WO2011034832A1 - Phénoxyméthyl-dihydro-oxazolopyrimidinones substituées, leur préparation et leur utilisation - Google Patents

Phénoxyméthyl-dihydro-oxazolopyrimidinones substituées, leur préparation et leur utilisation Download PDF

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Publication number
WO2011034832A1
WO2011034832A1 PCT/US2010/048697 US2010048697W WO2011034832A1 WO 2011034832 A1 WO2011034832 A1 WO 2011034832A1 US 2010048697 W US2010048697 W US 2010048697W WO 2011034832 A1 WO2011034832 A1 WO 2011034832A1
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Prior art keywords
dihydro
oxazolo
phenoxymethyl
pyrimidin
cyclohexyl
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PCT/US2010/048697
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English (en)
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Raymond Walter Kosley, Jr.
Rosy Sher
Kent W. Neuenschwander
Vieroslava Gurunian
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Sanofi-Aventis
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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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/18—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
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to a series of substituted dihydro benzocycloalkyloxymethyl oxazolopyrimidinones. More specifically, the present invention relates to a series of substituted 2-phenoxymethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- ones. This invention also relates to methods of making these compounds.
  • the compounds of this invention are allosteric modulators of metabotropic glutamate receptors (mGluR), particularly, mGluR2. Therefore, the compounds of this invention are useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases including diseases associated with the central nervous system.
  • EAA excitatory amino acid receptors
  • the EAA receptors are classified into two types: 1) "ionotropic” - which are directly coupled to the opening of cation channels in the cell membrane of the neurons; and 2) "metabotropic” - which are G-protein coupled receptors (GPCR).
  • GPCR G-protein coupled receptors
  • the metabotropic glutamate receptors are a highly heterogeneous family of glutamate receptors that are linked to multiple second-messenger pathways.
  • One function of these receptors is to modulate the presynaptic release of glutamate and the postsynaptic sensitivity of the neuronal cell to glutamate excitation.
  • agonists and antagonists of these receptors are useful in the treatment of a variety of disease conditions including acute and chronic neurodegenerative conditions, psychoses, convulsions, anxiety, depression, migraine, pain, sleep disorders and emesis.
  • mGluR metabotropic glutamate receptors
  • MGS0039 a selective group II mGluR antagonist, has been shown to exhibit dose-dependent antidepressant-like effects in some animal models. See, e.g., Kawashima, et al, Neurosci. Lett., 2005, 378(3): 131-4.
  • NMDAR glutamate/N-methyl-D-aspartate glutamate receptors
  • WO2008/112483 discloses a series of 2-substituted-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-ones and 2-substituted-2,3 ,5 ,6-tetra-hydro-oxazolo[3 ,2-a]pyrimidin-7-ones, which are allosteric modulators of metabotropic glutamate receptors (mGluR), particularly, mGluR2.
  • mGluR metabotropic glutamate receptors
  • the intended drug substance In addition to exhibiting required allosteric modulation properties the intended drug substance must also meet various "drug-like" properties including but not limited to good adsorption, distribution, metabolism and excretion (ADME) properties as well as pharmacokinetics. For instance, in order for the drug substance to be effective it must interact suitably with various enzymes produced in the body, including cytochrome P450 enzyme or CYPs, esterases, proteases, reductases, dehydrogenases, and the like. Generally it is necessary that the compounds that are suitable as "drugs” must have good CYP-isozyme interaction properties.
  • CYP isozymes include CYP3A4, CYP2D6, CYP2C9, among others.
  • the compounds of the instant invention notably, substituted 2- phenoxymethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-ones are found to be not only effective potentiators of mGluR2 but also exhibit improved "drug-like" properties as described herein.
  • P 3 are the same or different and independently of each other selected from the group consisting of hydrogen, halogen, CF 3 , (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, cyclohexyl, 1-methylcyclohexyl, 4-methoxycyclohexyl,
  • R 3 , P and R 5 are on adjacent carbons and taken together with the carbons to which they are attached form a five or a six-membered ring.
  • compositions comprising various compounds of this invention as well as their use in the treatment of a variety of disorders and/or disease conditions as disclosed herein are also part of this invention all of which are described in detail below.
  • (Ci_C 4 )alkyl includes methyl and ethyl groups, and straight-chain or branched propyl and butyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and tert-butyl. It should particularly be noted that any of the feasible branched (Ci-C 4 )alkyl group known in the art is encompassed by this expression.
  • mono- or di-fluoro(Ci-C 4 )alkyl shall mean that one or two of the hydrogens are replaced with fluorine.
  • Representative examples of monofluoro(Ci-C 4 )alkyl include fluoromethyl, 2-fluoro- eth-l-yl or 1-fluoro-eth-l-yl, 1-fluoro-l-methyl-eth-l-yl, 2-fluoro-l-methyl-eth-l-yl, 3-fluoro- prop-l-yl, and the like.
  • difluoro(Ci-C 4 )alkyl include difluoromethyl, 2,2-difluoro-eth-l-yl, 1,2-difluoro-eth-l-yl or 1,1-difluoro-eth-l-yl, 1,2- difluoro-l-methyl-eth-l-yl, 2,2-difluoro-l-methyl-eth-l-yl, 1 ,3-difluoro-prop-l-yl, and the like.
  • (C 3 -Cv)cycloalkyl or “(C 3 -Cy)carbocyclic ring” includes all of the known cyclic radicals.
  • Representative examples of “cycloalkyl” or “carbocyclic” includes without any limitation cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • Derived expressions such as “cycloalkoxy” or “cycloalkyloxy”, “cycloalkyloxyethoxy", “cycloalkylalkyl", “cycloalkylaryl”, “cycloalkylcarbonyl” are to be construed accordingly.
  • the expression “(C5-C8)carbocyclic” shall have the same meaning as
  • Halogen means chlorine (chloro), fluorine (fluoro), bromine (bromo), and iodine (iodo).
  • patient means a warm blooded animal, such as for example rats, mice, dogs, cats, guinea pigs, and primates such as humans.
  • the expression "pharmaceutically acceptable carrier” means a non- toxic solvent, dispersant, excipient, adjuvant, or other material which is mixed with the compound of the present invention in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient.
