- Y is an optionally substituted phenyl or (unsaturated heterocyclyl, and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts and/or hydrates and/or solvates thereof, by reacting an oxime derivative of formula (II):
- the reaction may be carried out by known methods, preferably by suspending or dissolving the appropriate oxime derivative of formula (II) and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts and/or hydrates and/or solvates thereof, in a suitable solvent (e.g. tetrahydrofurane, dimethylformamide or chlorinated hydrocarbons or hydrocarbons), and' reacting it with the appropriate phenylisocyanate derivative of formula (III) optionally in the presence of a base (e.g. triethylamine).
- a suitable solvent e.g. tetrahydrofurane, dimethylformamide or chlorinated hydrocarbons or hydrocarbons
- a base e.g. triethylamine
- the reaction can be carried out advantageously between 0 0 C and 60 0 C.
- the reactions are followed by thin layer chromatography.
- the necessary reaction time is about 6- 24
- the compounds of formula (I) can optionally be intercoverted to a different compound of formula (I) by conventional synthetic methods.
- the mGluR5 receptor binding was determined according to the modified method of Gasparini et.al. (Bioorg. Med. Chem. Lett., 2000, 12, 407). 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 the reference compounds and novel compounds to the rat mGluR5. The Al 8 cell line expressing hniGluR5a (purchased from Euroscreen) was used to determine binding characteristics of the chemical compounds to the human mGluR5a receptor. [ 3 H]-M-MPEP (2 nM) was used as radioligand. The nonspecific binding was determined in the presence of 10 ⁇ M M-MPEP.
- Functional potency at native rat mGluR.5 receptors was estimated using primary neocortical cell cultures derived from 17 day old Charles River rat embryos (for the details on the preparation of neural cell cultures see Johnson, M.I.; Bunge, R.P.: Primary cell cultures of peripheral and central neurons and glia. In: Protocols for Neural Cell Culture, eds: Fedorojf, S.; Richardson A., The Humana Press Inc., 1992, 51-77). After isolation the cells were plated onto standard 96- well microplates and the cultures were maintained in an atmosphere of 95% air-5% CO 2 at 37 0 C. The neocortical cultures were used for the calcium measurements after 5-7 days in vitro.
- CHO cells stably expressing recombinant human mGluR5a (CHO-mGluR5a, 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% CO 2 /95% air and were passaged three times a week.
- Cells were plated at 2.5-3.5x104 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 cell cultures and on CH0-mGluR5a cells stably expressing human mGluR5a receptors.
- active ingredient of formula (I) 0.1-2 % of sodium hydroxide, 0.1-3 % of citric acid, 0.05-0.2 % of nipagin (sodium methyl 4-hydroxybenzoate), 0.005-0.02 % of nipasol, 0.01-0.5 % of carbopol (polyacrilic acid), 0.1-5 % of 96 % ethanol, 0.1-1 % of flavoring agent, 20
Abstract
The present invention relates to new mGluR5 receptor subtype preferring ligands of formula (I): (I) wherein R1 and R2 represent independently a substituent selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl and cyano; X is a CHR6 group or O; R3 represents an alkyl substituent, R4 and/or R5 represent hydrogen, R6 is hydrogen or alkyl, or R3 and R4 with the intermediate two carbon atoms together form a cyclohexane or cyclopentane ring and/or R5 and R6 together form a bond; Y is an optionally substituted phenyl or heterocyclyl, and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts and/or hydrates and/or solvates thereof, to the process for producing the same, to pharmaceutical compositions containing the same and to their use in therapy and/or prevention of pathological conditions which require the modulation of niGluR5 receptor such as neurological disorders, psychiatric disorders, acute and chronic pain and neuromuscular dysfunctions of the lower urinary tract.
Description
MGLUR5 ANTAGONISTIC CARBAMOYL-OXIME DERIVATIVES
FIELD OF THE INVENTION
The present invention relates to new niGluR5 receptor subtype preferring ligands of formula (I) and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts and/or hydrates and/or solvates thereof, to the processes for their preparation, to pharmaceutical compositions containing these compounds and to their use in therapy and/or prevention of a condition which requires modulation of mGluR5 receptors.
BACKGROUND OF THE INVENTION
A major excitatory neurotransmitter in the mammalian central nervous system (CNS) is the glutamate molecule, which binds to neurons, 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, the means by which the receptors transduce signals into the cell, and pharmacological profiles.
The metabotropic glutamate receptors (niGluRs) 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. (Trends Pharmacol. ScL, 1993, 14, 13; Neurochem. Int., 1994, 24, 439; Neuropharmacology, 1995, 34, 1; Prog. Neurobiol, 1999, 59, 55).
Eight distinct mGluR subtypes, termed mGluRl through mGluR8, have been identified by molecular cloning (Neuron, 1994, 13, 1031; Neuropharmacology, 1995, 34, 1; J. Med. Chem., 1995, 38, 1417). Further receptor diversity occurs via expression of alternatively
spliced forms of certain mGluR subtypes (PNAS, 1992, 89, 10331; BBRC, 1994, 199, 1136; J. NeuroscL, 1995, 15, 3970).
Metabotropic glutamate receptor subtypes may be subdivided into three groups, Group I, Group II, and Group III niGluRs, based on amino acid sequence homology, the second messenger systems utilized by the receptors, and by their pharmacological characteristics. Group I mGluR comprises niGluRl, mGluR5 and their alternatively spliced variants.
Attempts at elucidating the physiological roles of Group I mGluRs suggest that activation of these receptors elicits neuronal excitation. Evidence indicates that this excitation is due to direct activation of postsynaptic mGluRs, but it also has been suggested that activation of presynaptic mGluRs occurs, resulting in increased neurotransmitter release (Trends Pharmacol. ScL, 1992, 15, 92; Neurochem. Int., 1994, 24, 439; Neuropharmacology, 1995, 34, 1; Trends Pharmacol. ScL, 1994, 15, 33).
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 (Nature, 1993, 363, 347; Nature, 1994, 368, 740; Cell, 1994, 79, 365; Cell, 1994, 79, 377). A role for mGluR activation in nociception and analgesia also has been demonstrated (Neuroreport, 1993, 4, 879; Brain Res., 1999, 871, 223).
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 (Trends Pharmacol. ScI, 1993, 14, 13; Life ScL 1994, 54, 135; Ann. Rev. NeuroscL, 1994, 17, 31; Neuropharmacology, 1995, 34, 1; /. Med. Chem., 1995, 22, 331; Trends Pharmacol. ScL, 2001, 22, 331; Curr. Opin. Pharmacol, 2002, 2, 43; Pain, 2002, 98, 1). Further, mGluR5- selective compounds such as 2-methyl-6-(phenylethynyl)-ρyridine ("MPEP") are effective in animal models of mood disorders, including anxiety and depression (J. Pharmacol. Exp. Ther., 2000, 295, 1267; Brit. J. Pharmacol, 2001, 132, 1423; Pol J. Pharmacol, 2001, 132, 1423). Much of the pathology in these conditions is thought to be due to excessive glutamate- induced excitation of CNS neurons. As Group I mGluRs appear to increase glutamate- mediated neuronal excitation via postsynaptic mechanisms and enhanced presynaptic glutamate release, their activation probably contributes to the pathology. Accordingly,
selective antagonists of Group I mGluR receptors could be therapeutically beneficial, specifically as neuroprotective agents, analgesics or anticonvulsants.
Various O-[[[(un)substituded-phenyl]ammo]carbonyl]-oxime (carbamoyl-oxime) derivatives can be purchased from chemical libraries without known biological activity. For example cyclohexanone carbamoyl oxime derivatives can be purchased from ComGenex International Inc. (Monmouth, NJ, USA), Ambinter (Paris, France), Interchim (Montlucon, France) or Zelinsky Institute of Organic Chemistry (Moscow, Russia); cyclopentanone carbamoyl oxime derivatives from ComGenex International Inc. (Monmouth, NJ, USA) or Interchim (Montlucon, France); 2-butanone carbamoyl oxime derivatives from Interchim (Montlucon, France).
Some cyclic arylidene ketones and related oxime derivatives were synthetized by J. R. Dimmock et al. (J. Pharm. ScL, 1994, 852) and their cytotoxic activities were evaluated against murine L1210 lymphoid leukemia cells. Earlier, about 8000 compounds that incorporate a carbamate or thiocarbamate moiety, which have been tested as potential anticancer agents at the National Cancer Institute (NCI), were classified and their structure- activity correlations against the in vivo P388 and L1210 leukemias were evaluated with the aid of the computer (/. Pharm. ScL, 1985, 831).
