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WO2019158634A1 - Dérivés deutérés de 9-(2,5-difluorophénéthyl)-4-éthyl-2-méthyl-1-oxa-4,9-diazaspiro[5.5]undécan-3-one - Google Patents

Dérivés deutérés de 9-(2,5-difluorophénéthyl)-4-éthyl-2-méthyl-1-oxa-4,9-diazaspiro[5.5]undécan-3-one Download PDF

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WO2019158634A1
WO2019158634A1 PCT/EP2019/053646 EP2019053646W WO2019158634A1 WO 2019158634 A1 WO2019158634 A1 WO 2019158634A1 EP 2019053646 W EP2019053646 W EP 2019053646W WO 2019158634 A1 WO2019158634 A1 WO 2019158634A1
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compound
deuterium
formula
compound according
pain
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Carmen ALMANSA-ROSALES
Monica Garcia-Lopez
Carlos ALEGRET-MOLINA
Marina VIRGILI-BERNADO
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Esteve Pharmaceuticals SA
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Esteve Pharmaceuticals SA
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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
    • C07D498/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention relates to deuterated derivatives of 9-(2,5-difluorophenethyl)-4- ethyl-2-methyl-1 -oxa-4,9-diazaspiro[5.5]undecan-3-one having pharmacological activity, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain. BACKGROUND OF THE INVENTION
  • NSAIDs non-steroidal anti-inflammatory drugs
  • opioid agonists opioid agonists
  • calcium channel blockers and antidepressants
  • antidepressants but they are much less than optimal regarding their safety ratio. All of them show limited efficacy and a range of secondary effects that preclude their use, especially in chronic settings.
  • the technical problem can therefore be formulated as providing new derivatives of 9-(2,5-difluorophenethyl)-4-ethyl-2-methyl-1 -oxa-4,9-diazaspiro[5.5]undecan-3-one exhibiting a improved/modulated metabolic stability.
  • the invention is directed in a main aspect to a compound of general formula (I) with at least one deuterium substitution.
  • the invention is directed to deuterated derivatives of 9-(2,5-difluorophenethyl)-4-ethyl- 2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one.
  • the present invention is directed to compounds of general formula
  • Ri, Rr, Rr, R2, R2’, R3, R 4 , R 4' , R5, R5’, R6, R6’, R7, R7’, Re, Re’, R9, R9’, R10, R10’, R11 , Rir, R11 R12, R13 and R M are independently selected from hydrogen and deuterium, wherein at least one of Ri, Rr, Rr, R2, R2', R3, R 4 , R 4 ⁇ , Rs, Rs ⁇ , R6, R6 ⁇ , R7, R7', Rs, Rs ⁇ , R 9 , Rg ⁇ , R10, Rio ⁇ , R11 , Rir, R11” R12, R13 and RM is deuterium;
  • stereoisomers optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding salt thereof, or a corresponding solvate thereof.
  • salt is to be understood as meaning any form of the active compound used according to the invention in which it assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution. By this are also to be understood complexes of the active compound with other molecules and ions, in particular complexes via ionic interactions.
  • physiologically acceptable salt means in the context of this invention any salt that is physiologically tolerated (most of the time meaning not being toxic- especially not caused by the counter-ion) if used appropriately for a treatment especially if used on or applied to humans and/or mammals.
  • physiologically acceptable salts can be formed with cations or bases and in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention - usually a (deprotonated) acid - as an anion with at least one, preferably inorganic, cation which is physiologically tolerated - especially if used on humans and/or mammals.
  • the salts of the alkali metals and alkaline earth metals are particularly preferred, and also those with NH 4 , but in particular (mono)- or (di)sodium, (mono)- or (di)potassium, magnesium or calcium salts.
  • Physiologically acceptable salts can also be formed with anions or acids and in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention as the cation with at least one anion which are physiologically tolerated - especially if used on humans and/or mammals.
  • the salt formed with a physiologically tolerated acid that is to say salts of the particular active compound with inorganic or organic acids which are physiologically tolerated - especially if used on humans and/or mammals.
  • physiologically tolerated salts of particular acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid or citric acid.
  • the compounds of the invention may be present in crystalline form or in the form of free compounds like a free base or acid.