  • a pharmaceutical composition i.e., a dosage form capable of administration to the patient.
  • pharmaceutically acceptable oil typically used for parenteral administration.
  • Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, hydroxymaleic acid, malic acid, ascorbic acid, succinic acid, glutaric acid, acetic acid, salicylic acid, cinnamic acid, 2-phenoxybenzoic acid, hydroxybenzoic acid, phenylacetic acid, benzoic acid, oxalic acid, citric acid, tarta
  • a pharmaceutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, fumaric
  • the acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate can also be formed.
  • the salts so formed may present either as mono- or di- acid salts and can exist substantially anhydrous or can be hydrated.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts, and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
  • prodrug shall have the generally accepted meaning in the art.
  • One such definition includes a pharmacologically inactive chemical entity that when metabolized or chemically transformed by a biological system such as a mammalian system is converted into a pharmacologically active substance.
  • stereoisomers is a general term used for all isomers of the individual molecules that differ only in the orientation of their atoms in space. Typically it includes mirror image isomers that are usually formed due to at least one asymmetric center (enantiomers). Where the compounds according to the invention possess two or more asymmetric centers, they may additionally exist as diastereoisomers, also certain individual molecules may exist as geometric isomers (cis/trans). Similarly, certain compounds of this invention may exist in a mixture of two or more structurally distinct forms that are in rapid equilibrium, commonly known as tautomers.
  • tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
  • solvate means that an aggregate that consists of a solute ion or molecule with one or more solvent molecules.
  • a "hydrate” means that a solute ion or molecule with one or more water molecules.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • substituted means substituted with one or more substituents independently selected from the group consisting of (Ci_C 2 o)alkyl, (C 2 _C 6 )alkenyl, (Ci_C 6 )perfluoroalkyl, phenyl, hydroxy, -C0 2 H, an ester, an amide, (Ci-C 6 )alkoxy, (Ci-C 6 )thioalkyl, (Ci-C 6 )perfluoroalkoxy, -NH 2 , CI, Br, I, F, CN, SF 5 , -NH-lower alkyl, and -N(lower alkyl) 2 , unless otherwise noted.
  • any of the other suitable substituents known to one skilled in the art can also be used in
  • “Therapeutically effective amount” means an amount of the compound which is effective in treating the named disease, disorder or condition.
  • treating refers to: (i) preventing a disease, disorder or condition from occurring in a patient that may be predisposed to the disease, disorder and/or condition, but has not yet been diagnosed as having it;
  • Ri is selected from the group consisting of hydrogen, methyl, fluoromethyl, ethyl, 2-fluoroethyl, propyl, hydroxyethyl, 2-(tetrahydro-pyran-2-yloxy)-ethyl;
  • R 2 is selected from the group consisting of hydrogen, methyl, fluoromethyl, ethyl, 2-fluoroethyl, propyl, methoxymethyl, ethoxymethyl, 2-fluoroethoxymethyl, ethoxy-l-fluoroethyl, isopropoxymethyl, -COOH, phenyl, benzyl, 2-, 3-, 4-, or 5 -fluorophenyl, 2-, 3-, 4-, or 5-f uorobenzyl, 2,4-dif uorophenyl, 2,4- difluorobenzyl, phenoxy, benzyloxy, 2-, 3-, 4-, or 5-fluorophenoxy, 2-, 3-, 4-, or 5-fluorobenzyloxy, 2,4-difluorophenoxy, 2,4-dif uorobenzyloxy, hydroxymethyl, hydroxyethyl, morpholinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, t
  • R 3 , R4 and R 5 are the same or different and independently of each other selected from the group consisting of hydrogen, halogen, CF 3 , (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, cyclohexyl, 1-methylcyclohexyl, 4-methoxycyclohexyl,
  • the compound of formula (I) may be present as a salt when such possibility exists. All forms of salts that can be envisaged are part of this invention. As also all other possible forms of diastereoisomers or tautomers of compound of formula (I) are also part of this invention.
  • the compound of formula (I) of this invention has the following definitions for the substituents Ri through R5 :
  • Ri is selected from the group consisting of hydrogen, methyl and ethyl
  • R 2 is selected from the group consisting of hydrogen, methyl, fluoromethyl,
  • R 3 , R 4 and R 5 are the same or different and independently of each other selected from the group consisting of hydrogen, fluorine, iso-propyl, iso-butyl, tert-butyl, cyclohexyl, methoxy and ethoxy.
  • the compounds of formula (I) may present in any of the possible salt form, all of which are part of this invention.
  • Ri is hydrogen or ethyl
  • R 2 is hydrogen
  • R 3 , R 4 and R 5 are the same or different and independently of each other selected from the group consisting of hydrogen, fluorine, tert-butyl, methoxy and ethoxy; Additionally, as noted above all of the compounds of this embodiment may also present as a salt where possible and such salts are also part of this invention.
  • the compounds of this invention can be synthesized by any of the procedures known to one skilled in the art. Specifically, several of the starting materials used in the preparation of the compounds of this invention are known or are themselves commercially available. The compounds of this invention and several of the precursor compounds may also be prepared by methods used to prepare similar compounds as reported in the literature and as further described herein.
  • Scheme 1 illustrates the synthesis of several of the compounds of formula (I) of this invention wherein Ri is hydrogen. However, a modified synthetic scheme may be adopted for other compounds of formula (I) of this invention wherein Ri is other than hydrogen as defined herein.
  • Step 1 Scheme 1, (S)-glycidyltosylate of formula (II) is reacted with a suitable cyanamide compound to form an oxazolylamine of formula (III) in a suitable solvent.
  • a suitable cyanamide compound Any of the known cyanamide compounds that react with an epoxide to form oxazolylamines can be employed in this reaction.
  • Suitable cyanamides for this purpose include without any limitation, sodium hydrogen cyanamide, lithium hydrogen cyanamide, potassium hydrogen cyanamide, cesium hydrogen cyanamide, and the like.
  • Scheme 1 exemplifies sodium hydrogen cyanamide as a suitable cyanamide compound.