German Patent DE 1802739 describes biocidal ureas and carbamates (among them cyclohexanone O-[4-(trifluoromethyl)-carbamoyl]oxime) having herbicidal, bactericidal, insecticidal, coccidistatic, anthelmintic, fungicidal and nematocidal properties.
German (East) Patent DD 32540 relates to O-carbamoyl ketoxime derivatives. These compounds controlled a wide variety of weeds at doses of 2-6 kg/ha.
By E. Ocelli et al. (Farmaco, Ed. ScL, 1985, 40, 86) 3-aminopropiophenone and 3- (aminomethyl)-camphor derivatives were synthetized and their CNS, analgesic, and antiinflammatory activities were evaluated. At the pharmacological tests the 3- (aminomethyl)-camphor carbamoyl oximes proved to be inactive.
The compounds mentioned in the above publications are not declared or even not suggested having activity on the mGluR5 receptors.
SUMMARY OF THE INVENTION
The present invention relates to new mGluR.5 receptor subtype preferring ligands of formula (I):
(D wherein
R1 and R2 represent independently a substituent selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl and cyano;
X is a CHR6 group or O;
R3 represents an alkyl substituent, R4 and/or R5 represent hydrogen, R6 is hydrogen or alkyl, or R3 and R4 with the intermediate two carbon atoms together form a cyclohexane or cyclopentane ring and/or R5 and R6 together form a bond;
Y is an optionally substituted phenyl or heterocyclyl, and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts and/or hydrates • and/or solvates thereof, to the process for producing the same, to pharmaceutical compositions containing the same and to their use in therapy and/or prevention of pathological conditions which require the modulation of mGluR5 receptor such as neurological disorders, psychiatric disorders, acute and chronic pain and neuromuscular dysfunctions of the lower urinary tract.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to new mGluR5 receptor subtype preferring ligands of formula (I):
(D wherein
R1 and R2 represent independently a substituent selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl and cyano;
X is a CHR6 group or O;
R3 represents an alkyl substituent, R4 and/or R5 represent hydrogen, R6 is hydrogen or alkyl, or R3 and R4 with the intermediate two carbon atoms together form a cyclohexane or cyclopentane ring and/or R5 and R6 together form a bond;
Y is an optionally substituted phenyl or heterocyclyl, and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts and/or hydrates and/or solvates thereof.
When R1 and/or R2 and/or R3 and/or R6 represent alkyl, the alkyl group contains 1 to 4 carbon atom(s) with straight or branched chain.
When R1 and/or R2 represent alkoxy and/or haloalkyl group, the alkyl moiety inside the group contains 1 to 4 carbon atom(s) with straight or branched chain.
When Y is phenyl, the phenyl group may be optionally substituted with one or more substituent(s) selected from halogen, hydroxy, cyano, C1-4 alkylamino, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl.
When Y is heterocyclyl, the heterocyclyl group may be a saturated or unsaturated monocyclic or bicyclic ring, which contains 1-4 heteroatom(s) selected from O, N or S, and which may be optionally substituted with one or more substituent(s) selected from halogen, hydroxy, cyano, C1-4 alkylamino, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl.
The term "halogen" includes fluorine, chlorine, bromine and iodine atoms.
In this specification the term "halo" may be fluoro, chloro, bromo or iodo.
In this specification, the term "haloalkyl" means an alkyl group as defined above, wherein at least one and up to all of the hydrogen atoms are replaced with a halogen.
Certain compounds of formula (I) contain basic function(s) so may form salts with acids. The invention relates also to the salts of compounds of formula (I) formed with acids, especially the salts formed with pharmaceutically acceptable acids. The meaning of compound of formula (I) is either the free base or the salt even if it is not referred separately.
Both organic and inorganic acids can be used for the formation of acid addition salts. Suitable inorganic acids can be for example hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid. Representatives of monovalent organic acids can be for example formic acid, acetic acid, propionic acid, and different butyric acids, valeric acids and capric acids. Representatives of bivalent organic acids can be for example oxalic acid, malonic acid, maleic acid, fumaric acid and succinic acid. Other organic acids can also be used, such as hydroxy acids for example citric acid, tartaric acid, or aromatic carboxylic acids for example benzoic acid or salicylic acid, as well as aliphatic and aromatic sulfonic acids for example methanesulfonic acid, naphthalenesulfonic acid and p-toluenesulfonic acid. Especially valuable group of the acid addition salts is in which the acid component itself is physiologically acceptable and does not have therapeutical effect in the applied dose or it does not have unfavourable influence on the effect of the active ingredient. These 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.
Solvates and/or hydrates of compounds of formula (I) are also included within the scope of the invention.
The compounds of formula (I) exist in the form of ,,E" or ,,Z" isomers with respect of the configuration of the oxime moiety. These and their mixtures are likewise within the scope of the present invention. The compounds of the invention are preferably in ,,E" configuration.
When R5 and R6 together form a bond, the compounds of formula (I) exist in the form of ,,E" or ,,Z" isomers with respect of the configuration of the so obtained double bond. These and their mixtures are likewise within the scope of the present invention. The compounds of the invention are preferably in ,,E" configuration.
Certain compounds of formula (I) can exist as enantiomers and racemates and diastereomers, too. These and the mixtures thereof are likewise within the scope of the present invention.
Preferred compounds of the invention are those compounds of formula (I), wherein
R1 and R2 represent independently a substituent selected from hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, Cj-4 haloalkyl and cyano;
X is a CHR6 group;
R3 represents a C1-4 alkyl substituent, R4 and/or R5 represent hydrogen, R6 is hydrogen or C1-4 alkyl, or R3 and R4 with the intermediate two carbon atoms together form a cyclohexane or cyclopentane ring and/or R5 and R6 together form a bond;
Y is phenyl optionally substituted with one or more substituent(s) selected from halogen, hydroxy, cyano, C1-4 alkylamino, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, or unsaturated heterocyclyl optionally substituted with one or more substituent(s) selected from halogen, hydroxy, cyano, C1-4 alkylamino, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts and/or hydrates and/or solvates thereof.
Particulary preferred compounds of the invention are those compounds of formula (I), wherein
R1 and R2 represent independently a substituent selected from hydrogen, halogen, methyl, methoxy, trifluoromethyl and cyano;
X is a CHR6 group;
R3 represents a C1-4 alkyl substituent, R4 and/or R5 represent hydrogen, R6 is hydrogen, or R3 and R4 with the intermediate two carbon atoms together form a cyclohexane ring;
Y is phenyl optionally substituted with halogen, or pyridyl, thiophenyl, pyrrolyl, furanyl, imidazolyl optionally substituted with one or two methyl substituent(s), and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts and/or hydrates and/or solvates thereof.