  • solvate any compound that is a solvate of a compound according to the invention like a compound according to general formula I defined above is understood to be also covered by the scope of the invention. Methods of solvation are generally known within the art. Suitable solvates are pharmaceutically acceptable solvates.
  • the term“solvate” according to this invention is to be understood as meaning any form of the active compound according to the invention in which this compound has attached to it via non- covalent binding another molecule (most likely a polar solvent). Especially preferred examples include hydrates and alcoholates, like methanolates or ethanolates.
  • prodrug is used in its broadest sense and encompasses those Derivatives that are converted in vivo to the compounds of the invention. Such Derivatives would readily occur to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the following Derivatives of the present compounds: esters, amino acid esters, phosphate esters, metal salts sulfonate esters, carbamates, and amides. Examples of well known methods of producing a prodrug of a given acting compound are known to those skilled in the art and can be found e.g. in Krogsgaard-Larsen et al.“Textbook of Drug design and Discovery” Taylor & Francis (April 2002).
  • the compounds of formula (I) as well as their salts or solvates of the compounds are preferably in pharmaceutically acceptable or substantially pure form.
  • pharmaceutically acceptable form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • Purity levels for the drug substance are preferably above 50%, more preferably above 70%, most preferably above 90%. In a preferred embodiment it is above 95% of the compound of formula (I) or, or of its salts. This applies also to its solvates or prodrugs.
  • the compound according to the invention according to general formula (I) is a compound of general formula (G)
  • 1 to 26 is meaning, that 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25 or 26 of R1 , Rr, Rr, R2, R2’, R3, R4, R4’, Rs, Rs , R6, R6’, R7, R7’, Rs, Rs ⁇ , Rg, Rg ⁇ , R10, Rio ⁇ , R11 , Rir, R11” R12, R13 and RM being deuterium.
  • 1 to 20 is meaning, that 1 , 2,3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 of Ri, Rr, R1 ', R2, R2’, R3, R4, R4’, Rs, Rs , R6, R6’, R7, R7’, Rs, Rs , Rg, Rg , R10, R10’, R11 , Rir, R11” R12, R13 and RM being deuterium.
  • 1 to 15 is meaning, that 1 , 2,3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14 or 15 of R1 , Rr, Rr, R2, R2’, R3, R 4 , R 4’ , Rs, Rs , Re, R6’, R7, R7’, Rs, Re’, R9, R9’, R10, R10’, R11 , Rir, R11 R12, R13 and R M being deuterium.
  • 1 to 12 is meaning, that 1 , 2,3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 of Ri, Rr, Ri ", R2, R2', R3, R 4 , R 4’ , Rs, Rs , Re, R6’, R7, R7’, Re, Rs , R9, R9’, R10, R10’, R11 , Rir, R11” R12, R13 and RM being deuterium.
  • 1 to 10 is meaning, that 1 , 2,3, 4, 5, 6, 7, 8, 9 or 10 of Ri, Rr, Rr, R2, R2', R3, R 4 , R 4 ⁇ , Rs, Rs ⁇ , R6, R6', R7, R7', Rs, Rs ⁇ , R9, R9', R10, R10', R1 1, Rir, R11 R12, R13 and RM being deuterium.
  • 1 to 9 is meaning, that 1 , 2,3, 4, 5, 6, 7, 8, or 9 of Ri , Rr, Rr, R2, R2', R 3 , F , R 4’ , Rs, Rs ⁇ , R6, R6', R7, R7', Rs, Re’, R9, R9', R10, R10', R11 , Rir, R11”’ R12, R13 and RM being deuterium.
  • the compound according to the invention according to general formula (I) is a compound of general formula (II”)
  • Ri, Rr, Rr, R 2 , R2', R3, R 4 , R 4 ⁇ , Rs, Rs ⁇ , R6 and R6 ⁇ are independently selected from hydrogen and deuterium, wherein at least one of Ri, Rr, Rr, R2, R2', R 3 , R 4 , R 4 ⁇ , Rs, Rs ⁇ , R6 and Re ⁇ is deuterium;
  • the compound according to the invention according to general formula (II”) is a compound of formula (II’)
  • the compound according to the invention according to general formula (I) is a compound of formula (II’)
  • 1 to 12 of Ri, Rr, Rr, R 2 , R 2 ⁇ , R3, R 4 , Rr, Rs, Rs ⁇ , R6 and R6 ⁇ is deuterium.
