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WO2014065270A1 - Dérivé de tétrahydrooxazolo-pyridine - Google Patents

Dérivé de tétrahydrooxazolo-pyridine Download PDF

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Publication number
WO2014065270A1
WO2014065270A1 PCT/JP2013/078553 JP2013078553W WO2014065270A1 WO 2014065270 A1 WO2014065270 A1 WO 2014065270A1 JP 2013078553 W JP2013078553 W JP 2013078553W WO 2014065270 A1 WO2014065270 A1 WO 2014065270A1
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Prior art keywords
disorder
oxazolo
pharmaceutically acceptable
dihydro
fluoropyridin
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Japanese (ja)
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耕三 吉田
亘 広瀬
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Sumitomo Pharma Co Ltd
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Sumitomo Dainippon Pharma Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a novel tetrahydrooxazolopyridine derivative useful as a medicament having an action as a metabotropic glutamate receptor subtype 5 (mGluR5) negative modulator. More specifically, schizophrenia, anxiety disorder, obsessive-compulsive disorder, PTSD, depressive disorder, bipolar disorder, drug addiction, neurodegenerative diseases (levodopa-induced dyskinesia, Parkinson's disease, Huntington's disease, etc.), developmental disorders ( Fragile X syndrome, autism spectrum disorder, Rett syndrome, tuberous sclerosis, etc.), pain (inflammatory pain, neuropathic pain, etc.), other neurological diseases (epilepsy, oxygen deficiency, ischemic disorder, etc.)
  • the present invention relates to novel compounds useful as therapeutic agents.
  • L-glutamate is a major excitatory neurotransmitter in the central nervous system, binds to nerve cells, and activates cell surface receptors. L-glutamate acts through two heterogeneous receptor families: ion channel and metabotropic glutamate receptors (mGluR). mGluR is a G-protein coupled receptor and activates a second messenger in the cell when bound to glutamic acid. Eight mGluR subtypes have been cloned and classified into three groups based on sequence similarity and pharmacological properties.
  • mGluR1 and mGluR5 belong to group I and initiate cellular responses by G-protein coupled mechanisms, activate phospholipase C, cause inositol phospholipid hydrolysis and intracellular calcium mobilization (Schoepp, DD, et al ., Neuropharmacology 1999, 38, 1431).
  • MGluR5 is expressed in both the central nervous system and the periphery (Chizh, B.A., et al., Amino Acids 2002, 23, 169). Thus, modulation of mGluR5 activity is useful for the treatment of disorders in both the peripheral and CNS. With respect to peripheral disorders, mGluR5 negative modulators have been shown to be effective in the treatment of gastrointestinal (GI) tract disorders such as gastroesophageal reflux disease (GERD).
  • GI gastrointestinal
  • GTD gastroesophageal reflux disease
  • mGluR5 negative modulators are effective in various animal models of anxiety such as stress hyperthermia and fear-enhancing startle.
  • mGluR5 modulation include schizophrenia, anxiety disorder, obsessive compulsive disorder, PTSD, depressive disorder, bipolar disorder, drug addiction, neurodegenerative diseases (levodopa-induced dyskinesia, parkinson Disease, Huntington's disease, etc.), developmental disorders (fragile X syndrome, autism spectrum disorder, Rett syndrome, tuberous sclerosis, etc.), pain (inflammatory pain, neuropathic pain, etc.), other neurological diseases (epilepsy, Oxygen deficiency, ischemic injury, etc.). Therefore, the usefulness of an mGluR5 modulator that is effective as a method for treating various disorders such as neuropathy is very high.