  • the reaction can generally be carried out in alcoholic solvents such as methanol, ethanol, isopropanol and the like or a mixture thereof.
  • the reaction is further carrier out at a suitable temperature, for example, at about ambient to super-ambient temperatures.
  • Step 2 the oxazolylamine of formula (III) is reacted with an ⁇ , ⁇ - unsaturated alkynoic ester of formula (IV), wherein R c is (Ci-C4)alkyl, phenyl or benzyl, to form the compound of formula (V).
  • This reaction can again be carried out using any of the procedures known to one skilled in the art. Typically, such an addition reaction is carried out in a suitable alcoholic solvent such as methanol, ethanol or isopropanol or a mixture thereof. Such addition reactions can also be carried out using ⁇ , ⁇ -unsaturated alkynoic ester of formula (IV) itself as the solvent.
  • the reaction is generally carried out at ambient to super- ambient temperature conditions. More generally, the reaction is carried out at the reflux temperature of the solvent. However, super-ambient temperatures involving the microwave oven can also be employed to carry out this reaction at a temperature ranging from about 100°C to about 200°C.
  • Step 3 the compound of formula (V) obtained in Step 2 is reacted with a suitably substituted phenol of formula (VI), which can be prepared in accordance with any of the known procedures or may be available from commercial sources.
  • substitution reactions are generally carried out in an aprotic polar solvent, such as DMF or acetonitrile and in the presence of a suitable base such as alkali carbonates for example cesium carbonate or an organic base such as triethylamine.
  • a compound of formula (V) in an aprotic solvent such as DMF or acetonitrile/dichloromethane/DMSO can be treated with a mixture of sodium hydride and compound of formula (VI) in a suitable solvent such as acetonitrile or DMF.
  • the reaction temperatures can be sub-ambient to ambient to super-ambient, but typically the reaction is carried out under ambient to moderately higher temperatures in the range of 30 to 60°C.
  • Various other compounds of formula (I) can similarly be prepared using appropriate starting materials.
  • a suitably substituted phenol of formula (VI) is reacted with R-epichlorohydrin to form a substituted phenoxy oxirane of formula (VII).
  • substitution reactions can be carried out using any of the known procedures in the art. For example such reactions are generally carried out in a suitable organic solvent in the presence of a suitable base at ambient to super-ambient temperature conditions. Solvents that can be used in this step can be any of the solvents routinely used for such reactions. For instance, suitable solvents are ketones, such as acetone, methyl ethyl ketone (MEK) and the like.
  • suitable base for this reaction include but not limited to lithium carbonate, sodium carbonate, potassium carbonate, and the like.
  • the temperature at which the reaction is carried out may control the stereoselectivity of this reaction.
  • a temperature of the reaction below 50°C favors higher stereoselectivity.
  • a temperature range of about 40°C to about 50°C can be employed depending upon the solvent used and, the substituents on phenol of formula (VI).
  • sub-ambient temperature conditions can also be employed depending upon the type of phenol of formula (VI) employed.
  • Step 2 the oxirane of formula (VII) is reacted with a cyanamide compound to form a oxazolylamine of formula (VIII).
  • a cyanamide compound to form a oxazolylamine of formula (VIII).
  • Such reactions can be carried out using similar procedures as described above in Step 1 , Scheme 1 , such as for example employing sodium cyanamide as illustrated in Scheme 2.
  • Step 3 the oxazolylamine of formula (VIII) is reacted with an ⁇ , ⁇ - unsaturated alkynoic ester of formula (IV), wherein R c is (Ci-C4)alkyl, phenyl or benzyl, to form the compound of formula (I) wherein Ri is hydrogen.
  • This reaction can again be carried out using any of the procedures known to one skilled in the art, such as for example as described above in Step 2, Scheme 1.
  • Scheme 3 illustrates another approach for the preparation of compounds of formula (I) wherein R 2 is hydrogen. However, various modifications thereof can be made to prepare various compounds of formula (I) as disclosed herein.
  • Step 1 oxazolylamine of formula (III) is reacted with a ⁇ -formyl- alkanoic ester of formula (IX) wherein R is (Ci-C 4 )alkyl, phenyl or benzyl.
  • This step is typically carried out using a variety of art recognized reaction conditions. For instance, it can be carried out in an organic solvent in the presence of a suitable base to form a compound of formula (X).
  • Step 2 Scheme 3 the compound of formula (X) is then allowed to react with a suitably substituted phenol of formula (VI).
  • substitution reactions are generally carried out similar to the procedures employed in Step 3, Scheme 1 as described above in order to obtain compounds of formula (I) wherein R 2 is hydrogen.
  • Scheme 4 illustrates another approach for the preparation of compounds of formula (I) of this invention wherein R 2 is hydrogen.
  • the oxazolylamine of formula (VIII) as prepared in accordance with the procedures of Step 2 Scheme 2 is reacted with ⁇ -formyl- alkanoic ester of formula (IX) wherein R is (Ci-C 4 )alkyl, phenyl or benzyl.
  • This step can be carried out using any of the procedures known in the art such as for example as described above in Step 1, Scheme 3 to obtain compounds of formula (I) wherein R 2 is hydrogen.
  • this invention also relates to a method of modulating one or more metabotropic glutamate receptor functions in a patient requiring such treatment.
  • a method involves administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the compounds of formula (I) exhibit surprisingly superior biological properties even when compared with the corresponding (R)- enantiomers as further discussed below.
  • the compounds of this invention not only exhibit superior mGluR2 receptor potentiation activity but also exhibit desirable metabolic stability thereby providing significant advantages over other structural variants including the corresponding (R)-enantiomers.
  • the compounds of formula (I) of this invention are also useful in the preparation of a medicament for modulating one or more metabotropic glutamate receptor functions in a patient requiring such modulation.
  • the medicaments can be prepared using any of the methods known in the art.
  • compounds of formula (I) or a pharmaceutically acceptable salt thereof can be mixed with one or more pharmaceutically excipients, diluents or carriers in order to form the medicament.
  • this invention also involves a method of treating a specific disease, a disorder or a condition using an effective amount of a compound of formula (I) of this invention.