Especially important compounds of formula (I) of the present invention are the following:
(lE)-2-benzyl-cyclohexanone O-[(3-methylphenyl)carbamoyl]oxime, (l£)-2-benzyl-cyclohexanone O-[(3-chlorophenyl)carbamoyl]oxime,
(lE)-2-(l-phenylethyl)-cyclohexanone O-[(3-chlorophenyl)carbamoyl]oxime,
(l£)-2-(2-fluorobenzyl)-cyclohexanone O-[(3-chlorophenyl)carbamoyl]oxime,
(lE)-2-(3-fluorobenzyl)-cyclohexanone O-[(3-chlorophenyl)carbamoyl]oxime,
(lE)-2-(4-fluorobenzyl)-cyclohexanone O-[(3-chlorophenyl)carbamoyl]oxime,
(lE)-2-(3-fluorobenzyl)-cyclohexanone O-[(3-methylphenyl)carbamoyl]oxime,
(lE)-2-(thiophen-2-ylmethyl)-cyclohexanone O-[(3-methylplienyl)carbamoyl]oxime,
(lE)-2-(thiophen-2-ylinethyl)-cycloliexanone O-[(3-chloroplienyl)carbarnoyl]oxime,
(lE)-2-(thiophen-3-ylmethyl)-cyclohexanone O-[(3-chloroρhenyl)carbamoyl]oxime,
(lE)-2-(thiophen-2-ylmethyl)-cyclohexanone O-[(3-fluorophenyl)carbamoyl]oxime,
(lE)-2-(thiophen-2-ylmethyl)-cyclohexanone O-[(3-bronioρhenyl)carbamoyl]oxime,
(lE)-2-(thioplien-3-ylinethyl)-cyclohexaiione O-[(3-fluoroρhenyl)carbamoyl]oxime,
(lE)-2-(thiophen-2-ylmethyl)-cyclohexanone O-[(3-metlioxyphenyl)carbamoyl]oxime,
(lE)-2-(pyrrol-2-ylmethyl)-cyclohexanone O-[(3-chloroρhenyl)carbamoyl]oxime,
(l£)-2-(pyrrol-2-ylmethyl)-cyclohexanone O-[(3-methylphenyl)carbamoyl]oxime,
(l£)-2-(furan-2-ylmethyl)-cyclohexanone O-[(3-chlorophenyl)carbamoyl]oxime,
(lE)-2-(furan-2-ylmethyl)-cyclohexanone O-[(3-fluoiOphenyl)carbamoyl]oxime,
(lE)-2-(imidazol-l-ylmethyl)-cyclohexanone O-[(3-chlorophenyl)carbamoyl]oxime,
(+)-(lJΕ)-2-(imidazol-l-ylmethyl)-cyclohexanone O-[(3-chlorophenyl)carbamoyl]oxime,
(l£)-2-(imidazol-l-ylmethyl)-cyclohexanone O-[(3-fluorophenyl)carbamoyl]oxime,
(lE)-2-(imidazol-l-ylmethyl)-cycloliexanone O-[(3-cyanophenyl)carbamoyl]oxime,
( lE)-2- [ (4-methylimidazol)- 1 -ylmethyl] -cyclohexanone O- [(3 -chloropheny^carbamoyl] - oxime,
(l£)-2-(imidazol-l-ylmethyl)-cyclohexaiione O-[(3--trifluoromethyl-phenyl)carbamoyl]oxiine,
( lE)-2- (pyridin-2-ylmethyl)-cy clohexanone O- [(3 -chlorophenyl)carbamoyl] oxime,
( lE)-2- (pyridin-3 -ylmethyl)-cy clohexanone O- [(3 -chlorophenyl)carbamoyl] oxime,
(lE,2E)-2-(pyridin-2-ylmethylidene)-cyclohexanone O-[(3-chlorophenyl)carbamoyl]oxime.
The invention also relates to the pharmaceutical compositions containing the compounds of formula (I) and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof as active ingredient and one or more physiologically acceptable carriers.
The compounds of formula (I) and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or
hydrates and/or solvates 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 compounds of formula (I) and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or hydrates and/or solvates 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 enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof generally consist of a suspension or solution of the compound of formula (I) and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof in a suitable liquid carrier(s) for example an aqueous solvent, such as water and 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. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid etc. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques.
A composition in the solid form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then these are 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 is 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 physiologically acceptable salts and/or hydrates and/or solvates thereof in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol,
polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, 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 enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or hydrates and/or solvates 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) and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or hydrates and/or solvates in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in a single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, 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. If 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 of a pump-atomiser.
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 physiologically acceptable salts and/or hydrates and/or solvates 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.
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 physiologically acceptable salts and/or hydrates and/or solvates 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. 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 physiologically acceptable salts and/or hydrates and/or solvates thereof for transdermal administration include ointments, gels and patches.
The 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 physiologically acceptable salts and/or hydrates and/or solvates 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 physiologically acceptable salts and/or hydrates and/or solvates thereof calculated as a free base.
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 physiologically acceptable salts and/or hydrates and/or solvates thereof calculated as a free base.
The compounds of formula (I) and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof can normally be administered in a daily dosage regimen. In the treatment of 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. For example, 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, 250-300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.
It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
The compounds of formula (I) and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or hydrates and/or solvates have been found to exhibit biological activity at niGluR5 receptors and are expected to be useful in the treatment of mGluR5 mediated disorders.
It has been found that the compounds of formula (I) and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof, exhibit a high degree of potency and selectivity for individual metabotropic glutamate receptor (mGluR) subtypes. In particular the compounds according to the present invention are potent and selective for mGluR5 receptor. Accordingly, the compounds of the present invention are expected to be useful in the prevention and/or treatment of conditions associated with excitatory activation of mGluR5 receptors and for inhibiting neuronal damage caused by excitatory activation of mGluR5 receptors. The compounds of the present invention may be used to produce an inhibitory effect on mGluR5 receptors in mammals - including human.
Thus, it is expected that 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.
The compounds of the present invention 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 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) and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof 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 Miliary 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 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.
In the context of the present specification, 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.
In this specification, unless stated otherwise, 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.
The term "disorder", unless stated otherwise, means any condition and disease associated with metabotropic glutamate receptor activity.
Methods of preparation
The present invention provides a process for preparing compounds of formula (I):
(D wherein
R1 and R2 represent independently a substituent selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl and cyano;
X is a CHR6 group or O;
R3 represents an alkyl substituent, R4 and/or R5 represent hydrogen, R6 is hydrogen or alkyl, or R3 and R4 with the intermediate two carbon atoms together form a cyclohexane or cyclopentane ring and/or R5 and R6 together form a bond;
Y is an optionally substituted phenyl or (unsaturated heterocyclyl, and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts and/or hydrates and/or solvates thereof, by reacting an oxime derivative of formula (II):
(II) wherein the meaning of R3, R4, R5, X and Y is as described above for the formula (I) and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts and/or hydrates and/or solvates thereof, with a phenylisocyanate derivative of formula (III):
(in) wherein the meaning of R1 and R2 is as described above for the formula (I).
The reaction may be carried out by known methods, preferably by suspending or dissolving the appropriate oxime derivative of formula (II) and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts and/or hydrates and/or solvates thereof, in a suitable solvent (e.g. tetrahydrofurane, dimethylformamide or chlorinated hydrocarbons or hydrocarbons), and' reacting it with the appropriate phenylisocyanate derivative of formula (III) optionally in the presence of a base (e.g. triethylamine). The reaction can be carried out advantageously between 0 0C and 60 0C. The reactions are followed by thin layer chromatography. The necessary reaction time is about 6- 24 h. The work-up of the reaction mixture can be carried out by known methods. The products can be purified, e.g. by crystallization or by column chromatography.
The obtained carbamoyl oximes of formula (I) exist in the form of ,,E" and/or ,,Z" isomers with respect of the configuration of the oxime moiety, and certain compounds of formula (I) have other geometric isomers, too. These geometric isomers can optionally be separated by known methods, e.g. by crystallization or by column chromatography.
Certain compounds of formula (I) can exist as enantiomers and racemates and diastereomers, too. These stereoisomers can optionally be separated, e.g. by chiral column chromatography or by crystallization (in the case of diastereomers).
The pure enantiomers and/or racemates and/or diastereomers and/or geometric isomers of compounds of formula (I) can be prepared from stereochemical^ and/or geometrically pure precursors, too.
Compounds of formula (I) containing basic function(s) can be transformed into the salts thereof with acids and/or can be liberated from the obtained acid addition salts by treatment with a base.
Compounds of formula (I) can be transformed into hydrates and/or solvates.
The compounds of formula (I) can optionally be intercoverted to a different compound of formula (I) by conventional synthetic methods.
Compounds of formula (II) are either known (e.g. (lE)-2-benzylcyclohexanone oxime and (lZ)-2-benzylcyclohexanone oxime: J. Org. Chem., 1976, 41, 439; (lE)-2-(3,4- dimethoxybenzyl)-cyclohexanone oxime: Chem. Pharm. Bull, 1961, 9, 104; (lZ,2E)-2~(4- methylbenzylidene)-cyclohexanone oxime:J. Pharm. ScL, 1994, 83, 852; (2E)-4- ρhenylbutane-2-one oxime and (2Z)-4-phenylbutane-2-one oxime: Synthesis, 2003, 15, 2415; 4-(piperidine-l-yl)-butan-2-one oxime: /. Chem. Soc, 1931, 3096; (lE)-2-(piperidin-l- ylmethyl)-cyclohexanone oxime: Arch. Pharm., 1927, 601; 4-(thiophen-2-yl)-but-3-en-2-one oxime: Gazz. CMm. Ital., 1959, 1736; (lE)-2-phenoxycyclohexanone oxime: Chem. Pharm. Bull, 1976, 24, 1691) or can be prepared from the appropriate ketone derivative of fomula (IV):
(IV) wherein the meaning of R3, R4, R5, X and Y is as described above for the formula (I) and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts and/or hydrates and/or solvates thereof, by conventional synthetic methods (e.g. J. Org. Chem., 1976, 41, 439).