  • Patent Document 1 As a compound having an action as an mGluR5 negative modulator, a compound having a bicyclic skeleton condensed with a 5-membered heterocycle shown below has been reported (Patent Document 1). Specifically, the formula (A): [Where: R 1 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be optionally substituted; R 2 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be optionally substituted; R 3 and R 4 are each independently a hydrogen atom, halogen, or lower alkyl; When R 3 and R 4 are attached to the same carbon atom, CR 3 R 4 is C ⁇ O or R 3 and R 4 together with the carbon atom to which they are attached are 3 to 7 membered spiro May form a cycloalkyl; or, when R 3 and R 4 are attached to different carbon atoms, R 3 and R 4 together with the carbon atom to which
  • Optionally substituted cycloalkyl, optionally substituted heterocyclyl; optionally substituted aryl, or optionally substituted heteroaryl; L 2 is a bond, -O -, - NR 9 - , - CR 5 R 6 - or -CR 5 R 6 -CR 7 R 8 - and is;
  • X is C or N;
  • Y is O, S, N, NR 10 , or CR 10 ;
  • Z is O, S, N, NR 10 , or CR 10 ; where Y and Z are not both O or both S;
  • R 5 and R 6 are each independently a hydrogen atom, halogen, or lower alkyl, or CR 5 R 6 is C ⁇ O; or R 5 and R 6 together with the carbon atom to which they are attached May form a 3 to 7 membered cycloalkyl;
  • R 7 and R 8 are each independently a hydrogen atom, halogen, or lower alkyl, or CR 7 R 8
  • GSH glutathione
  • the problem to be solved by the present invention is to provide a novel compound having an action as an mGluR5 negative modulator. Since such an mGluR5 negative modulator is expected to be useful as a therapeutic agent for mental disorders or neurodegenerative diseases in which mGluR5 is involved, it is possible to provide a drug with excellent therapeutic effect and higher safety. It is a subject of the invention. Specific problems include the action as a strong mGluR5 negative modulator, pharmacokinetically excellent oral absorption, high bioavailability, and excellent safety, such as GSH adducts. For example, providing a drug that does not produce or is unlikely to occur.
  • a tetrahydrooxazolopyridine derivative having a 2-pyridyl group and a benzoyl group optionally substituted at the 5-position nitrogen atom or a pharmaceutically acceptable salt thereof is a strong mGluR5 negative modulator
  • the present inventors have found that the GSH adduct is not produced or hardly produced, and has excellent pharmacokinetic oral absorption. Based on these findings, the present invention has been completed.
  • the present invention relates to a tetrahydrooxazolopyridine derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof having the following action as an mGluR5 negative modulator.
  • R 1 is fluorine or chlorine.
  • Item 12 The compound according to Item 1 or a pharmaceutically acceptable salt thereof.
  • R 1 is fluorine.
  • Item 3 The compound according to Item 1 or Item 2, or a pharmaceutically acceptable salt thereof.
  • R 2 and R 3 are each independently a hydrogen atom, fluorine, chlorine, methyl, methoxy or cyano.
  • Item 4 The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof.
  • R 2 and R 3 are each independently a hydrogen atom, fluorine, chlorine, or methyl.
  • Item 5 The compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising the compound according to any one of Items 1 to 7 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • a mental disorder or neurodegeneration involving the metabotropic glutamate receptor subtype 5 comprising the compound according to any one of Items 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Psychiatric disorders or neurodegenerative disorders involving metabotropic glutamate receptor subtype 5 are schizophrenia, anxiety disorder, obsessive compulsive disorder, PTSD, depressive disorder, bipolar disorder, drug dependence, nerve Degenerative diseases (levodopa-induced dyskinesia, Parkinson's disease, Huntington's disease, etc.), developmental disorders (fragile X syndrome, autism spectrum disorder, Rett syndrome, tuberous sclerosis, etc.), pain (inflammatory pain, neuropathic pain, etc.) ) Or other neurological diseases (epileptic, hypoxia, ischemic injury, etc.) Item 10. The therapeutic agent according to Item 9.
  • ⁇ disorders such as anxiety and obsessive-compulsive disorder
  • mood disorders such as depression and bipolar disorder
  • cognition such as Alzheimer's disease Disorders
  • psychosis such as schizophrenia
  • Parkinson's disease levodopa-induced dyskinesia
  • neurodegenerative diseases such as Huntington's disease, amyotrophic lateral sclerosis; autism spectrum disorder; fragile X syndrome, Rett syndrome, tuberous sclerosis Or developmental disorder of attention deficit / hyperactivity disorder
  • intellectual disability such as Down syndrome; inflammatory pain; neuropathic pain; postoperative pain; acute thermal hyperalgesia; mechanical allodynia; pain such as visceral pain / chronic pain
  • neurodegenerative diseases levodopa-induced dyskinesia, Parkinson's disease, Huntington's disease, etc.
  • developmental disorders fragmentile X syndrome, autism spectrum disorder, Rett syndrome, tuberous sclerosis, etc.
  • pain inflammatory pain
  • Neuropathic pain etc.
  • other neurological diseases epileptic, hypoxia, ischemic disorder, etc
  • a tetrahydrooxazolopyridine derivative having an action as a strong mGluR5 negative modulator and having no or hardly generated GSH adduct and having excellent pharmacokinetic oral absorption or a derivative thereof. It is possible to provide a pharmaceutically acceptable salt.
  • the compounds provided by the present invention or pharmaceutically acceptable salts thereof may exist in the form of hydrates and / or solvates, these hydrates and / or solvates may also be present. Also included in the compounds of the present invention.