  • Specific diseases that can be treated using the compounds of formula (I) of this invention include, without any limitation, neurological or psychiatric disorders.
  • psychotic disorders shall have the same meaning as "psychotic disorder” as defined in Diagnostic and Statistical Manual of Mental Disorders, 4 th Ed., ("DSM-IV") American Psychiatric Association, 1995, incorporated herein by reference.
  • the essential feature of brief psychotic disorder is a disturbance that involves the sudden onset of at least one of the following positive psychotic symptoms: delusions, hallucinations, disorganized speech, (e.g., frequent derailment or incoherence), or grossly disorganized or catatonic behavior (Criterion A).
  • An episode of the disturbance lasts at least one day but less than one month, and the individual eventually has a full return to the premorbid level of functioning (Criterion B).
  • the disturbance is not better accounted for by a mood disorder with psychotic features, by schizoaffective disorder, or by schizophrenia and is not due to the direct physiological effects of a substance (e.g., hallucinogen) or a general medical condition (e.g., subdural hematoma) (Criterion C).
  • a substance e.g., hallucinogen
  • a general medical condition e.g., subdural hematoma
  • treatment and “treating” are intended to refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the neurological and psychiatric disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms, and is intended to include prophylactic treatment of such neurological and psychiatric disorders.
  • specific diseases that can be treated using the compounds of formula (I) of this invention include without any limitation: anxiety, migraine, schizophrenia, epilepsy and pain.
  • the compounds of this invention may be used to treat any disease involving the effects of metabotropic glutamate receptor functions. That is, the compounds of the present invention are modulators of metabotropic glutamate receptors (mGluR), particularly, mGluR2, and may be effectively administered to ameliorate any disease state which is mediated all or in part by mGluR2.
  • mGluR metabotropic glutamate receptors
  • the compounds used in the methods of this invention as disclosed herein can be used in the method of treating various disease states as described herein.
  • the compounds used in the method of this invention are capable of modulating the effects of mGluR2 and thereby alleviating the effects and/or conditions caused due to the activity of mGluR2.
  • the compounds of this invention can be administered by any of the methods known in the art. Specifically, the compounds of this invention can be administered by oral, intramuscular, subcutaneous, rectal, intratracheal, intranasal, intraperitoneal, intracerebroventricular (icv) or topical route.
  • composition comprising a pharmaceutically acceptable carrier and a compound of formula (I) of this invention, including pharmaceutically acceptable salts, solvates or derivatives thereof, with said compound having the general structure shown in formula I as described herein.
  • the pharmaceutical compositions of this invention feature modulation of mGluR2 and thus are useful in treating any disease, condition or a disorder involving the effects of mGluR2 in a patient.
  • all of the preferred embodiments of the compounds of this invention as disclosed herein can be used in preparing the pharmaceutical compositions as described herein.
  • various compounds of formula (I) as described herein can be used in the preparation of pharmaceutical formulations for modulating the effects of mGluR2 and to treat all of the diseases as disclosed herein.
  • the pharmaceutical compositions of this invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • the compositions may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
  • An erodible polymer containing the active ingredient may be envisaged.
  • the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of formula (I) of the present invention.
  • a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water
  • a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums,
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
  • Flavored unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
  • compositions of this invention can be administered by any of the methods known in the art.
  • the pharmaceutical compositions of this invention can be administered by oral, intramuscular, subcutaneous, rectal, intratracheal, intranasal, intraperitoneal, intracerebroventricular (icv) or topical route.
  • the preferred administrations of the pharmaceutical composition of this invention are by oral and intranasal routes. Any of the known methods to administer pharmaceutical compositions by an oral or an intranasal route can be used to administer the composition of this invention.
  • a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 20 mg/kg per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day.
  • Reactions generally are run under a nitrogen atmosphere. Solvents are dried over sodium or magnesium sulfate and are evaporated under vacuum on a rotary evaporator. TLC analyses are performed with EM Science silica gel 60 F254 plates with visualization by UV irradiation wherever possible. Flash chromatography is performed using Isco prepacked silica gel cartridges.
  • the 1H NMR spectra are run at 300 MHz on a Gemini 300 or Varian VXR 300 spectrometer and are determined in a deuterated solvent, such as DMSO-d 6 or CDC1 3 unless otherwise noted. Chemical shifts values are indicated in parts per million (ppm) with reference to tetramethylsilane (TMS) as the internal standard.
  • the LC/MS are run on a Micromass Platform LCZ.
  • [ ⁇ ] ⁇ 25 were measured using a Perkin Elmer polarimeter model 341 with a sodium lamp, D line (589 nm), path length 100 mm at 25°C temperature at a concentration (g/100 ml) and solvent as specified in the respective examples below.
  • Step 1 Toluene-4-sulfonic acid (S)-5-methoxymethyl-7-oxo-2,3-dihydro-7H-oxazolo[3,2- a]pyrimidin-2-ylmethyl ester
  • Step5 (S)-2-(4-Bicyclo[3.3.1 ]non-9-yl-3-fluoro-phenoxymethyl)-5-methoxymethyl-2,3-dihydro oxazolo[3,2-a]pyrimidin-7-one
  • Step 1 1 - [4-(Tetrahydro-pyran-2-yloxy)-phenyl] -cyclohexanol
  • Step 3 (S)-2-(4-Cyclohex-l-enyl-phenoxymethyl)-5-methoxymethyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one
  • Step 1 9-(4-Benzyloxy-phenyl)-9-methyl-bicyclo[3.3.1 Jnonane
  • Step3 (S)-5-Methoxymethyl-2-[4-(9-methyl-bicyclo[3.3.1 ]non-9-yl)-phenoxymethyl]-2,3- dihydro-oxazolo[3,2-a]pyrimidin-7-one
  • Step 1 1 -Cyclohex- 1 -enyl-2-fluoro-4-methoxy-benzene l-(2-Fluoro-4-methoxy-phenyl)-cyclohexanol (prepared as in Example 2 from 1- bromo-2-fluoro-4-methoxy-benzene and cyclohexanone) (2.5 g, 1 1.2 mmol) was dissolved in EtOH (200 ml) and concentrated hydrochloric acid (20 ml) was added. The mixture was stirred at 50°C overnight. The solvent was removed under reduced pressure. Water and EtOAc were added and the mixture was basified with aqueous ammonia and extracted three times with EtOAc. The organic phase was dried and concentrated. Silica gel chromatography (EtO Ac/heptane) provided the title compound (1.9 g).