Compounds of formula (IV) are either known (e.g. 2-(2-bromobenzyl)-cyclohexanone: /. Chem. Soc. Perkin Trans. 1, 1994, 23, 3499; (2Ε)-2-(2-chlorobenzylidene)-cyclohexanone: /. Am. Chem. Soc, 1955, 77, 624; 2-(pyridm-2-ylmethylene)-cyclohexanone and 2-(ρyridin- 2-ylmethyl)-cyclohexanone: J. Pharm. ScL, 1967, 56, 644; 2-(2~bromophenoxy)- cyclohexanone: /. Org. Chem., 1963, 28, 1112; 2-(l-phenylethyl)-cyclohexanone: Chem.
Ber., 1984, 117, 322; 2-(l-phenylethylidene)-cyclohexanone: /. Am. Chem. Soc, 1993, 115, 3362; 2-(furan-2-ylmethyl)-cyclohexanone: J. Org. Chem., 1957, 22, 1161; 2-(thiazolidin-3- ylmethyl)-cyclohexanone: Bull. Soc. CMm. Fr., 1964, 2493; 2-(piperidin-l-ylmethyl)- cyclohexanone: Pharmazie, 1995, 50, 668) or can be synthetized by different known methods. Compounds of formula (III) are either commercially available or can be synthetized by known methods (e.g. from the appropriate aniline derivative: Chem. Pharm. Bull, 2002, 50, 1280).
Biological test methods
Biological test methods
mGluR5 receptor binding test
The mGluR5 receptor binding was determined according to the modified method of Gasparini et.al. (Bioorg. Med. Chem. Lett., 2000, 12, 407). 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 the reference compounds and novel compounds to the rat mGluR5. The Al 8 cell line expressing hniGluR5a (purchased from Euroscreen) was used to determine binding characteristics of the chemical compounds to the human mGluR5a receptor. [3H]-M-MPEP (2 nM) was used as radioligand. The nonspecific binding was determined in the presence of 10 μM M-MPEP.
Assessment of functional activity
Cell cultures for native rat mGluR5 receptors
Functional potency at native rat mGluR.5 receptors was estimated using primary neocortical cell cultures derived from 17 day old Charles River rat embryos (for the details on the preparation of neural cell cultures see Johnson, M.I.; Bunge, R.P.: Primary cell cultures of peripheral and central neurons and glia. In: Protocols for Neural Cell Culture, eds: Fedorojf, S.; Richardson A., The Humana Press Inc., 1992, 51-77). After isolation the cells were plated onto standard 96- well microplates and the cultures were maintained in an atmosphere of 95%
air-5% CO2 at 37 0C. The neocortical cultures were used for the calcium measurements after 5-7 days in vitro.
Cell cultures for recombinant human mGluR5a receptors
Chinese hamster ovary (CHO) cells stably expressing recombinant human mGluR5a (CHO-mGluR5a, Euroscreen) receptors were cultured in F12 medium containing 10% FCS, 1% antibiotic antimycotic solution, 400 μg/ml G418, 250 μg/ml zeocin, 5 μg/ml puromycin. Cells were kept at 37 0C in a humidified incubator in an atmosphere of 5% CO2/95% air and were passaged three times a week. Cells were plated at 2.5-3.5x104 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.
Fluorimetric measurement of cytosolic calcium concentration
Measurements of cytosolic calcium concentration ([Ca2+Ji) were carried out on primary neocortical cell cultures and on CH0-mGluR5a cells stably expressing human mGluR5a receptors. Cells were grown in standard 96- well microplates and before the measurement were loaded with a fluorescent Ca2+-sensitive dye, fluo-4/AM (2 μM): the neural cultures were loaded in their growth medium, CHO-mGluR5a cells were loaded in assay buffer (145 mM NaCl, 5 mM KCl, 2 mM MgCl2, 2 mM CaCl2, 10 mM HEPES, 20 mM D-glucose, 2 mM probenecid, pH=7.4) supplemented with 2 mM Na-pyruvate and 30 μg/ml glutamate-pyruvate transaminase (in case of CHO-mGluR5a cells these supplements were also present during the course of the [Ca2+Ji measurements). Loading was done by incubating the cells with 100 μl/well dye solution at 37 0C in a humidified incubator in an atmosphere of 5% CO2/95% air for 40-120 min. To stop dye loading cells were washed twice with assay buffer. After washing, various concentrations of the test compounds (diluted in assay buffer from a DMSO or a dimethylformamide (DMF) stock solution, final DMSO/DMF concentration was <0.1%) or buffer were added to each well depending on the experimental setup. In the case of neocortical cultures the assay buffer also contained TTX (0.5 μM, to suppress spontaneous oscillations of [Ca2+]i.
After incubation at 37 0C for 10-20 minutes baseline and agonist-evoked changes of [Ca2+Ji 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 0C and was controlled by custom software. Inhibitory potency of the test compounds was assessed by measuring the reduction in the agonist-evoked [Ca2+]i -elevation in the presence of different concentrations of the compounds. DHPG was used as agonist for both cultures, the concentration was 20 μM for the neocortical cultures. In the case of CHO-mGluR5a cells DHPG was applied at an EC80 concentration, the EC80-values were derived from daily determined dose-response curves.
Fluorescence data were expressed as ΔF/F (fluorescence change normalized to baseline). All treatments on a single plate were measured in multiple wells. Data from all wells with the same treatment were averaged and the average values were used for analysis. Inhibitory potency of a compound at a single concentration point was expressed as percent inhibition of the control agonist response. Sigmoidal concentration-inhibition curves were fitted to the data (derived from at least three independent experiments) and ICso-values were determined as the concentration that produces half of the maximal inhibition caused by the compound. Raw fluorescence data were analyzed using Soft Max Pro (Molecular Devices), curve fitting was done with GraphPad Prism.
Results
Compounds of formula (I) of the present invention showed affinity for both rat and human mGluR5 receptors and proved to be functional antagonists, that is they inhibited functional responses elicited by stimulation of mGluR5 receptors.
The invention is further illustrated by the following non-limiting examples.
Unless specifically stated otherwise, all operation were carried out at room temperature, that is at a temperature range of 18-25 0C. The course of reactions was followed by thin layer chromatography (TLC) and reaction times are given for illustration only. The structure of all intermediates and end products were elucidated by IR, NMR and MS spectroscopy. When given yields are for illustration only. When given, NMR data are in the form of delta (δ) values for major diagnostic protons, given in parts per million (ppm) relative
to tetramethylsilane (TMS) as internal standard, using the indicated solvent. Conventional abbreviations are used for signal shape.
Examples
All starting materials are either commercially available or can be synthesized by different known methods described in the literature.
Example 1
(2E)-2-(3-fluorobenzylidene)-cyclohexanone and (2Z)-2-(3-fluorobenzylidene)- cyclohexanone (intermediates)
To a mixture of 20.7 ml (0.2 mol) cyclohexanone and 1 g sodium hydroxide in water (90 ml) 5.3 ml (0.05 mol) 3-fluorobenzaldehyde was added, and the resulting suspension was stirred for 12 hours. The reaction mixture was extracted with chloroform (1x75 ml and 2x25 ml), the combined organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was crystallized from n-hexane to obtain the mixture of the title compounds (7.8 g) (MS: M+= 205.3). The pure isomers can be separated by column chromatography on silica gel (Kieselgel 60, eluent: dichloromethane : acetone = 9:1).
Applying the above procedure the following compounds were prepared by the reaction of cyclohexanone and the appropriate aldehyde: e.g. (2E)-2-(pyridine-3-ylmethylene)- cyclohexanone and (2Z)-2-(pyridine-3-ylmethylene)-cyclohexanone, (2E)-2-(indole-3- ylmethylene)-cylohexanone and (2Z)-2-(indole-3-ylmethylene)-cylohexanone, (2E)-2- (thiophen-3-ylmethylene)-cyclohexanone and (2Z)-2-(thiophen-3-ylmethylene)- cyclohexanone.