  • the compounds of formula (I) are included within the scope of the present invention in the case where rotational isomers and tautomers can exist, both of individual single compounds and mixtures thereof. Also included in the compound represented by the general formula (I) is a deuterium converter obtained by converting any one or two or more 1 H of the compound represented by the general formula (I) to 2 H (D). Is done.
  • a crystal polymorph may exist in the compound represented by the general formula (I) obtained as a crystal or a pharmaceutically acceptable salt thereof, and the crystal polymorph is also included in the present invention.
  • C 1-3 represents 1 to 3 carbon atoms
  • C 3 represents 3 carbon atoms. The same applies to other numbers.
  • C 1-3 alkyl means a straight or branched saturated aliphatic hydrocarbon having 1 to 3 carbon atoms, and specific examples thereof include methyl, ethyl, 1-propyl, 2-propyl. Etc., preferably methyl.
  • Halogen means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom.
  • C 1-3 alkoxy means an oxy group substituted with the above “C 1-3 alkyl”, and specific examples thereof include methoxy, ethoxy, propoxy, isopropoxy, etc., preferably methoxy is Can be mentioned.
  • R 1 is halogen, methyl or cyano, preferably fluorine or chlorine, more preferably fluorine.
  • R 2 and R 3 are each independently a hydrogen atom, halogen, C 1-3 alkyl, C 1-3 alkoxy or cyano, preferably a hydrogen atom, fluorine, chlorine, methyl, methoxy or cyano. More preferably, a hydrogen atom, fluorine, and chlorine are mentioned.
  • the term “pharmaceutically acceptable salt” is prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Meaning salt. For example, but not limited to, acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, formic acid, fumaric acid, furonic acid, gluconic acid, glutamic acid, glucorenic acid, Galacturonic acid, glycidic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucinic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, propionic acid, phosphoric acid Salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric
  • solvate refers to a compound of the present invention or salt thereof further comprising a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Means. When the solvent is water, the solvate is a hydrate.
  • the term “pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, composition or medium, such as a liquid or solid extender, Mean diluent, solvent or encapsulating material.
  • each ingredient is “pharmaceutically acceptable” in the sense that it is compatible with the other ingredients of the pharmaceutical formulation, and excessive toxicity, irritation, allergic reaction, antigenicity, or other problems Or suitable for use in contact with human or animal tissues or organs commensurate with a reasonable benefit / risk ratio without causing complications.
  • the tetrahydrooxazolopyridine compound of the present invention can be produced from known compounds by appropriately combining synthetic methods well known to those skilled in the art by the following production method or a method according to the following production method.
  • the raw material compound may be a known compound, or may be produced by appropriately combining synthetic methods well known to those skilled in the art according to the method described in Examples below or the method according to Examples below.
  • the compound used in the following production method may form a salt as long as it does not interfere with the reaction. Also, the reaction may be scaled up or down depending on the amount of substance to be produced.
  • a method for introducing a protecting group and a method for removing a protecting group are methods known to those skilled in the art [Protective Groups in Organic Synthesis 3rd edition, John Willy and Sands (John). Wiley & Sons, INC.) Etc.].
  • the protecting groups used in this case may be those described in Protective Group's Organic Organic Synthesis 3rd edition, John Wiley & Sons, Inc., etc. it can.
  • This reaction is advantageously performed using a solvent inert to the reaction (inert solvent).
  • the “inert solvent” include aromatic solvents such as benzene, toluene, xylene and pyridine; hydrocarbon solvents such as hexane, pentane and cyclohexane; tetrahydrofuran (THF), diethyl ether, 1,2-dimethoxyethane, Ether solvents such as 1,4-dioxane; ester solvents such as ethyl acetate and ethyl formate; alcohol solvents such as methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone Amide solvents such as N, N-dimethylformamide, N-methylpyrrolidone and N, N-dimethylacetamide; sulfoxide solvents such as dimethyl sulfoxide
  • the “base” is, for example, an alkali metal or alkaline earth metal hydride such as lithium hydride, sodium hydride, potassium hydride, calcium hydride; lithium amide, sodium amide, Alkali metal or alkaline earth metal amides such as lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; sodium methoxide, sodium ethoxide, potassium tert -Lower alkoxides of alkali metals or alkaline earth metals such as butoxide; alkyllithiums such as butyllithium, sec-butyllithium, tert-butyllithium, methyllithium; sodium hydroxide, hydroxide Alkali metal or alkaline earth metal hydroxides such as potassium, lithium hydroxide, and barium hydroxide;
  • Examples of the “acid” include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, and acetic acid. These acids are appropriately selected according to various reaction conditions known to those skilled in the art.