  • Step 4 (S)-2-(4-Cyclohexyl-3-fluoro-phenoxymethyl)-5-methoxymethyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one
  • the title compound was prepared from 4-cyclohexyl-3-fluoro-phenol employing the procedure as described in Example 1.
  • Step 1 4-(4,4-Difluoro-cyclohexyl)-phenol
  • Step 2 (S)-2-[4-(4,4-Difluoro-cyclohexyl)-phenoxymethyl]-5-methoxymethyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one
  • Toluene-4-sulfonic acid (S)-5-cyclopropyl-7-oxo-2,3-dihydro-7H-oxazolo[3,2- a]pyrimidin-2-ylmethyl ester was prepared using the procedure of Example 1 with toluene-4- sulfonic acid (S)-2-amino-4,5-dihydro-oxazol-5-ylmethyl ester and cyclopropyl-propynoic acid ethyl ester as starting materials.
  • Step 2 (S)-5-Cyclopropyl-2-[4-(4,4-difluoro-cyclohexyl)-phenoxymethyl]-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one
  • the title compound was prepared from toluene-4-sulfonic acid (S)-5-cyclopropyl-7- oxo-2,3-dihydro-7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester and 4-(4,4-difluoro- cyclohexyl)-phenol employing the procedures described in Example 1.
  • Step 1 Toluene -4-sulfonic acid (S)-5-fluoromethyl-7-oxo-2,3-dihydro-7H-oxazolo[3,2- a]pyrimidin-2-ylmethyl ester
  • Step 2 (S)-5-Fluoromethyl-2-[4-(9-methyl-bicyclo[3.3.1]non-9-yl)-phenoxymethyl]-2,3- dihydro-oxazolo[3,2-a]pyrimidin-7-one
  • Step 1 (S)-2-[4-(l-Methyl-cyclohexyl)-phenoxymethyl]-oxirane
  • Step3 (S)-2-[4-(l-Methyl-cyclohexyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2-a]pyrimidin- 7-one
  • Step 1 (S)-5-(4-tert-Butyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine
  • Step 3 (S)-2-(4-tert-Butyl-phenoxymethyl)-6-propyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one
  • the title compound was prepared from (S)-5-(4-tert-butyl-phenoxymethyl)-4,5- dihydro-oxazol-2-ylamine and 2-formyl-pentanoic acid ethyl ester employing the procedures described in Comparative Example 1.
  • Step 2 (S)-2-(4-tert-Butyl-phenoxymethyl)-6-isopropyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one
  • Step 2 (S)-2-(4-tert-Butyl-phenoxymethyl)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin- 7-one
  • Step 1 3 -Oxo-2-phenyl-propionic acid ethyl ester
  • Step 2 (S)-2-(4-tert-Butyl-phenoxymethyl)-6-phenyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one
  • Step2 (S)-2-[4-(l,l-Dimethyl-propyl)-phenoxymethyl]-6-phenyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one
  • Step 1 4,4,4-Trifluoro-2-formyl-butyric acid ethyl ester
  • Step 2 (S)-2-(4-tert-Butyl-phenoxymethyl)-6-(2,2,2-trifluoro-ethyl)-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one
  • Step 1 2-Formyl-4-(tetrahydro-pyran-2-yloxy)-butyric acid methyl ester
  • the title compound was prepared from (S)-2-(4-tert-butyl-phenoxymethyl)-6-[2- (tetrahydro-pyran-2-yloxy)-ethyl] -2,3 -dihydro-oxazolo [3 ,2-a]pyrimidin-7-one employing p- toluenesulfonic acid in methanol.
  • Step 1 (S)-5-(4-tert-Butyl-2-fluoro-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine
  • Step 1 4-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-cyclohexanol
  • Step 2 tert-Butyl-[4-(4-methoxy-cyclohexyl)-phenoxy]-dimethyl-silane
  • Step 4 (S)-2-[4-(4-Methoxy-cyclohexyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one
  • Step 1 4-Prop-2-ynyl-morpholine
  • Step 2 4-Morpholin-4-yl-but-2-ynoic acid ethyl ester
  • Step 3 (S)-2-(4-Cyclohexyl-phenoxymethyl)-5-morpholin-4-ylmethyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one
  • the title compound was prepared from (5)-5-(4-cyclohexyl-phenoxymethyl)-4,5- dihydro-oxazol-2-ylamine and 4-morpholin-4-yl-but-2-ynoic acid ethyl ester in accordance with procedure in Example 34.
  • Step 1 l-Prop-2-ynyl-pyrrolidine
  • Step 2 4-Pyrrolidin-l-yl-but-2-ynoic acid ethyl ester
  • the title compound was prepared from l-prop-2-ynyl-pyrrolidine and ethyl chloroformate following the literature procedure (see Tetrahedron, 2006, 5697-5708).