  • 1 to 12 is meaning, that 1 , 2,3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12 of Ri, Rr, Rr, R2, R2', R3,
  • R 4 , Rr, R 5 , R S ⁇ , R 6 and R 6 ⁇ being deuterium.
  • 1 to 10 of Ri, Rr, Rr, R2, R2', R3, R 4 , Rr, Rs, Rs ⁇ , R6 and R6 ⁇ is deuterium.
  • 1 to 10 is meaning, that 1 , 2,3, 4, 5, 6, 7, 8, 9 or 10 of Ri, Rr, Rr, R2, R2', R3, R 4 , Rr,
  • 1 to 9 of Ri, Rr, Ri , R2, R2', R3, R 4 , Rr, Rs, Rs ⁇ , R6 and R6 ⁇ is deuterium.
  • 1 to 9 is meaning, that 1 , 2,3, 4, 5, 6, 7, 8, or 9 of Ri, Rr, Rr, R2, R2', R3, R 4 , Rr, Rs,
  • At least Ri, Rr, Rr, R 2 , and R 2 ⁇ are deuterium.
  • the compound according to the invention according to general formula (I) is selected from the group consisiting of:
  • the compound according to the invention according to general formula (I) is a compound wherein R 1 , Rr, Rr, R 2 and R 2' are deuterium, whereas R3, R 4 , R 4 ⁇ , Rs, Rs ⁇ , R6 and R6 ⁇ are hydrogen.
  • the compound according to the invention according to general formula (I) is a compound wherein R 3 is deuterium, whereas R 1 , Rr, Rr, R 2 ,
  • R2’, R 4 , R 4’ , R5, R5’, Re, R6’, R7, R7’, Re, Re , R9, R9’, R10, R10’, R11 , Rir, R11 ', R12, R13 and R M are hydrogen.
  • the compound according to the invention according to general formula (I) is a compound wherein R 3 , R 4 and R 4 ⁇ are deuterium, whereas R 1 ,
  • the compound according to the invention according to general formula (I) is a compound wherein R 1 , Rr, Rr, R2, R2', R 4 and R 4 ⁇ are deuterium, whereas R3, Rs, Rs ⁇ , R6, R6 ⁇ , R7, R7’, Re, Re ⁇ , R9, R9', R10, Rio ⁇ , R11, Rn ⁇ R11 ", R12, R13 and Ri 4 are hydrogen.
  • the compound according to the invention according to general formula (I) is a compound wherein R3, R6 and R6 ⁇ are deuterium, whereas Ri,
  • Rr, Rr, R2, R2', R 4 Rr, Rs, Rs", R7, R7’, Re, Re", R9, R9', R10, R10', R11 , Rir, R11 ", R12, R13 and Ri 4 are hydrogen.
  • the compound according to the invention according to general formula (I) is a compound wherein Ri , Rr, Rr, R 2 , R2', R 4 , Rr, Rs and R 5" are deuterium, whereas R3, R6, R6 ⁇ , R7, R7’, Rs, Rs ⁇ , R9, R9', R10, Rio ⁇ , R11 , Ri r and Rn - are hydrogen.
  • the compound according to the invention according to general formula (I) is a compound wherein R3, R 4 , Rr, Rs, Rs ⁇ , are deuterium, whereas
  • Ri, Rr, Rr, R 2 , R2’, Re, R6’, R7, R7’, Re, Re’, R9, R9’, R10, R10’, R11, Rir, Rn”, R12, R13 and Ri 4 are hydrogen.
  • Ri, Rr, Rr, R2, R2’, R3, R4, R 4’ , R5, R5’, R6, R6’, R7, R7’, Re, Re R9, R9’, R10, R10’, R11 , Rir, R11 ⁇ , R12, R13 and R14 are independently selected from hydrogen and deuterium, wherein at least one of Ri, Rr, Rr, R2, R2', R3, R 4 , R 4 ⁇ , Rs, Rs ⁇ , R6, R6 ⁇ , R7, Rr, Rs, Rs ⁇ , Rg, Rg ⁇ , R10, Rio ⁇ , R11 , Rir, R11” R12, R13 and RM is deuterium.
  • HCI salt To a solution of the free base obtained, in a suitable solvent, preferably in anhydrous diethyl ether, HCI was added, and the mixture was stirred, preferably at room temperature, preferably for 1 h. The solvent was evaporated, preferably under vacuum, to give the corresponding HCI salt.