  • Step 1 Compound (I) can be obtained by forming amide bond between compound (A-1) or a salt thereof and carboxylic acid (A-2) by various amidation reactions known to those skilled in the art. .
  • compound (A-1) and carboxylic acid halide (A-3) can be obtained by an amidation reaction in an inert solvent in the presence or absence of a base.
  • the amidation reaction using compound (A-1) or a salt thereof and carboxylic acid (A-2) is, for example, O- (7-azabenzotriazole in an inert solvent in the presence or absence of a base.
  • amidation reaction using a condensing agent such as 1,1′-carbonyldiimidazole (CDI), ethyl chlorocarbonate, isobutyl chlorocarbonate or trimethylacetate Rukurorido the like amidation reaction via a mixed acid anhydride using, for example.
  • a condensing agent such as 1,1′-carbonyldiimidazole (CDI), ethyl chlorocarbonate, isobutyl chlorocarbonate or trimethylacetate Rukurorido the like amidation reaction via a mixed acid anhydride using, for example.
  • a condensing agent such as 1,1′-carbonyldiimidazole (CDI), ethyl chlorocarbonate, isobutyl chlorocarbonate or trimethylacetate Rukurorido the like amidation reaction via a mixed acid anhydride using, for example.
  • a condensing agent such as 1,1′-carbonyldiimidazole (CDI
  • Step 2 Compound (A-7) can be produced by reacting Compound (A-4) or a salt thereof, which can be produced by the method described in WO2011 / 029046, with various substituted picolines in an inert solvent in the presence or absence of a base. It can be obtained by subjecting it to an amidation reaction with acid (A-5) or various substituted picolinic acid halides (A-6).
  • the condensing agent and additive described in Step 1 can be used.
  • Step 3 Compound (A-8) can be obtained by subjecting Compound (A-7) to an appropriate oxidation reaction in an inert solvent.
  • An appropriate oxidation reaction here is an oxidation reaction that can oxidize alcohol to convert it into a ketone.
  • DMSO oxidation using Swan oxidation or sulfur trioxide / pyridine complex hypervalent iodine such as Dess-Martin reagent, etc.
  • examples thereof include an oxidation reaction using a reagent and a chromium (VI) reagent such as PCC and PDC.
  • Step 4 Compound (A-9) can be obtained by reacting Compound (A-8) in an inert solvent with a suitable dehydrating agent.
  • suitable dehydrating cyclizing agents include thionyl chloride, phosphorus oxychloride, diphosphorus pentoxide, Burgess reagent, and the like.
  • Step 5 Compound (A-1) can be obtained by subjecting compound (A-9) to a deprotection reaction by a method known in the literature relating to the protecting group shown above.
  • Step 6 Compound (A-8) is a commercially available compound (A-10) or a salt thereof that can be produced by a method according to CN10185565, etc., in an inert solvent in the presence or absence of a base. It can be obtained by subjecting it to an amidation reaction with a substituted picolinic acid halide (A-6).
  • the compound represented by the compound (A-8) is a series of the following steps 7-1, 7-2 and 7-3 from a compound (A-11) which is commercially available or can be produced by a method according to the description of CN10185565. It can also be manufactured by conversion.
  • LG represents a leaving group such as a methanesulfonyloxy group, a p-toluenesulfonyloxy group or an o-nitrobenzenesulfonyloxy group
  • Ra represents a lower alkyl group such as a methyl group or an ethyl group
  • Steps 7-1 and 7-2 The reaction intermediate represented by the compound (A-12) was prepared by appropriately combining the compound (A-11) that can be obtained commercially or prepared by a method according to CN10187565 in an inert solvent.
  • the rearrangement reaction (step 7-1) was performed with the action of a suitable base, and then the amidation reaction (step 7-2) with various substituted picolinic acid halides (A-6) in the presence or absence of a base. It can obtain by providing.
  • suitable bases used in Step 7-1 include alkali metal lower alkoxides such as sodium methoxide and sodium ethoxide.
  • Step 7-3 The compound (A-8) can be obtained by subjecting the reaction intermediate represented by the compound (A-12) to a ring-opening reaction with an acidic aqueous solution in an inert solvent.
  • Step 8 Among the compounds represented by the compound (A-9), the compound (A-9-b) in which R 1 is cyano is obtained in the presence of a palladium catalyst, a ligand, and a base in an inert solvent.
  • the compound (A-9-a) produced by the method described in Production Method 2 wherein R 1 is a bromo group and the metal cyanide It can obtain also by cyanation reaction.