Example 2
2-(pyridine-2-ylmethyl)-cyclohexanone (intermediate)
To a solution of 1.3 g (6.95 mmol) (2E)-2-(pyridine-2-ylmethylene)-cyclohexanone and (2Z)-2-(pyridine-2-ylmethylene)-cyclohexanone in methanol (30 ml) 10% palladium on charcoal (0.3 g) was added, and the mixture was stirred under hydrogen (1 bar) for 3 hours. The catalyst was filtered out, washed with methanol (2x5 ml), and the filtrate was concentrated in vacuo to obtain the title compound (1.1 g) (MS: M+= 190.3).
Applying the above procedure the following compounds were prepared: e.g. 2- (thiophen-2-ylmethyl)-cyclohexanone, 2-(4-dimethylaminobenzyl)-cyclohexanone, 2-[2- methyl-tiophen-5-ylmethyl)-cyclohexanone.
Example 3
2-(2,4-dimethyl-imidazol-l-ylmethyl)-cyclohexanone (intermediate)
The mixture of 2,4-dimethylimidazole (9.61 g, 0.1 mol), cyclohexanone (20.7 ml, 0.2 mol), paraformaldehyde (3.2 g, 0.107 mol) and acetic acid (40 ml) was heated at 75 0C for 10 hours. The obtained solution was concentrated in vacuo. To the residue water (25 ml) and dichloromethane (150 ml) was added, and the pH was adjusted to 10 with aqueous sodium hydroxide solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (Kieselgel 60, eluent: chloroform : methanol = 9:1) to obtain the title compound (4.1 g) (MS: M+= 208.3).
Applying the above procedure the following compounds were prepared: e.g. 2- (piperidin-l-ylmethyl)-cyclohexanone, 2-(imidazol-l-ylmethyl)-cyclopentanone, 2- (morpholin-4-ylmethyl)-cyclohexanone.
Example 4
2-(pyridin-3-yloxy)-cyclohexanone (intermediate)
The mixture of 2-chlorocyclohexanone (5 g, 37.7 mmol), 3-hydroxypyridine (3.6g, 37.7 mmol), anhydrous potassium carbonate (10.4 g, 75.4 mmol), anhydrous potassium iodide (0.5 g) and acetone (100 ml) was heated at 60 0C for 10 hours. The solid was filtered out, washed with acetone (2x10 ml), and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (Kieselgel 60, eluent: chloroform : methanol = 98:2) to obtain the title compound (3.11 g) (MS: M+= 192.3).
Applying the above procedure the following compounds can be prepared: e.g. 2-(2- bromophenoxy)-cyclohexanone, 2-(3-chlorophenoxy)-cyclohexanone, 2-(pyridin~2-yloxy)- cyclohexanone.
Example 5 l-Cl-phenyl-ethyO-cyclohexanone (intermediate)
The mixture of l-(trimethylsiloxy)-cyclohexene (2.5 ml, 12.3 mmol), (1-bromoethyl)- benzene, zinc chloride (5 mg) and dichloromethane (12 ml) was stirred for 24 hours. The reaction mixture was diluted with dichloromethane (50 ml), washed with IM aqueous sodium hydrogencarbonate solution and water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (Kieselgel 60, eluent: n-hexane : ethyl acetate = 5:1) to obtain the title compound (1.29 g) (MS: M+= 203.3).
Applying the above procedure the following compounds can be prepared: e.g. 2-(l- phenyl-propyl)-cyclohexanone, 2-[l-(3-fluoro-phenyl)-cyclohexanone.
Example 6
General procedure for the preparation of compounds of formula (II)
To a solution or suspension of a compound of formula (IV) (20 mmol), wherein the meaning of R3, R4, R5, X and Y is as described for the formula (I) hereinbefore, in methanol (40 ml) sodium acetate (3.6 g, 44 mmol) and hydroxylamine hydrochloride (1.6 g, 23 mmol) was added, and the reaction mixture was stirred at 45 0C for 2-8 hours. The solvent was evaporated in vacuo, to the residue water (100 ml) was added, and the mixture was extracted with chloroform (3x80 ml). The combined organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give the appropriate compound of formula (II), wherein the meaning of R3, R4, R5, X and Y is as described for the formula (I) hereinbefore, as the mixture of its "E" and "Z" isomers. The isomers can be separated by crystallization or by column chromatography on silica gel (Kieselgel 60) generally using chloroform : methanol = 98:2 as eluent.
Applying the above procedure all of the compounds of formula (II) can be prepared, e.g. (IE)- 2-(pyridm-2-ylmethyl)-cyclohexanone oxime [1H (DMSOd6, 300 MHz) δl.18-1.50 (m, 3H), 1.54-1.74 (m, 3H), 1.92-2.06 (m, IH), 2.60-2.80 (m, 2H), 2.80-2.92 (m, IH), 3.17 (dd, IH), 7.17 (ddd, IH), 7.23 (dt, IH), 7.66 (td, IH), 8.46 (ddd, IH), 10.27 (s, IH), 13C (DMSO-d6, 75 MHz) 523.1, 23.8, 25.8, 32.4, 39.0, 41.5, 121.0, 123.5, 136.1, 148.9, 159.0, 160.4] and (IE)- 2-(2-methyl-imidazol-l-ylmethyl)-cyclohexanone oxime [1H (DMSOd6, 300 MHz) δl.19- 1.76 (m, 6H), 1.86-2.00 (m, IH), 2.25 (s, 3H), 2.50-2.64 (m, IH), 2.86-2.96 (m, IH), 3.82 (dd,
IH), 4.21 (dd, IH), 6.69 (d, IH), 7.01 (d, IH), 10.57 (s, IH), 13C (DMSO-d6, 75 MHz) $13.5, 23.8, 24.3, 26.2, 31.0, 43.0, 47.1, 120.8, 126.8, 144.6, 158.1].
Example 7
General procedure for the preparation of compounds of formula (I)
A solution of a compound of formula (II) (3 mmol), wherein the meaning of R3, R4, R5, X and Y is as described for the formula (I) hereinbefore, and a compound of formula (III) (4.5 mmol), wherein the meaning of R1 and R2 is as described for the formula (I) hereinbefore, in dry dichloromethane or tetrahydrofuran (50 ml) was stirred at room temperature for 6-24 hours. The reaction mixture was concentrated in vacuo. The obtained crude product was purified by crystallization or by column chromatography on silica gel (Kieselgel 60) generally using chloroform or dichloromethane as eluent. Applying the above procedure all of the compounds of formula (I) can be prepared, e.g. (IE)- 2-(3-fluorόbenzyl)-cyclohexanone O-[(3-methylphenyl)carbamoyl]oxime [1H (DMSOd6, 300 MHz) δl.30-1.64 (m, 3H), 1.64-1.84 (m, 3H), 2.29 (s, 3H), 2.20-2.40 (m, IH), 2.60-2.80 (m, 2H), 2.90-3.00 (m, IH), 3.12-3.28 (m, IH), 6.83-6.89 (m, IH), 6.95-7.05 (m, IH), 7.07-7.22 (m, 3H), 7.25-7.36 (m, 3H), 9.43 (s, IH), 13C (DMSOd6, 75 MHz) 521.1, 23.0, 25.2, 26.0, 32.0, 35.9, 43.0, 112.7 d /C,F=21.0 HZ, 115.8 d /C,F=21.0 HZ, 116.0, 119.3, 123.6, 125.2 d /C,F=2.6 Hz, 128.6, 129.9 d JC)F=8.4 Hz, 138.0, 138.4, 143.1 d JC,F=1.3 Hz, 162.1 d Jc,F=243.0 Hz, 168.0], (lE)-2-(imidazol-l-ylmethyl)-cyclohexanone O-(phenylcarbamoyl)oxime [1H (CDCl3, 500 MHz) δl.30-1.40 (m, IH), 1.40-1.60 (m, 2H), 1.71-1.86 (m, 3H) 2.00-2.12 (m, IH), 2.62-2.76 (m, IH), 3.04-3.20 (m, IH), 3.99 (dd, IH), 4.39 (dd, IH), 6.91 (t, IH), 7.02 (t, IH), 7.02-7.07 (m, IH), 7.24-7.30 (m, 2H), 7.38-7.43 (m, 2H), 7.51 (s, IH), 7.75 (br s, IH), 13C (CDCl3, 125 MHz) 523.9, 25.9, 26.4, 30.9, 43.9, 47.5, 119.3, 119.7, 124.2, 129.1, 129.5, 137.0, 137.6, 165.8], (lZ)-2-(imidazol-l-ylmethyl)-cyclohexanone O(phenylcarbamoyl)- oxime [1H (CDCl3, 500 MHz) 51.52-1.66 (m, 4H), 1.80-1.86 (m, IH), 1.90-2.00 (m, IH), 2.20-2.30 (m, IH), 2.50-2.60 (m, IH), 3.87-3.94 (m, IH), 4.01-4.12 (m, 2H), 6.91 (t, IH), 6.98 (t, IH), 7.02-7.07 (m, IH), 7.23-7.30 (m, 2H), 7.38-7.43 (m, 2H), 7.57 (s, IH), 8.09 (br s, IH), 13C (CDCl3, 125 MHz) 520.3, 25.9, 26.8, 29.0, 36.4, 46.6, 119.3, 119.7, 124.1, 129.0, 129.4, 137.1, 137.4, 152.0], (lE)-2-(pyridin-3-yloxy)-cyclohexanone O-[(3-chlorophenyl)- carbamoyl]-oxime [1H (DMSOd6, 300 MHz) δl.42-1.75 (m, 2H), 1.75-2.00 (m, 3H), 2.15- 2.30 (m, IH), 2.30-2.42 (m, IH), 2.90-3.02 (m, IH), 5.15-5.21 (m, IH), 7.08-7.14 (m, IH),
7.28-7.44 (m, 3H), 7.53 (ddd, IH), 7.62 (t, IH), 8.20 (dd, IH), 8.40 (d, IH), 9.98 (s, IH), 1 "3C, (DMSO-d6, 75 MHz) 519.9, 23.5, 25.0, 32.3, 74.3, 117.1, 118.1, 122.7, 122.9, 124.0, 130.5, 133.2, 139.3, 139.9, 142.5, 151.4, 153.1, 164.3], (lZ)-2-(ρyridin-3-yloxy)-cyclohexanone O- [(3-chlorophenyl)carbamoyl]-oxime [1H (DMSO-d6, 300 MHz) δl.42-2.10 (m, 5H), 2.20-2.50 (m, 3H), 5.80-5.90 (m, IH), 7.13 (ddd, IH), 7.26-7.50 (m, 4H), 7.66 (t, IH), 8.22 (dd, IH), 8.38 (d, IH), 10.07 (s, IH), 13C (DMSOd6, 75 MHz) 519.1, 27.0, 27.9, 31.3, 67.5, 117.2, 118.1, 122.5, 122.8, 124.3, 130.6, 133.3, 138.7, 139.9, 143.0, 151.1, 152.5, 164.5].
Examples of compounds of formula (I) and their affinity for rat mGluR5 receptors are given in the table below.
*** Ki < 10OnM
** 10OnM < K1 < 30OnM
* Ki > 30OnM
Example 8
Preparation of pharmaceutical compositions; a) Tablets:
0.01-50 % of active ingredient of formula (I), 15-50 % of lactose, 15-50 % of potato starch, 5-15 % of polyvinyl pyrrolidone, 1-5 % of talc, 0.01-3 % of magnesium stearate, 1-3 % of colloid silicon dioxide and 2-7 % of ultraamylopectin were mixed, then granulated by wet granulation and pressed to tablets. b) Dragees, filmcoated tablets:
The tablets made according to the method described above were coated by a layer consisting of entero- or gastrosolvent film, or of sugar and talc. The dragees were polished by a mixture of beeswax and carnuba wax. c) Capsules:
0.01-50 % of active ingredient of formula (I), 1-5 % of sodium lauryl sulfate, 15-50 % of starch, 15-50 % of lactose, 1-3 % of colloid silicon dioxide and 0.01-3 % of magnesium stearate were thoroughly mixed, the mixture was passed through a sieve and filled in hard gelatin capsules. d) Suspensions:
Ingredients: 0.01-15 % of active ingredient of formula (I), 0.1-2 % of sodium hydroxide, 0.1-3 % of citric acid, 0.05-0.2 % of nipagin (sodium methyl 4-hydroxybenzoate), 0.005-0.02 % of nipasol, 0.01-0.5 % of carbopol (polyacrilic acid), 0.1-5 % of 96 % ethanol, 0.1-1 % of flavoring agent, 20-70 % of sorbitol (70 % aqueous solution) and 30-50 % of distilled water.
To solution of nipagin and citric acid in 20 ml of distilled water, carbopol was added in small portions under vigorous stirring, and the solution was left to stand for 10-12 h. Then the sodium hydroxide in 1 ml of distilled water, the aqueous solution of sorbitol and finally the ethanolic raspberry flavor were added with stirring. To this carrier the active ingredient was added in small portions and suspended with an immersing homogenizator. Finally the suspension was filled up to the desired final volume with distilled water and the suspension syrup was passed through a colloid milling equipment. e) 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 0C and the mixture of active ingredient and lactose was mixed in it with homogenizator. The obtained mixture was mould in cooled forms, f) 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.
Claims
1. A compound of formula (I) :
(I) wherein
R1 and R2 represent independently a substituent selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl and cyano;
X is a CHR6 group or O;
R3 represents an alkyl substituent, R4 and/or R5 represent hydrogen, R6 is hydrogen or alkyl, or R3 and R4 with the intermediate two carbon atoms together form a cyclohexane or cyclopentane ring and/or R5 and R6 together form a bond;
Y is an optionally substituted phenyl or heterocyclyl, and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts and/or hydrates and/or solvates thereof.
2 A compound as claimed in claim 1 :
(I) wherein
R1 and R2 represent independently a substituent selected from hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl and cyano;
X is a CHR6 group; R3 represents a C1-4 alkyl substituent, R4 and/or R5 represent hydrogen, R6 is hydrogen or C1-4 alkyl, or R3 and R4 with the intermediate two carbon atoms together form a cyclohexane or cyclopentane ring and/or R5 and R6 together form a bond;
Y is phenyl optionally substituted with one or more substituent(s) selected from halogen, hydroxy, cyano, C1-4 alkylamino, Ci-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, or unsaturated heterocyclyl optionally substituted with one or more substituent(s) selected from halogen, hydroxy, cyano, Ci-4 alkylamino, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts and/or hydrates and/or solvates thereof.
3. A compound as claimed in claim 1 and 2:
(D wherein
Ri and R2 represent independently a substituent selected from hydrogen, halogen, methyl, methoxy, trifluoromethyl and cyano;
X is a CHR6 group;
R3 represents a Ci-4 alkyl substituent, R4 and/or R5 represent hydrogen, R6 is hydrogen, or R3 and R4 with the intermediate two carbon atoms together form a cyclohexane ring;
Y is phenyl optionally substituted with halogen, or pyridyl, thiophenyl, pyrrolyl, furanyl, imidazolyl optionally substituted with one or two methyl substituent(s), and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts and/or hydrates and/or solvates thereof.