  • leaving group means a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage.
  • Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as CI-, Br-, and I-, and sulfonate esters, such as tosylate (TsO-) or mesylate.
  • TsO- tosylate
  • the optical isomers can be obtained by convenient enantioselective methods or via chiral HPLC separation or fractional crystallization of diastereomeric salts of the corresponding racemic mixtures.
  • reaction products may, if desired, be purified by conventional methods, such as crystallisation and chromatography.
  • these isomers may be separated by conventional techniques such as preparative chromatography. If there are chiral centers the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • One preferred pharmaceutically acceptable form of a compound of the invention is the crystalline form, including such form in pharmaceutical composition.
  • the additional ionic and solvent moieties must also be non-toxic.
  • the compounds of the invention may present different polymorphic forms, it is intended that the invention encompasses all such forms.
  • Another aspect of the invention refers to a pharmaceutical composition which comprises a compound according to the invention as described above according to general formulas (I), (I’), (II’) or (II”) or a pharmaceutically acceptable salt or steroisomer thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • the present invention thus provides pharmaceutical compositions comprising a compound of this invention, or a pharmaceutically acceptable salt or stereoisomers thereof together with a pharmaceutically acceptable carrier, adjuvant, or vehicle, for administration to a patient.
  • compositions include any solid (tablets, pills, capsules, granules etc.) or liquid (solutions, suspensions or emulsions) composition for oral, topical or parenteral administration.
  • the pharmaceutical compositions are in oral form, either solid or liquid.
  • Suitable dose forms for oral administration may be tablets, capsules, syrops or solutions and may contain conventional excipients known in the art such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers for example lactose, sugar, maize starch, calcium phosphate, sorbitol or
  • the solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are conventional in the art.
  • the tablets may for example be prepared by wet or dry granulation and optionally coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • compositions may also be adapted for parenteral administration, such as sterile solutions, suspensions or lyophilized products in the apropriate unit dosage form.
  • Adequate excipients can be used, such as bulking agents, buffering agents or surfactants.
  • Administration of the compounds or compositions of the present invention may be by any suitable method, such as intravenous infusion, oral preparations, and intraperitoneal and intravenous administration. Oral administration is preferred because of the convenience for the patient and the chronic character of the diseases to be treated. Generally an effective administered amount of a compound of the invention will depend on the relative efficacy of the compound chosen, the severity of the disorder being treated and the weight of the sufferer. However, active compounds will typically be administered once or more times a day for example 1 , 2, 3 or 4 times daily, with typical total daily doses in the range of from 0.1 to 1000 mg/kg/day.
  • the compounds and compositions of this invention may be used with other drugs to provide a combination therapy.
  • the other drugs may form part of the same composition, or be provided as a separate composition for administration at the same time or at different time.
  • Another aspect of the invention refers to the use of a compound of the invention or a pharmaceutically acceptable salt or isomer thereof in the manufacture of a medicament.
  • Another aspect of the invention refers to a compound of the invention according as described above according to general formulas (I), (I’), (II’) or (II”) ( or a pharmaceutically acceptable salt or isomer thereof), for use as a medicament
  • Another aspect of the invention refers to a compound of the invention according as described above according to general formulas (I), (I’), (II’) or (II”) ( or a pharmaceutically acceptable salt or isomer thereof), for use as a medicament for the treatment of pain.
  • the pain is medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, allodynia or hyperalgesia. This may include mechanical allodynia or thermal hyperalgesia.
  • Another aspect of the invention refers to the use of a compound of the invention in the manufacture of a medicament for the treatment or prophylaxis of pain.
  • the pain is selected from medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, allodynia or hyperalgesia, also preferably including mechanical allodynia or thermal hyperalgesia.
  • Another aspect of this invention relates to a method of treating or preventing pain which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound as above defined or a pharmaceutical composition thereof.
  • a compound as above defined or a pharmaceutical composition thereof are medium to severe pain, visceral pain, chronic pain, cancer pain, migraine, inflammatory pain, acute pain or neuropathic pain, allodynia or hyperalgesia, whereas this could also include mechanical allodynia or thermal hyperalgesia.