  • the palladium catalyst is a palladium compound such as tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium chloride, bis (benzonitrile) palladium chloride, tris (dibenzylideneacetone) dipalladium, palladium chloride or palladium acetate. It is.
  • Ligand is dimethylphenylphosphine, diphenylphosphinoferrocene (DPPF), trimethylphosphine, triethylphosphine, tritert-butylphosphine, tricyclohexylphosphine, trimethoxyphosphine, triethoxyphosphine, tritert-butoxyphosphine, triphenyl.
  • DPPF diphenylphosphinoferrocene
  • the metal cyanide include sodium cyanide, potassium cyanide, copper cyanide, zinc cyanide, potassium hexacyanide iron (II) and potassium hexacyanide iron (III).
  • the raw materials and reagents used in the above production method are commercially available compounds or can be produced from known compounds using known methods unless otherwise specified.
  • another compound of the formula (I) may be obtained by appropriately converting a functional group.
  • the functional group can be converted by a commonly used general method [for example, Comprehensive Organic Transformations, Earl. Sea. Can be carried out according to R. C. Larock (1989), etc.].
  • the functional group is described in advance in the above-mentioned document or the like.
  • the target compound can be obtained by carrying out the reaction after protecting with an appropriate protecting group and then deprotecting.
  • the protecting group for amine include ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, benzoyl, benzyl and the like
  • examples of the hydroxyl protecting group include trialkylsilyl, acetyl, benzoyl, benzyl and the like. be able to.
  • Examples of the protecting group for the ketone include dimethyl acetal, 1,3-dioxane, 1,3-dioxolane, S, S'-dimethyldithioacetal, 1,3-dithiane, oxime and the like.
  • this invention compound (I) and an intermediate body are isolated and purified by a well-known means (For example, solvent extraction, neutralization, filtration, washing
  • the compound used in each production method can be isolated and purified by the same known means as described above. Isolation and purification may be performed after each reaction or after completion of several reactions.
  • the compound (I) may be purified as it is when obtained in the form of a pharmaceutically acceptable salt, When it is obtained in a free form, it may be dissolved or suspended in a suitable organic solvent, and the acid mentioned above may be added to form a salt by a conventional method.
  • a salt can be obtained by mixing with a pharmaceutically acceptable acid in a solvent such as water, methanol, ethanol, acetone or the like.
  • room temperature means a temperature of 0 to 30 ° C.
  • % means percent by weight unless otherwise specified.
  • Silica gel” and “NH silica gel” when purified using column chromatography were silica gel and NH silica gel commercially available from Yamazen Co., Ltd. Each device data described in the production examples and examples was measured by the following measuring devices.
  • NMR measurement conditions are as follows, and in order to simplify the description, the following abbreviations may be used in the examples and tables in the examples.
  • the symbols used in NMR are as follows: s is a single line, d is a double line, dd is a double double line, t is a triple line, td is a triple double line, q is a quadruple line, m is Multiple lines, br means broad, brs means wide single line, brd means wide double line, and brt means wide triple line.
  • NMR spectrum 400 MHz (JEOL AL400, JEOL) or 300 MHz (JEOL LA300, JEOL)
  • Example 1 [2- (5-Fluoropyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] (phenyl) methanone 2- (5-Fluoropyridin-2-yl) -4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridine (Preparation Example 1-3, 10.0 g) and triethylamine A solution of benzoyl chloride (6.94 g) in dichloromethane (30 mL) was added dropwise to a solution of (6.73 g) in dichloromethane (230 mL) under ice cooling, and the mixture was stirred for 1 hour.
  • Example 1 2- (5-Fluoropyridin-2-yl) -4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridine used in the production of Example 1 (Preparation Example 1 3) was prepared by the following method using benzyl 3-amino-4-oxopiperidine-1-carboxylate hydrochloride and 5-fluoropicolinic acid.
  • the aqueous layer was washed twice with ethyl acetate / hexane (1/4), adjusted to pH 9-10 with aqueous sodium hydroxide (7.5 mol / L), and extracted with chloroform.
  • the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from acetonitrile to give the title compound (5.34 g) as a solid.
  • Example 2 (3-Chloro-5-fluorophenyl) [2- (5-fluoropyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl ] Methanone
  • 3-chloro-5-fluorobenzoic acid (0.72 g)
  • EDC hydrochloride (1.15 g)
  • HOBt monohydrate (0 .81 g
  • Example 3 [2- (5-Methylpyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] (phenyl) methanone
  • 2- (5-methylpyridin-2-yl) -4,5,6,7-tetrahydro [1,3] oxazolo
  • the title compound was prepared using [4,5-c] pyridine (Preparation Example 3-4).