  • Step 3 (S)-2-(4-Cyclohexyl-phenoxymethyl)-5-pyrrolidin- 1 -ylmethyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one
  • Step 1 1 -Prop-2-ynyl-piperidine
  • Step 2 4-piperdine-l-yl-but-2-ynoic acid ethyl ester
  • Step 3 (S)-2-(4-Cyclohexyl-phenoxymethyl)-5-piperidin- 1 -ylmethyl-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one
  • Step 1 l-tert-Butyl-2, 4-dimethoxy-benzene
  • Step 4 (S)-2-(4-tert-Butyl-3-methoxy-phenoxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin- 7-one
  • Step 1 Toluene -4-sulfonic acid (S)-5-ethyl-7-oxo-2,3-dihydro-7H-oxazolo[3,2-a]pyrimidin- 2-ylmethyl ester
  • Step 2 (S)-2-(4-tert-Butyl-3-methoxy-phenoxymethyl)-5-ethyl-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one
  • Step 1 (S)-2-(4-Cyclohexyl-phenoxymethyl)-7-oxo-2,3-dihydro-7H-oxazolo[3,2- a]pyrimidine-5-carboxylic acid tert-butyl ester
  • Step 2 (S)-2-(4-Cyclohexyl-phenoxymethyl)-7-oxo-2,3-dihydro-7H-oxazolo[3,2- a]pyrimidine-5-carboxylic acid
  • Step 1 4-(2,2-Dimethyl-propyl)-phenol
  • Step 2 (S)-2-[4-(2,2-Dimethyl-propyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one
  • Step 1 4-(Tetrahydro-pyran-2-yloxy)-but-2-ynoic acid ethyl ester
  • Step 2 Toluene -4-sulfonic acid (S)-7-oxo-5-(tetrahydro-pyran-2-yloxymethyl)-2,3-dihydro- 7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester
  • Step 3 (S)-2-(4-Bicyclo[3.3.1 ]non-9-yl-phenoxymethyl)-5-(tetrahydro-pyran-2- yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one
  • Step 1 (S)-2-(4-bicyclo[3.3.1 ]non-9-yl-phenoxymethyl)-5-[2-(tetrahydro-pyran-2-yloxy)- ethyl]-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one
  • Step 2 (S)-2-(4-Bicyclo[3.3.1 ]non-9-yl-phenoxymethyl)-5-(2-hydroxy-ethyl)-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one
  • Step 1 [3-(4-Fluoro-phenyl)-prop-l-ynyl]-trimethyl-silane
  • Step 2 1 -Fluoro-4-prop-2-ynyl-benzene
  • Step 3 4-(4-Fluoro-phenyl)-but-2-ynoic acid ethyl ester
  • the title compound was prepared from 1 -fluoro-4-prop-2-ynyl-benzene and ethyl chloroformate following the literature procedure (see Tetrahedron, 2006, 5697-5708).
  • Step 4 (S)-2-(4-Cyclohexyl-phenoxymethyl)-5-(4-fluoro-benzyl)-2,3-dihydro-oxazolo[3,2- a]pyrimidin-7-one
  • Step 1 Toluene -4-sulfonic acid (S)-7-oxo-5-pyrrolidin-l-ylmethyl-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester
  • Step 2 (S)-2-[4-(4,4-Difluoro-cyclohexyl)-phenoxymethyl]-5-pyrrolidin-l-ylmethyl-2,3- dihydro-oxazolo[3,2-a]pyrimidin-7-one
  • Step 1 3-(4-Hydroxy-phenyl)-cyclohex-2-enone
  • Step 2 2-[4-(3-Oxo-cyclohex-l-enyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one
  • Step 1 5,5-Dimethyl-3-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-cyclohex-2-enone
  • ⁇ , ⁇ , ⁇ ', ⁇ '-Tetramethylethylenediamine (0.04 ml, 0.25 mmol) was added to a suspension of Cul (0.048 g, 0.25 mmol) in 10 ml of THF. The suspension dissolved to give a clear green solution. This green solution was added to an ice-cold solution of 3-chloro-5,5- dimethyl-cyclohex-2-ene-l-one (5 g, 31.5 mmol) in 100 ml of ether. To this ice-cold solution was added dropwise 50 ml of a 0.5 M THF solution of 4-(2-tetrahydo-2H-pyranoxy)phenyl magnesium bromide.
  • Step 3 2-[4-(5,5-Dimethyl-3-oxo-cyclohex-l-enyl)-phenoxymethyl]-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one
  • Step 1 3-Methyl-3-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-cyclohexanone
  • ⁇ , ⁇ , ⁇ ', ⁇ '-Tetramethylethylenediamine (0.04 ml, 0.25 mmol) was added to a suspension of Cul (0.048 g, 0.25 mmol) in 50 ml of ether. The mixture was stirred 15 minutes at room temperature until all the Cul had dissolved. The mixture was cooled to 0°C and 50 ml of a 0.5 M THF solution of 4-(2-tetrahydro-2H-pyranoxy)phenyl magnesium bromide was added. The mixture was stirred for 15 minutes at 0°C, after which a 0.5 M ether solution of 3-methyl-2-cyclohexenone (2.9 ml, 25 mmol) was added dropwise over a 30 minute period.
  • the thick reaction mixture was allowed to warm to room temperature and stirred overnight. After 15 hours at room temperature the thick reaction mixture had dissolved to give a clear solution.
  • the clear solution was poured into 30 ml of 1 N HC1 and after shaking the layers were separated. The organic layer was extracted with saturated NaHC0 3 , brine, dried over 4 A molecular sieves, filtered, and concentrated under vacuum to yield 8.8 g of a yellow oil.
  • the yellow oil was purified by chromatography on silica gel using ethyl acetate/heptane(l/10) as the eluent to give 1.97 g of the title compound as a white solid.
  • Step 3 2-[4-(l -Methyl-3-oxo-cyclohexyl)-phenoxymethyl]-2,3-dihydro- oxazolo [3 ,2a]pyrimidin-7-one
  • Step 1 3,3,5-Trimethyl-5-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-cyclohexanone ⁇ , ⁇ , ⁇ ', ⁇ '-Tetramethylethylenediamine (0.15 ml, 1 mmol) was added to a suspension of Cul (0.095 g, 0.5 mmol) in 100 ml of ether. The mixture was stirred 15 minutes at room temperature until all the Cul had dissolved. The mixture was cooled to 0°C and 100 ml of a 0.5 M THF solution of 4-(2-tetrahydo-2H-pyranoxy)phenyl magnesium bromide was added.
  • Step 3 3,3,5-Trimethyl-5-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-cyclohexanone CS 2 CO 3 (0.39 g, 1.2 mmol) was added to a solution of 3-(4-hydroxy-phenyl)-3,5,5- trimethyl-cyclohexanone (0.232 g, 1 mmol) in 20 ml of MeCN. The mixture was stirred overnight at room temperature. Solid toluene-4-sulfonic acid 7-oxo-2,3-dihydro-7H- oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.322 g, 1 mmol) was added.
  • the mixture was stirred for 6 days at room temperature.
  • the reaction mixture was poured into dichloromethane and extracted with an aqueous solution of NaHC0 3 .