  • a compound of formula (III) is prepared by treating a compound of formula (II) with a suitable methyl-transfer reagent such as trimethylsulfoxonium iodide or trimethylsulfonium iodide, in a suitable aprotic solvent such as dimethylsulfoxide or 1 ,2- dimethoxyethane or mixtures, and in the presence of a strong base such as sodium hydride or potassium tert- butoxide, at a suitable temperature, preferably comprised between 0 °C and 60 °C.
  • a suitable methyl-transfer reagent such as trimethylsulfoxonium iodide or trimethylsulfonium iodide
  • a suitable aprotic solvent such as dimethylsulfoxide or 1 ,2- dimethoxyethane or mixtures
  • a strong base such as sodium hydride or potassium tert- butoxide
  • the preparation of a compound of formula (III) from a compound of formula (II) can be carried out in 2 steps by performing a Wittig olefination followed by epoxidation of the resulting olefine, using conventional procedures described in the literature.
  • the Wittig reaction is carried out by treating a compound of formula (II) with methylenetriphenylphosphorane (prepared in situ from methyltriphenylphosphonium bromide and a strong base such as butyllithium), in a suitable solvent, such as tetrahydrofuran, at a suitable temperature, preferably comprised between -78 °C and room temperature; and the epoxidation reaction is carried out by treating the olefin obtained in the Wittig reaction with a suitable oxidizing agent, such as hydrogen peroxide or an alkyl hydroperoxide in the presence of a metal catalyst, or preferably using a peroxyacid such as mefa-chloroperoxybenzoic acid in a suitable solvent such as dichloromethane or chloroform.
  • a suitable oxidizing agent such as hydrogen peroxide or an alkyl hydroperoxide
  • a peroxyacid such as mefa-chloroperoxybenzoic acid
  • suitable solvent such as dichlor
  • Step2 A compound of formula (V) is prepared by reacting a compound of formula (III) with an amine of formula (IV), in a suitable solvent such as an alcohol, preferably ethanol-water mixtures, at a suitable temperature comprised between room temperature and the reflux temperature, preferably at room temperature.
  • Step3 A compound of formula (VII) is prepared by reacting a compound of formula (V) with an acylating agent of formula (VI).
  • the acylation reaction is carried out in a suitable solvent, such as dichloromethane or ethyl acetate-water mixtures; in the presence of an organic base such as triethylamine or diisopropylethylamine or an inorganic base such as K 2 CO 3 ; and at a suitable temperature, preferably comprised between -78 °C and room temperature.
  • a suitable solvent such as dichloromethane or ethyl acetate-water mixtures
  • an organic base such as triethylamine or diisopropylethylamine or an inorganic base such as K 2 CO 3
  • K 2 CO 3 inorganic base
  • the acylation reaction can be carried out using a suitable coupling reagent such as /V-(3-dimethylaminopropyl)-/V- ethylcarbodiimide (EDO), dicyclohexylcarbodiimide (DCC), /V-[(dimethylamino)-1 H- 1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-/V-methylmethanaminium
  • a suitable coupling reagent such as /V-(3-dimethylaminopropyl)-/V- ethylcarbodiimide (EDO), dicyclohexylcarbodiimide (DCC), /V-[(dimethylamino)-1 H- 1 ,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-/V-methylmethanaminium
  • HATU hexafluorophosphate N- oxide
  • HBTU hexafluorophosphate N- oxide
  • HBTU hexafluorophosphate N- oxide
  • 1- hydroxybenzotriazole optionally in the presence of 1- hydroxybenzotriazole
  • an organic base such as N- methylmorpholine or diisopropylethylamine
  • a suitable solvent such as dichloromethane or dimethylformamide
  • Step4 The intramolecular cyclization of a compound of formula (VII) renders a compound of formula (I).
  • the cyclization reaction is carried out in a suitable solvent, such as tetrahydrofuran; in the presence of a strong base such as potassium tert- butoxide or sodium hydride; and at a suitable temperature, comprised between -78 °C and room temperature, preferably cooling.
  • the group defined as B in Scheme 1 can be incorporated in the last step of the synthesis by reaction of a compound of formula (VII IH) with a compound of formula (IX) or (X), as shown in Scheme 1.
  • a compound of formula (VIIIH) is obtained by deprotection of a compound of formula (VIIIP), wherein P represents a suitable protecting group, preferably Boc (tert- butoxycarbonyl).