  • Example 3 2- (5-Methylpyridin-2-yl) -4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridine used in the production of Example 3 (Preparation Example 3- 4) was prepared by the following method using benzyl trans-3-amino-4-hydroxypiperidine-1-carboxylate hydrochloride and 5-methylpicolinic acid.
  • Production Example 3-2 Benzyl 3- ⁇ [(5-methylpyridin-2-yl) carbonyl] amino ⁇ -4-oxopiperidine-1-carboxylate
  • oxalyl chloride (1.09 mL) in dichloromethane (40 mL) at ⁇ 78 ° C. in DMSO ( 1.36 mL) was added dropwise and stirred for 10 minutes.
  • DMSO 1.36 mL
  • a solution of Production Example 3-1 (2.35 g) in dichloromethane (30 mL) was added dropwise and stirred for 1 hour.
  • Triethylamine (4.43 mL) was added dropwise, and the mixture was further stirred for 1 hour while warming to room temperature.
  • Production Example 3-3 Benzyl 2- (5-methylpyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridine-5 (4H) -carboxylate described in Preparation Example 1-2
  • the title compound was produced in the same manner as in Production Example 3-2 instead of Production Example 1-1.
  • Example 4 [2- (5-Chloropyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] (phenyl) methanone
  • 2- (5-chloropyridin-2-yl) -4,5,6,7-tetrahydro [1,3] oxazolo
  • the title compound was prepared using [4,5-c] pyridine (Preparation Example 4-4).
  • Example 4 2- (5-Chloropyridin-2-yl) -4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridine used in the production of Example 4 (Preparation Example 4- 4) was prepared by the following method using trans-benzyl 4-hydroxy-3-aminopiperidine-1-carboxylate hydrochloride and 5-chloropicolinic acid.
  • Production Example 4-3 Benzyl 2- (5-chloropyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridine-5 (4H) -carboxylate described in Preparation Example 1-2
  • the title compound was produced in the same manner as in Production Example 4-2 instead of Production Example 1-1.
  • Example 5 [2- (5-Bromopyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridin-5 (4H) -yl] (phenyl) methanone
  • 2- (5-bromopyridin-2-yl) -4,5,6,7-tetrahydro [1,3] oxazolo
  • the title compound was prepared using [4,5-c] pyridine (Preparation Example 5-3).
  • Example 5 2- (5-Bromopyridin-2-yl) -4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridine used in the production of Example 5 (Preparation Example 5- 3) was prepared by the following method using benzyl 4- ⁇ [(methylsulfonyl) oxy] imino ⁇ piperidine-1-carboxylate and 5-bromopicolinic acid.
  • Production Example 5-2 Benzyl 2- (5-bromopyridin-2-yl) -6,7-dihydro [1,3] oxazolo [4,5-c] pyridine-5 (4H) -carboxylate described in Preparation Example 1-2
  • the title compound was produced in the same manner as in Production Example 5-1 instead of Production Example 1-1.
  • Production Example 5-3 2- (5-Bromopyridin-2-yl) -4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridine
  • Example 6 6- [5- (Phenylcarbonyl) -4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridin-2-yl] pyridine-3-carbonitrile
  • 2- 5-cyanopyridin-2-yl
  • 2- 5-cyanopyridin-2-yl
  • Production Example 6-2 2- (5-Cyanopyridin-2-yl) -4,5,6,7-tetrahydro [1,3] oxazolo [4,5-c] pyridine A method similar to the method described in Preparation Example 4-4 Thus, the title compound was produced using Production Example 6-1 instead of Production Example 4-3.
  • Examples 7 to 19 The compounds of Examples 7 to 19 were produced in the same manner as described in Examples 1 to 6 using the corresponding starting materials and reagents.
  • Example 12 (2-Fluoro-3-methylphenyl) [2- (5-fluoropyridin-2-yl)]-6,7-dihydro [1,3] oxazolo [4,5-c] pyridine-5 (4H)- Il] methanone
  • 1 H NMR 400 MHz, CDCl 3 ): ⁇ 8.55 (m, 1H), 8.13 (m, 1 / 2H), 8.02 (m, 1 / 2H), 7.55-7.49 (m , 1H), 7.26-7.04 (m, 3H), 4.83 (brs, 1 / 2H), 4.40 (brs, 1H), 3.68 (brs, 1 / 2H), 3.