  • the aqueous NaHC0 3 layer was extracted three more times with dichloromethane.
  • the combined dichloromethane extracts were dried over 4 A molecular sieves, filtered, and concentrated under vacuum to yield 0.27 g of a light yellow oil.
  • the oil was partially dissolved in ethyl acetate and filtered.
  • the filtrate was diluted with heptane until cloudy.
  • the cloudy mixture was allowed to stand and the ethyl acetate to evaporate.
  • the mother liquors were decanted from a white solid and the white solid was dried under vacuum to yield 0.11 g of the title compound.
  • Step 1 4,6,6-Trimethyl-4-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-bicyclo[3.1.1 ]heptan-2-one ⁇ , ⁇ , ⁇ ', ⁇ '-Tetramethylethylenediamine (0.15 ml, 1 mmol) was added to a suspension of Cul (0.095 g, 0.5 mmol) in 100 ml of ether. The mixture was stirred 15 minutes at room temperature until all of the Cul had dissolved. The mixture was cooled to 0°C and 100 ml of a 0.5 M THF solution of 4-(2-tetrahydo-2H-pyranoxy)phenyl magnesium bromide was added.
  • the organic extract was dried over 5A molecular sieves, filtered and concentrated under vacuum to yield 16.5 g of a yellow oil.
  • the yellow oil was purified by chromatography on silica gel using ethyl acetate / heptane (1/20 then 1/10) as the eluent to give 10 g the title compound as a light yellow oil that was contaminated with a small amount of verbenone.
  • Step 2 4-(4-Hydroxy-phenyl)-4,6,6-trimethyl-bicyclo[3.1.1 ]heptan-2-one
  • Step 3 2-[4-(2,6,6-Trimethyl-4-oxo-bicyclo[3.1.1 ]hept-2-yl)-phenoxymethyl]-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one
  • Step 1 3,3,5-Trimethyl-5-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-cyclohexanone
  • ⁇ , ⁇ , ⁇ ', ⁇ '-Tetramethylethylenediamine (0.15 ml, 1 mmol) was added to a suspension of Cul (0.095 g, 0.5 mmol) in 100 ml of ether. The mixture was stirred for 15 minutes at room temperature until all the Cul had dissolved. The mixture was cooled to 0°C and 100 ml of a 0.5 M THF solution of 4-(2-tetrahydo-2H-pyranoxy)phenyl magnesium bromide was added.
  • the mixture was stirred for 15 minutes at 0°C, after which a 0.5 M ether solution of 3,5,5-trimethyl-cyclohex-2-enone (isophorone) (7.66 ml, 50 mmol) was added dropwise over a 90 minute period.
  • the reaction mixture was allowed to warm to room temperature and stirred overnight. After 15 hours at room temperature the reaction mixture was quenched with a saturated aqueous solution of ammonium chloride. The quenched reaction mixture was poured into more water and extracted with ether. The organic layer was extracted with an aqueous solution of Na 2 S 2 0 5 and K 2 C0 3 and then brine.
  • the ether extract was dried over 5 A molecular sieves after which it was filtered and concentrated under vacuum to yield 16 g of a yellow oil.
  • the yellow oil was purified by chromatography on silica gel using ethyl acetate / heptane (1/20) as the eluent to give 7 g of the title compound as a colorless oil.
  • Step 2 1 ,3,3,5-Tetramethyl-5-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-cyclohexanol
  • the oil was purified by chromatography on silica gel using ethyl acetate / heptane (1/20 then 1/10) as the eluent. Two products were isolated resulting from syn- and anti-addition to the ketone.
  • Step 4 2-[4-(2,6,6-Trimethyl-4-oxo-bicyclo[3.1.1]hept-2-yl)-phenoxymethyl]-2,3-dihydro- oxazolo[3,2-a]pyrimidin-7-one
  • a saturated aqueous solution of NaHC0 3 was added to the water layer and the layers were separated.
  • the aqueous NaHC0 3 layer was extracted three times with dichloromethane.
  • the combined dichloromethane extracts were dried over 4 A molecular sieves, filtered, and concentrated under vacuum to yield a colorless oil.
  • the oil was partially dissolved in a small amount of dichloromethane and filtered.
  • the filtrate was diluted with heptane until cloudy.
  • the cloudy mixture was allowed to stand and the dichloromethane to evaporate.
  • the mother liquors were decanted from a white solid and the white solid was recrystallized a second time from THF and heptane to yield 0.01 g ot the title compound.
  • the title compound was prepared from toluene-4-sulfonic acid (S)-5-(l,l-difluoro- propyl)-7-oxo-2,3-dihydro-7H-oxazolo[3,2-a]pyrimidin-2-ylmethyl ester (0.188 mmol) and 4- tert-butyl-phenol (0.281 mmol,) according to the procedure described in Example 1 to afford 36.6 mg of the title compound.
  • reaction mixture was quenched with acetic acid (-17 ml), diluted with diethyl ether, washed with water, brine, dried (Na 2 S0 4 ).
  • Silica gel chromatography (methyl acetate/hexane) provided 12.5 g of the title compound as a mixture of isomers.
  • Step 2 (R)-2-(4-tert-Butyl-phenoxymethyl)-6-ethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7- one
  • a calcium ion (Ca 2+ ) mobilization assay was used to identify and determine the activity for allosteric modulators of the rat or human mGluR2 receptor.
  • Two formats were used: (1) examine the ability of glutamate to affect the potency of the modulator, by looking at a concentration-response curve of compound at different submaximal glutamate concentrations, and (2) look at the ability of the modulator to affect the potency of glutamate by looking at a concentration-response curve of glutamate at a maximal modulator concentration.
  • a cell line stably expressing the rat or human mGluR2 receptor (normally coupled to its intracellular effector molecules through an inhibitory G-protein, Gcri) and Ga 16 , in a tetracycline-inducible vector was created.
  • G l 6 can promiscuously couple Gs and Gi-coupled receptors to the inositol phospholipid signaling pathway by activating phospholipase CP resulting in a Ca 2+ signal (normally Gaq-mediated), that can be monitored with fluorescence plate readers such as FLIPR (Molecular Devices, Fluorescence Imaging Plate Reader), FDSS6000 (Hamamatsu, Fluorescence Drug Screening System), or FlexStation (Molecular Devices).