  • P represents a suitable protecting group, preferably Boc (tert- butoxycarbonyl).
  • Boc tert- butoxycarbonyl
  • the deprotection can be conducted by adding a solution of a strong acid such as HCI, in a suitable solvent such as diethyl ether, 1 ,4-dioxane, methanol or ethanol, or with trifluoroacetic acid in dichloromethane.
  • a compound of formula (VIIIP) is prepared from a compound of formula (IIP) following the same sequence described for the synthesis of compounds of formula (I).
  • the alkylation reaction between a compound of formula (VI 11 H ) (or a suitable salt such as trifluoroacetate or hydrochloride) and a compound of formula (IX) is carried out in a suitable solvent, such as acetonitrile, dichloromethane, 1 ,4-dioxane or dimethylformamide, preferably in acetonitrile; in the presence of an inorganic base such as K2CO 3 or CS2CO 3 , or an organic base such as triethylamine or diisopropylethylamine, preferably K2CO 3; at a suitable temperature comprised between room temperature and the reflux temperature, preferably heating, or alternatively, the reactions can be carried out in a microwave reactor. Additionally, an activating agent such as Nal can be used.
  • the reductive amination reaction between a compound of formula (VIIIH) and a compound of formula (X) is carried out in the presence of a reductive reagent, preferably sodium triacetoxyborohydride, in a suitable solvent, preferably tetrahydrofuran or dichloroethane, optionally in the presence of an acid, preferably acetic acid.
  • a reductive reagent preferably sodium triacetoxyborohydride
  • a suitable solvent preferably tetrahydrofuran or dichloroethane
  • the substituent -C(R R ')C(R-iRrRr) present in a compound of formula (I) can be incorporated later in the sequence by the reaction of a compound of formula (XVII) with a compound of formula (XVIII).
  • the alkylation reaction is carried out in an aprotic solvent, preferably dimethylformamide, in the presence of a strong base such as NaH, at a suitable temperature, preferably between room temperature and 60°C.
  • a compound of formula (XVII) is synthesized following an analogous sequence as described for the synthesis of compounds of formula (I), but effecting Step 2 using ammonia instead of an amine of formula (IV).
  • a compound of formula (XVII) can be prepared by reaction of a compound of formula (XVIIH) (prepared from a compound of formula (XVIIP), wherein P represents a suitable protecting group) with a compound of formula (IX) or (X), as described above.
  • a compound of formula (XVII) can be prepared from a compound of formula (XIV), wherein P’ represents a suitable protecting group, preferably a 4- methoxybenzyl group.
  • P’ represents a suitable protecting group, preferably a 4- methoxybenzyl group.
  • the deprotection reaction is carried out with cerium ammonium nitrate in a suitable solvent such as mixtures of acetonitrile-water or by heating in trifluoroacetic acid or hydrochloric acid.
  • a compound of formula (XIV) is synthesized from a compound of formula (III) and an amine of formula (XI) following an analogous sequence as described for the synthesis of compounds of formula (I).
  • a compound of formula (XIV) can be prepared by reaction of a compound of formula (XIVH) (prepared from a compound of formula (XIVP), wherein P represents a suitable protecting group) with a compound of formula (IX) or (X), as described above.
  • suitably deuterated compounds in the reactions described in Scheme 1 allows for the introduction of deuterium in the different positions of a compound of formula (I).
  • the use of a deuterated compound of formula (II) allows for the introduction of deuterium in R 4 , R 4 ⁇ , Rs, Rs ⁇ , R7, Rr, Rs, Rs ⁇ , R9, RET, R10, R10 R12, R13 and RI 4.
  • the use of a deuterated compound of formula (IIP) allows for the introduction of deuterium in R 7 , Rr, Re, Re’, R9, R9', R10 and Rio ⁇ .
  • deuterated compound of formula (IV) or (XVIII) allows for the introduction of deuterium in R1 , Rr, Rr, R2 and R2'.
  • the use of a deuterated compound of formula (VI) allows for the introduction of deuterium in R3, R11 , R-irand Rn .
  • the use of a deuterated compound of formula (IX) or (X) allows for the introduction of deuterium in R 4 , R 4 ⁇ , R 5 , Rs ⁇ , R12, R13 and R M .
  • a suitably deuterated methyl-transfer or phosphorane reagent in Step 1 allows for the introduction of deuterium in R6 and R6 ⁇ .