  • Test Examples The results of pharmacological tests and pharmacokinetic tests of representative compounds of the present invention are shown below, but the present invention is not limited to these test examples.
  • mGluR5 in vitro functional assays were performed using an inducible cell line expressing the human recombinant mGluR5 receptor under the control of a tetracycline-inducible promoter. Specifically, the human mGluR5 gene was inserted into pcDNA4 / TO (invitrogen) and introduced into TR-expressing human kidney-derived HEK cells (ATCC). Thereafter, selection with Geneticin (invitrogen) was performed to obtain human mGluR5 stably expressing cells.
  • the mGluR5 cells grown in antibiotic (blastosidin, G418) medium were detached by gently flushing with 10-fold diluted TRYPLE EXPRESS (life technologies), and the assay buffer (HBSS, 20 mM HEPES, 0.1% BSA) was detached. It suspended so that it might become 3x10 ⁇ 4 > cells / ml.
  • Apoaequorin was transiently introduced under tetracycline (final concentration 100 ng / mL), and 50 ⁇ L was dispensed into a 384-well plate, followed by overnight culture in a CO 2 incubator. Cells were incubated with coelenterazine h (Promega, final concentration 5 nM) at room temperature for at least 4 hours.
  • Dansylated glutathione (dGSH) trapping assay As a method for detecting reactive metabolites, metabolites generated from test substances by metabolism in liver microsomes were detected and quantified by reacting with dansylated glutathione (dGSH). The metabolic reaction was measured using a screening robot (Tecan), and the metabolite-dGSH conjugate concentration was measured using a fluorescence detection UPLC system (Waters).
  • a test substance was dissolved in DMSO to prepare a 10 mmol / L test substance solution.
  • a microsome solution was prepared by adding 7.6 mL of potassium phosphate buffer (500 mmol / L, pH 7.4), 1.9 mL of human liver microsomes (Xenotech, 20 mg protein / mL) and 1.27 mL of pure water. Add 0.67 mL of pure water to 3.78 mL of microsome solution and add 1.14 mL of dGSH solution (20 mmol / L) to 6.48 mL of microsome solution and add microsome (dGSH (+)) A solution was prepared.
  • reaction 12 ⁇ L of the test substance solution was mixed with 388 ⁇ L of pure water, and 50 ⁇ L each was dispensed into 6 wells in a 96-well plate. The 6 wells were divided into 3 groups of 2 wells, which were designated as “reaction group”, “unreacted group” and “dGSH non-added group”, respectively.
  • the microsome (dGSH (+)) solution was added to the “reaction group” and “unreacted group”, and 50 ⁇ L of the microsome (dGSH ( ⁇ )) was added to the “dGSH non-addition group”.
  • Cofactor solution was added to the “reaction group” and “dGSH non-added group”, and 50 ⁇ L of pure water was added to the “non-reacted group”. After incubation at 37 ° C. for 60 minutes, 450 ⁇ L of reaction stop solution was added to stop the reaction.
  • DGSH adduct production in Example 2 is a detected concentration at which the risk is considered to be very low in terms of safety, and no adduct production is observed in other examples. Therefore, from the above test results, the tetrahydrooxazolopyridine derivative or the pharmaceutically acceptable salt of the present invention does not produce a dGSH adduct or hardly produces a reactive metabolite, or It was confirmed that the compound was difficult to produce and had excellent safety.
  • Table 1 shows the results of the above test for the preferred compounds of Example 1, Example 2, Example 7, Example 8, Example 9, Example 10, Example 11, Example 12 and Example 14. 3 shows.
  • Example 1 Example 2, Example 7, Example 8, and Example 9 had good oral absorption and showed a bioavailability close to 100%. (Values exceeding 100% are due to experimental errors and may be considered to be almost 100%.)
  • Solubility evaluation was performed using a DMSO solution of the compound. Specifically, a buffer solution adjusted to pH 7.4 or pH 1.2 is added to a DMSO solution of each compound dissolved in a small amount of DMSO to obtain a saturated aqueous solution, and the concentration of the soluble fraction is analyzed using HPLC. Calculated.
  • a DMSO solution (10 mmol / L) of a test compound was dispensed into a U tube on a 96-well rack at 15 ⁇ L each, and evaporated to dryness at 40 ° C. for 90 minutes using a centrifugal evaporator. After 3 ⁇ L of DMSO was added and redissolved, 300 ⁇ L of an isotonic buffer solution of pH 7.4 or pH 1.2 was added. The mixture was shaken at 110 rpm at 25 ° C. for 90 minutes and then allowed to stand for 16 to 20 hours. Insoluble matters were precipitated by centrifugation at 2000 g for 15 minutes, and 100 ⁇ L of the supernatant was collected in a 96-well plate.