4. A compound selected from (l£)-2-benzyl-cyclohexanone O-[(3-methylphenyl)carbamoyl]oxime, (lE)-2-benzyl-cyclohexanone O-[(3-chlorophenyl)carbamoyl]oxime,
(lE)-2-(l-phenylethyl)-cyclohexanone O-[(3-chlorophenyl)carbamoyl]oxime,
(l£)-2-(2-fluorobenzyl)-cyclohexanone O-[(3-chlorophenyl)carbamoyl]oxime,
(lE)-2-(3-fluorobenzyl)-cyclohexanone O-[(3-chlorophenyl)carbamoyl]oxime,
(lE)-2-(4-fluorobenzyl)-cyclohexanone O-[(3-chlorophenyl)carbamoyl]oxime,
(lE)-2-(3-fluorobenzyl)-cyclohexanone O-[(3-methylphenyl)carbamoyl]oxime,
(lE)-2-(thioρhen-2-ylmethyl)-cyclohexanone O-[(3-methylphenyl)carbamoyl]oxime,
(lE)-2-(thiophen-2-ylmethyl)-cyclohexanone O-[(3-chlorophenyl)carbamoyl]oxime,
(lE)-2-(thiophen-3-ylmethyl)-cyclohexanone O-[(3-chlorophenyl)carbamoyl]oxime,
(lE)-2-(thiophen-2-ylmethyl)-cyclohexanone O-[(3-fluorophenyl)carbamoyl]oxime,
(lE)-2-(thiophen-2-ylmethyl)-cyclohexanone O-[(3-bromophenyl)carbamoyl]oxime,
(lE)-2-(thiophen-3-ylmethyl)-cyclohexanone O-[(3-fluorophenyl)carbamoyl]oxime,
(lE)-2-(thiophen-2-ylmethyl)-cyclohexanone O-[(3-methoxyphenyl)carbamoyl]oxime,
(lE)-2-(pyrrol-2-ylmethyl)-cyclohexanone O-[(3-chlorophenyl)carbamoyl]oxime,
(lE)-2-(pyrrol-2-ylmethyl)-cyclohexanone O-[(3-methylphenyl)carbam.oyl]oxime,
(lE)-2-(furan-2-ylmethyl)-cyclohexanone 0-[(3-chlorophenyl)carbamoyl]oxime,
(lE)-2-(furan-2-ylmethyl)-cyclohexanone O-[(3-fluorophenyl)carbamoyl]oxime,
(lE)-2-(imidazol-l-ylmethyl)-cyclohexanone O-[(3-chloiOphenyl)carbamoyl]oxime,
(+)-(lE)-2-(imidazol-l-ylmethyl)-cyclohexanone O-[(3-clilorophenyl)carbamoyl]oxime,
(l£)-2-(imidazol-l-ylrQethyl)-cyclohexanone 0-[(3-fluorophenyl)carbamoyl]oxime,
(lE)-2-(imidazol-l-ylmethyl)-cyclohexanone O-[(3-cyanophenyl)carbamoyl]oxime,
( 1 £)-2- [(4-methylimidazol)- 1 -ylmethyl] -cyclohexanone O- [(3 -chlorophenyl)carb amoyl] - oxime,
(lE)-2-(imidazol-l-ylmethyl)-cyclohexanone O-[(3-trifluoromethyl-phenyl)carbamoyl]oxime,
(lE)-2-(pyridin-2-ylmethyl)-cyclohexanone O-[(3-chlorophenyl)carbamoyl]oxime,
(lE)-2-(pyridin-3-ylmethyl)-cyclohexanone O-[(3-chlorophenyl)carbamoyl]oxime,
(lE,2E)-2-(pyridin-2-ylmethylidene)-cyclohexanone O-[(3-chlorophenyl)carbamoyl]oxime, and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts and/or hydrates and/or solvates thereof.
5. A process for preparing a compound of formula (I):
(I) wherein
R1 and R2 represent independently a substituent selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl and cyano;
X is a CHR6 group or O;
R3 represents an alkyl substituent, R4 and/or R5 represent hydrogen, R6 is hydrogen or alkyl, or R3 and R4 with the intermediate two carbon atoms together form a cyclohexane or cyclopentane ring and/or R5 and R6 together form a bond;
Y is an optionally substituted phenyl or heterocyclyl, and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts and/or hydrates and/or solvates thereof, by reacting an oxime derivative of formula (II):
(H) wherein the meaning of R3, R4, R5, X and Y is as described above for the formula (I) and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts and/or hydrates and/or solvates thereof, with a phenylisocyanate derivative of formula (III):
(III) wherein the meaning Of R1 and R2 is as described above for the formula (I), or interconverting one compound of formula (I), wherein the meaning of R1, R2, R3, R4, R5, X and Y is as described above for the formula (I) to a different compound of formula (I), wherein the meaning Of R1, R2, R3, R4, R5, X and Y is as described above for the formula (I); where appropriate, separating the enantiomers and/or racemates and/or diastereomers and/or geometric isomers of compounds of formula (I), wherein the meaning Of R1, R2, R3, R4, R5, X and Y is as described above for the formula (I) by conventional methods; and optionally thereafter forming salts and/or hydrates and/or solvates of compounds of formula (I).
6. A process according to claim 5 for preparing a compound of formula (I):
(D wherein
R1 and R2 represent independently a substituent selected from hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl and cyano;
X is a CHR6 group;
R3 represents a C1-4 alkyl substituent, R4 and/or R5 represent hydrogen, R6 is hydrogen or C1-4 alkyl, or R3 and R4 with the intermediate two carbon atoms together form a cyclohexane or cyclopentane ring and/or R5 and R6 together form a bond;
Y is phenyl optionally substituted with one or more substituent(s) selected from halogen, hydroxy, cyano, C1-4 alkylamino, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, or unsaturated heterocyclyl optionally substituted with one or more substituent(s) selected from halogen, hydroxy, cyano, C1-4 alkylamino, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts and/or hydrates and/or solvates thereof, by reacting an oxime derivative of formula (II):
(H) wherein the meaning of R3, R4, R5, X and Y is as described above for the formula (I) and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts and/or hydrates and/or solvates thereof, with a phenylisocyanate derivative of formula (III):
(III) wherein the meaning Of R1 and R2 is as described above for the formula (I), or interconverting one compound of formula (I), wherein the meaning of R1, R2, R3, R4, R5, X and Y is as described above for the formula (I) to a different compound of formula (I), wherein the meaning of R1, R2, R3, R4, R5, X and Y is as described above for the formula (I); where appropriate, separating the enantiomers and/or racemates and/or diastereomers and/or geometric isomers of compounds of formula (I), wherein the meaning Of R1, R2, R3, R4, R5, X and Y is as described above for the formula (I) by conventional methods; and optionally thereafter forming salts and/or hydrates and/or solvates of compounds of formula (I).
7. A process according to claims 5 and 6 for preparing a compound of formula (I):
(D wherein
R1 and R2 represent independently a substituent selected from hydrogen, halogen, methyl, methoxy, trifluoromethyl and cyano;
X is a CHR6 group;
R3 represents a Ci-4 alkyl substituent, R4 and/or R5 represent hydrogen, R6 is hydrogen, or R3 and R4 with the intermediate two carbon atoms together form a cyclohexane ring;
Y is phenyl optionally substituted with halogen, or pyridyl, thiophenyl, pyrrolyl, furanyl, imidazolyl optionally substituted with one or two methyl substituent(s), and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts and/or hydrates and/or solvates thereof, by reacting an oxime derivative of formula (II):
(H) wherein the meaning of R3, R4, R5, X and Y is as described above for the formula (I) and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or salts and/or hydrates and/or solvates thereof, with a phenylisocyanate derivative of formula (III):
(III) wherein the meaning of Ri and R2 is as described above for the formula (I), or interconverting one compound of formula (I), wherein the meaning of R1, R2, R3, R4, R5, X and Y is as described above for the formula (I) to a different compound of formula (I), wherein the meaning of Ri, R2, R3, R4, R5, X and Y is as described above for the formula (I); where appropriate, separating the enantiomers and/or racemates and/or diastereomers and/or geometric isomers of compounds of formula (I), wherein the meaning of R1, R2, R3, R4, R5, X and Y is as described above for the formula (I) by conventional methods; and optionally thereafter forming salts and/or hydrates and/or solvates of compounds of formula (I).
8. A pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (I):
(D wherein
R1 and R2 represent independently a substituent selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl and cyano;
X is a CHR6 group or O;
R3 represents an alkyl substituent, R4 and/or R5 represent hydrogen, R6 is hydrogen or alkyl, or R3 and R4 with the intermediate two carbon atoms together form a cyclohexane or cyclopentane ring and/or R5 and R6 together form a bond;
Y is an optionally substituted phenyl or heterocyclyl, and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof in association with one or more physiologically acceptable diluents, excipients and/or inert carriers.
9. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I):
R1 and R2 represent independently a substituent selected from hydrogen, halogen, C1-4 alkyl, Ci-4 alkoxy, C1-4 haloalkyl and cyano;
X is a CHR6 group;
R3 represents a C1-4 alkyl substituent, R4 and/or R5 represent hydrogen, R6 is hydrogen or C1-4 alkyl, or R3 and R4 with the intermediate two carbon atoms together form a cyclohexane or cyclopentane ring and/or R5 and R6 together form a bond;
Y is phenyl optionally substituted with one or more substituent(s) selected from halogen, hydroxy, cyano, C1-4 alkylamino, Ci-4 alkyl, Ci-4 alkoxy, Ci-4 haloalkyl, or unsaturated heterocyclyl optionally substituted with one or more substituent(s) selected from halogen, hydroxy, cyano, Ci-4 alkylamino, Ci-4 alkyl, Ci-4 alkoxy, Ci-4 haloalkyl, and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof in association with one or more physiologically acceptable diluents, excipients and/or inert carriers.