  • the Ca 2+ mobilization assay was based on the detection of intracellular calcium changes using a selective, calcium-chelating dye: Fluo-3, Fluo-4, or Calcium-3. A large fluorescence intensity increase was observed upon calcium association with the dye.
  • the dye was delivered either with the acetoxy-methyl ester, and washed off, or using a no-wash kit (Molecular Devices). Fluorescence signals stimulated by glutamate were recorded and used to generate the following pharmacological parameters: (1) the potency (EC50) of the compound(s) of interest at approx. EC 10 for glutamate at the rat and human mGluR2 receptors respectively, and (2) a fold-shift of the glutamate EC50 by maximal concentration of compound(s) of interest.
  • the compounds of this invention exhibit good mGluR2 potentiation (EC50). Broadly speaking the activity of the compounds of this invention is in the range of about 1 - 1000 nm, and certain of the compounds exhibit mGluR2 potentiation in the range of 1 - 100 nm.
  • the efficacy of the compounds of formula (I) of this invention in treating a variety of diseases as disclosed herein can be confirmed by any of the methods known to one skilled in the art.
  • the efficacy in treating anxiety can be confirmed by using Vogel conflict test. See, for example, Tatarczynska et al, Psychopharmacology (Berl). 2001 Oct;158(l):94- 9 incorporated herein by reference in its entirety.
  • Tatarczynska et al. disclose the antianxiety-like effects of antagonists of group I and agonists of group II and III metabotropic glutamate receptors.
  • the preclinical anxiety and psychosis models also include stress induced hyperthermia, fear potentiated startle and PCP-induced hyperlocomotion. See Rorick-Kehn et al, J. Pharmacol. Exp. Ther. 2006 Feb;316(2):905-13. Epub 2005 Oct 13. Also see, Johnson et al, Psychopharmacology (Berl). 2005 Apr;179(l):271-83. Epub 2005 Feb 17.
  • Fear- potentiated startle and elevated plus maze models have been used by Helton et al, J Pharmacol Exp Ther. 1998 Feb;284(2):651-660 in order to demonstrate the anxiolytic and side-effect profile of LY354740: a potent, highly selective, orally active agonist for group II metabotropic glutamate receptors.
  • the efficacy of the compounds of formula (I) of this invention in treating schizophrenia may also be ascertained by various known models in the art.
  • PCP-induced hyperlocomotion, PCP-disrupted prepulse inhibition, stress-induced hyperthermia, and elevated plus maze models have been used to demonstrate the efficacy of allosteric modulators of mGluR2.
  • biphenyl-indanone A a positive allosteric modulator of the mGluR2
  • the compounds of formula (I) of this invention are also useful in treating sleep disorders and depression.
  • Feinberg et al., Pharmacol Biochem Behav. 2002, 73(2) 467-74 have reported that the selective group mGluR2/3 receptor agonist, LY379268, suppresses rapid eye movement (REM) sleep and fast EEG in the rat.
  • Gewirtz et al., Pharmacol Biochem Behav. 2002 Sep;73(2):317-26 have examined the effects of mGluR2/3 agonists on BDNF mRNA expression in medial prefrontal cortex induced by the hallucinogen and 5HT 2 A/ 2 B/2C agonist.
  • Schechter et al NeuroRx. 2005 Oct;2(4):590-611. Review, where innovative approaches for the development of antidepressant drugs are reviewed.
  • modulation mGluR2 receptors may also improve cognitive functions. See for example Moghaddam, Psychopharmacology (2004) 174:39-44. Accordingly, it has been further suggested that modulation of mGluR2 receptors may also improve cognitive deficits in patients suffering from either Parkinson's disease as well as Alzheimer's disease. See specifically Lee et al., Brain Research 1249 (2009), 244-250 for Alzheimer's disease and Samadi et al, Neuropharmacology 54 (2008) 258-268 for Parkinson's disease.
  • SIH Stress-induced hyperthermia
  • mice reflects the elevation in core body temperature experienced by mammals following a stressful experience.
  • Clinically active anxiolytics prevent SIH, indicating that this model may be useful in identifying novel anxiolytic agents (See, Olivier et al. Eur J Pharmacol. 2003, 463, 117-32).
  • SIH is measured in mice using the rectal test procedure adaptation of the classic SIH paradigm described by Borsini et al, Psychopharmacology (Berl). 1989, 98(2), 207-11. Individually housed mice are subjected to two sequential rectal temperature measurements, separated by a 10-minute interval.
  • the first measurement captured the animal's basal core body temperature (Tl), while the second temperature (T2) captured body temperature following the mild stress imposed by the first temperature measurement.
  • the difference between the first and second temperature (T2-T1 or ⁇ ) is the SIH.
  • Temperature measurements are made to the nearest 0.1°C with a lubricated thermistor probe inserted 2 cm into the rectum of each subject. Test compounds are administered 60 minutes before the first temperature measurement to allow for any stress effect created by the injection to dissipate completely.

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Abstract

La présente invention concerne une série de phénoxyméthyl-dihydro-oxazolopyrimidinones substituées de formule (I), comme définie ici. L'invention concerne également des procédés de fabrication desdits composés, dont des intermédiaires inédits. Les composés de la présente invention sont des modulateurs des récepteurs métabotropiques du glutamate (mGluR) et, en particulier, du récepteur mGluR2. En conséquence, les composés de la présente invention peuvent être utilisés en tant qu'agents pharmaceutiques, en particulier dans le cadre du traitement et/ou de la prévention de diverses affections du système nerveux central (SNC), dont, mais la liste n'est pas limitative, les affections neurodégénératives aiguës et chroniques, les psychoses, le déficit cognitif, les convulsions, l'anxiété, la dépression, la migraine, la douleur, les troubles du sommeil et les vomissements.
PCT/US2010/048697 2009-09-15 2010-09-14 Phénoxyméthyl-dihydro-oxazolopyrimidinones substituées, leur préparation et leur utilisation WO2011034832A1 (fr)

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