  • a DMSO solution (10 mmol / L) of a test compound was dispensed into a 96-well plate, and 198 ⁇ L of 50% acetonitrile aqueous solution was added and diluted to prepare a 100 ⁇ mol / L standard solution. Further, the 100 ⁇ mol / L standard solution was diluted 10-fold with 50% acetonitrile aqueous solution to prepare a 10 ⁇ mol / L standard solution.
  • Table 4 shows the results of the above tests performed on the tetrahydrooxazolopyridine derivatives of the present invention obtained in the examples.
  • the tetrahydrooxazolopyridine derivative of the present invention has a high solubility in an acidic or neutral aqueous solution and a high possibility of having an excellent oral absorbability.
  • the compound of the present invention has an action as a strong mGluR5 negative modulator and is excellent in safety and pharmacokinetics. Therefore, the compounds of the present invention are schizophrenia, anxiety disorder, obsessive compulsive disorder, PTSD, depressive disorder, bipolar disorder, drug dependence, neurodegenerative disease (levodopa-induced dyskinesia, Parkinson's disease, Huntington's disease, etc.) Developmental disorders (fragile X syndrome, autism spectrum disorder, Rett syndrome, tuberous sclerosis, etc.), pain (inflammatory pain, neuropathic pain, etc.), other neurological diseases (epilepsy, oxygen deficiency, ischemic disorder) It is useful as a therapeutic agent for psychiatric diseases or neurodegenerative diseases involving the mGluR5 receptor.

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Abstract

La présente invention concerne un agent thérapeutique pour des troubles neurodégénératifs et des troubles psychiatriques liés au mGluR5, l'agent thérapeutique contenant un composé représenté par la formule (I) ou un de ses sels pharmaceutiquement acceptables (dans la formule, R1 représente un halogène, un méthyle ou un cyano, et R2 et R3 représentent chacun indépendamment un atome d'hydrogène, un halogène, un alkyle en C1-3, un alcoxy en C1-3 ou un cyano), ayant la fonction d'un modulateur négatif du sous-type 5 des récepteurs métabotropiques au glutamate (mGluR5), ayant des propriétés d'absorption orale présentant d'excellentes caractéristiques pharmacocinétiques, et ayant une biodisponibilité élevée ainsi qu'une excellente stabilité.
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Publication number Priority date Publication date Assignee Title
WO2025153715A1 (fr) 2024-01-19 2025-07-24 Scenic Biotech Bv Inhibiteurs hétérocycliques de pla2g15 et leur utilisation en thérapie, dans le traitement de maladies caractérisées par une dysrégulation lysosomale

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JPH0377887A (ja) * 1989-08-07 1991-04-03 Science & Organisation オキサゾロピリジン誘導体、それらの製造方法およびそれらを含有する医薬組成物
JP2005514382A (ja) * 2001-11-30 2005-05-19 メルク　エンド　カムパニー　インコーポレーテッド メタボトロピックグルタミン酸受容体−５モジュレーター
WO2010114971A1 (fr) * 2009-04-03 2010-10-07 Sepracor Inc. Composés utilisables pour le traitement de troubles à médiation par le récepteur métabotropique 5 au glutamate et leurs procédés d'utilisation
WO2012004373A1 (fr) * 2010-07-09 2012-01-12 Abbott Healthcare Products B.V. Dérivés hétérocycliques fusionnés en tant que modulateurs de s1p

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JPH0377887A (ja) * 1989-08-07 1991-04-03 Science & Organisation オキサゾロピリジン誘導体、それらの製造方法およびそれらを含有する医薬組成物
JP2005514382A (ja) * 2001-11-30 2005-05-19 メルク　エンド　カムパニー　インコーポレーテッド メタボトロピックグルタミン酸受容体−５モジュレーター
WO2010114971A1 (fr) * 2009-04-03 2010-10-07 Sepracor Inc. Composés utilisables pour le traitement de troubles à médiation par le récepteur métabotropique 5 au glutamate et leurs procédés d'utilisation
WO2012004373A1 (fr) * 2010-07-09 2012-01-12 Abbott Healthcare Products B.V. Dérivés hétérocycliques fusionnés en tant que modulateurs de s1p

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2025153715A1 (fr) 2024-01-19 2025-07-24 Scenic Biotech Bv Inhibiteurs hétérocycliques de pla2g15 et leur utilisation en thérapie, dans le traitement de maladies caractérisées par une dysrégulation lysosomale

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