10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I):
(I) wherein
Ri and R2 represent independently a substituent selected from hydrogen, halogen, methyl, methoxy, trifluoromethyl and cyano;
X is a CHR6 group;
R3 represents a Ci-4 alkyl substituent, R4 and/or R5 represent hydrogen, R6 is hydrogen, or R3 and R4 with the intermediate two carbon atoms together form a cyclohexane ring;
Y is phenyl optionally substituted with halogen, or pyridyl, thiophenyl, pyrrolyl, furanyl, imidazolyl optionally substituted with one or two methyl substituent(s), and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof in association with one or more physiologically acceptable diluents, excipients and/or inert carriers.
11. A pharmaceutical composition according to any claims of 8 to 10 for use in the prevention and/or treatment of mGluR5 receptor-mediated disorders.
12. The use of a compound of formula (I):
(I) wherein
R1 and R2 represent independently a substituent selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl and cyano;
X is a CHR6 group or O;
R3 represents an alkyl substituent, R4 and/or R5 represent hydrogen, R6 is hydrogen or alkyl, or R3 and R4 with the intermediate two carbon atoms together form a cyclohexane or cyclopentane ring and/or R5 and R6 together form a bond;
Y is an optionally substituted phenyl or heterocyclyl, and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof in the manufacture of a medicament for the treatment and/or prevention of mGluR5 receptor-mediated disorders.
13. The use of a compound of formula (I):
R1 and R2 represent independently a substituent selected from hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl and cyano;
X is a CHR6 group;
R3 represents a Ci-4 alkyl substituent, R4 and/or R5 represent hydrogen, R6 is hydrogen or Ci-4 alkyl, or R3 and R4 with the intermediate two carbon atoms together form a cyclohexane or cyclopentane ring and/or R5 and R6 together form a bond;
Y is phenyl optionally substituted with one or more substituent(s) selected from halogen, hydroxy, cyano, Ci-4 alkylamino, Ci-4 alkyl, Ci-4 alkoxy, Ci-4 haloalkyl, or unsaturated heterocyclyl optionally substituted with one or more substituent(s) selected from halogen, hydroxy, cyano, Ci-4 alkylamino, Ci-4 alkyl, Ci-4 alkoxy, Ci-4 haloalkyl, and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof in the manufacture of a medicament for the treatment and/or prevention of mGluR5 receptor-mediated disorders.
14. The use of a compound of formula (I):
(D wherein
Ri and R2 represent independently a substituent selected from hydrogen, halogen, methyl, methoxy, trifluoromethyl and cyano;
X is a CHR6 group;
R3 represents a Ci-4 alkyl substituent, R4 and/or R5 represent hydrogen, R6 is hydrogen, or R3 and R4 with the intermediate two carbon atoms together form a cyclohexane ring;
Y is phenyl optionally substituted with halogen, or pyridyl, thiophenyl, pyrrolyl, furanyl, imidazolyl optionally substituted with one or two methyl substituent(s), and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof in the manufacture of a medicament for the treatment and/or prevention of mGluR5 receptor-mediated disorders.
15. The use of a compound according to any claims of 12 to 14 wherein said mGluR5 receptor-mediated disorders are psychiatric disorders.
16. The use of a compound according to any claims of 12 to 14 wherein said mGluR5 receptor-mediated disorders are neurological disorders.
17. The use of a compound according to any claims of 12 to 14 wherein said m.GluR.5 receptor-mediated disorders are chronic and acute pain.
18. The use of a compound according to any claims of 12 to 14 wherein said mGluR5 receptor-mediated disorders are neuromuscular dysfunctions of the lower urinary tract.
19. A method of prevention and/or treatment of mGluR5 receptor-mediated disorders, comprising administering to a mammal in need of such prevention and/or treatment, a therapeutically effective amount of a compound of formula (I):
(I) wherein
R1 and R2 represent independently a substituent selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl and cyano; X is a CHR6 group or O; R3 represents an alkyl substituent, R4 and/or R5 represent hydrogen, R6 is hydrogen or alkyl, or R3 and R4 with the intermediate two carbon atoms together form a cyclohexane or cyclopentane ring and/or R5 and R6 together form a bond;
Y is an optionally substituted phenyl or heterocyclyl, and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof.
20. A method of prevention and/or treatment of mGluR5 receptor-mediated disorders, comprising administering to a mammal in need of such prevention and/or treatment, a therapeutically effective amount of a compound of formula (I):
(I) wherein
R1 and R2 represent independently a substituent selected from hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl and cyano;
X is a CHR6 group;
R3 represents a C1-4 alkyl substituent, R4 and/or R5 represent hydrogen, R6 is hydrogen or C1-4 alkyl, or R3 and R4 with the intermediate two carbon atoms together form a cyclohexane or cyclopentane ring and/or R5 and R6 together form a bond;
Y is phenyl optionally substituted with one or more substituent(s) selected from halogen, hydroxy, cyano, C1-4 alkylamino, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, or unsaturated heterocyclyl optionally substituted with one or more substituent(s) selected from halogen, hydroxy, cyano, C1-4 alkylamino, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof.
21. A method of prevention and/or treatment of mGluR5 receptor-mediated disorders, comprising administering to a mammal in need of such prevention and/or treatment, a therapeutically effective amount of a compound of formula (I):
(D wherein
R1 and R2 represent independently a substituent selected from hydrogen, halogen, methyl, methoxy, trifluoromethyl and cyano;
X is a CHR6 group;
R3 represents a C1-4 alkyl substituent, R4 and/or R5 represent hydrogen, R6 is hydrogen, or R3 and R4 with the intermediate two carbon atoms together form a cyclohexane ring;
Y is phenyl optionally substituted with halogen, or pyridyl, thiophenyl, pyrrolyl, furanyl, imidazolyl optionally substituted with one or two methyl substituent(s), and/or enantiomers and/or racemates and/or diastereomers and/or geometric isomers and/or physiologically acceptable salts and/or hydrates and/or solvates thereof.
22. A method according to any claims of 19 to 21, wherein said mammal is a human.
23. A method according to any claims of 19 to 21, wherein said mGluR5 receptor- mediated disorders are psychiatric disorders.
24. A method according to any claims of 19 to 21, wherein said mGluR5 receptor- mediated disorders are neurological disorders.
25. A method according to any claims of 19 to 21, wherein said mGluR5 receptor- mediated disorders are chronic and acute pain disorders.
26. A method according to any claims of 19 to 21, wherein said niGluR5 receptor- mediated disorders are neuromuscular dysfunctions of the lower urinary tract.
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HU0501163A HUP0501163A2 (en) | 2005-12-20 | 2005-12-20 | New compounds |
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WO (1) | WO2007072089A1 (en) |
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2006
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Non-Patent Citations (12)
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"Comgenex Product List", 15 April 2005, COMGENEX INTERNATIONAL INC., MONMOUTH, NJ, 08852 * |
"Explore Library Collection", 14 May 2001, NANOSYN COMBINATORIAL SYNTHESIS INC., MOUNTAIN VIEW, CA, 94043-2213 * |
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COZUBSCHI-SCIUREVICI, ELENA: "Action of isothiocyanates on benzoin oximes", ANNALES SCIENTIFIQUES DE L'UNIVERSITE DE JASSY , 28(SECT. I), 209-44 CODEN: ASUJAH; ISSN: 0365-7264, 1942, XP001249216 * |
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; RUCHKIN, V. E. ET AL: "Synthesis of some N-substituted carbamoyl oximes", XP002424453, retrieved from STN Database accession no. 1968:95417 * |
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002424454 * |
DATABASE CHEMCATS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002424455 * |
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DIMMOCK J R ET AL: "Synthesis and Cytotoxic Evaluation of Some Cyclic Arylidene Ketones and Related Oximes, Oxime Esters, and Analogs", JOURNAL OF PHARMACEUTICAL SCIENCES, AMERICAN PHARMACEUTICAL ASSOCIATION. WASHINGTON, US, vol. 83, no. 6, 1994, pages 852 - 858, XP002180652, ISSN: 0022-3549 * |
OCCELLI, E. ET AL: "Synthesis and pharmacological activity of 3-aminopropiophenones and 3-(aminomethyl)camphors", FARMACO, EDIZIONE SCIENTIFICA , 40(2), 86-101 CODEN: FRPSAX; ISSN: 0430-0920, 1985, XP008076276 * |
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