  • LG represents a leaving group such as halogen, mesylate, tosylate, nosylate or triflate and
  • P represents a suitable protecting group (preferably Boc).
  • the hydrogen-deuterium exchange reaction is carried out by treating a compound of formula (la) with a strong base such as potassium tert- butoxide or sodium hydride, in a suitable deuterated solvent, such as methanol-c/, methanol-c/4, ethanol-c/ or ethanol-cfe, at a suitable temperature comprised between room temperature and the reflux temperature, preferably heating.
  • a strong base such as potassium tert- butoxide or sodium hydride
  • a suitable deuterated solvent such as methanol-c/, methanol-c/4, ethanol-c/ or ethanol-cfe
  • the hydrogen-deuterium exchange reaction can be carried out at a previous stage by treating a suitable precursor of formula (VlllaP) under the reaction conditions described above to render a compound of formula (VlllbP).
  • a compound of formula (VlllbP) is converted into a compound of formula (lb) under the same reaction conditions described in Scheme 1 for the conversion of a compound of formula (VIIIP) into a compound of formula (VIIIH) followed by reaction with a compound of formula (IX) or (X) to render a compound of formula (I).
  • a compound of formula (la) or (VlllaP) is prepared from a compound of formula (II) or (IIP), respectively, following the same sequence described in Scheme 1 for the synthesis of compounds of formula (I).
  • a compound of formula (I) can be obtained in enantiopure form by resolution of a racemic compound of formula (I) either by chiral preparative HPLC or by crystallization of a diastereomeric salt or co-crystal.
  • the resolution step can be carried out at a previous stage, using any suitable intermediate.
  • ACN acetonitrile aq.: aq.
  • CDCI3 chloroform-c/
  • Step 1 ferf-Butyl 4-(methylene-c/ 2 )piperidine-1 -carboxylate: To a solution of (methyl-c/3)triphenylphosphonium bromide (prepared according to J.Org.Chem., 35, 4256 (1970)) (8.14 g, 22.6 mmol) in dry THF (36 ml_), cooled at -78 °C under an argon atmosphere, n-butyllithium solution (2.5 M in hexanes, 9 ml_, 22.5 mmol) was added dropwise and the mixture was stirred at -78 °C for 1 h.
  • n-butyllithium solution 2.5 M in hexanes, 9 ml_, 22.5 mmol
  • Step 2 To a solution of the crude product obtained in Step 1 (3 g, 15.1 mmol) in CDCI3 (120 ml_), cooled at 0 °C under an argon atmosphere, 3- chloroperbenzoic acid (4.0 g, 77 wt%, 23.3 mmol) was added. The reaction mixture was stirred at 0 °C for 30 min, then it was allowed to warm up and it was stirred at r.t. overnight. It was diluted with additional CDC and the organic phase was consecutively washed with Na 2 SC> 3 aq. sol., NaHCC> 3 sat. sol. and brine, dried over MgS0 4 , filtered and concentrated to dryness. The residue was purified by flash chromatography, silica gel, gradient CH to EtOAc, to give the title compound (1 .4 g, 43% yield).
  • Step 1 (S)-ferf-Butyl 4-((2-chloro-/V-ethylpropanamido)methyl)-4- hydroxypiperidine-1 -carboxylate: To a solution of intermediate 2A (58.9 g, 228 mmol) in ethyl acetate (550 ml_), a solution of K2CO3 (88.2 g, 638 mmol) in water (630 mL) was added. After cooling to 0 °C, a solution of (S)-2-chloropropanoyl chloride (39.3 g, 310 mmol) in ethyl acetate (300 mL) was added dropwise.
  • Step 2 A solution of the crude product obtained in Step 1 (72 g, 206 mmol) in dry THF (1080 mL) was cooled to -78 °C using a dry ice/acetone bath under a N2 atmosphere. Potassium tert- butoxide solution (227 mL, 1 M in THF, 227 mmol) was slowly added and the reaction mixture was stirred at -78 °C for 30 min. NH 4 CI sat. solution was then added, and the aq. phase was extracted with ethyl acetate. The organic phases were combined, dried over MgS0 4 , filtered and concentrated under vacuum. The residue was crystallyzed from hot isopropyl acetate-heptane to give the title compound (39.9 g, 62% yield).
  • Step 1 2-(2,5-Difluorophenyl)ethan-1 ,1 -c/2-1 -ol: A solution of ethyl 2-(2,5- difluorophenyl)acetate (1.0 g, 5 mmol) in a mixture of EtOD (6 ml.) and deuterium oxide (1.5 ml.) was cooled to 0 °C under a nitrogen atmosphere. Calcium chloride (0.55 g, 5 mmol) was added and the mixture was stirred at 0-5 °C for 30 min.
  • Step 2 Title compound: Following the method described for the preparation of intermediate 5A but starting from the compound obtained in Step 1 (462 mg, 2.88 mmol), the desired compound was obtained. The crude product was alternatively purified by flash chromatography, Cie, gradient aq. NH4HCO 3 pH 8 to acetonitrile, to render the title compound (236 mg, 24% yield).
  • Step 1 2-(2,5-Difluorophenyl)acetic-2,2-d2 acid: A solution of 2-(2,5- difluorophenyl)acetic acid (5.0 g, 29 mmol) and potassium carbonate (20.47 g, 148 mmol) in deuterium oxide (25 ml.) was heated at 100 °C for 5 days. Then, it was cooled down to 0 °C, pH was adjusted to 2 with 6 M HCI and it was extracted with DCM. The organic phases were combined, dried over MgS0 4 , filtered and concentrated to dryness to obtain the title compound (2.83 g, 56% yield).
  • Step 2 Ethyl 2-(2,5-difluorophenyl)acetate-c/2: To a solution of the compound obtained in Step 1 (2.83 g, 16.2 mmol) in EtOD (30 ml_), sulfuric acid (1 ml.) was added and the mixture was stirred at r.t. overnight. The solvent was partially evaporated and the residue was diluted with EtOAc and NaHCOs sat. sol. The phases were separated and the aq. phase was back-extracted with EtOAc. The combined organic phases were washed with water and brine, dried over MgS0 4 , filtered and concentrated to dryness to give the title compound (3.3 g, quant yield).
  • Step 3 2-(2,5-Difluorophenyl)ethan-1 ,1,2,2-c/ 4 -1-ol: Following the method described for the preparation of Step 1 of intermediate 5B but starting from the compound obtained in Step 2 (1.58 g, 7.8 mmol), the title compound was obtained (815 mg, 64% yield).
  • Step 4 Title compound: Following the method described for the preparation of intermediate 5A but starting from the compound obtained in Step 3 (815 mg, 5 mmol), the desired compound was obtained. It was further purified by flash chromatography, silica gel, gradient DCM to MeOH/DCM (1 :9) to give the title compound (954 mg, 55% yield).
  • Step 1 (/?)-4-Ethyl-2-methyl-1 -oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride.
  • Hydrochloric acid 37% (58.6 ml_, 762 mmol) was slowly added to a solution of intermediate 3A (23.8 g, 76 mmol) in ethanol (298 ml.) and the reaction mixture was stirred at 30 °C overnight. Then, it was concentrated to dryness and the crude product was dried under high vacuum to give the title compound (26.0 g, overweight; theoretical weight 18.95 g assuming quantitative yield).
  • Step 2 (/?)-9-(2,5-Difluorophenethyl)-4-ethyl-2-methyl-1 -oxa-4,9- diazaspiro[5.5]undecan-3-one:
  • a mixture of intermediate 5A (1.95 g, 5.67 mmol), K2CO3 (2.85 g, 20.6 mmol) and the crude product obtained in Step 1 (1.76 g crude, 73 wt%, 1.28 g theory, 5.2 mmol) in ACN (16 ml.) was heated at 40 °C overnight. The precipitated solids were filtered off and the solvent was evaporated. Water was added and it was extracted with ethyl acetate. The organic phases were combined, washed with water, dried over MgS0 4 , filtered and concentrated to dryness to give the title compound (1.82 g, quant yield) as a crude product that was used as such without further purification.
  • Step 3 9-(2,5-Difluorophenethyl)-4-ethyl-2-methyl-1 -oxa-4,9- diazaspiro[5.5]undecan-3-one-2-d: Following the method described for the preparation of intermediate 4A but starting from the product obtained in Step 2 (200 mg, 0.57 mmol), the desired compound was obtained. The crude product was purified by flash chromatography, silica gel, gradient DCM to MeOH/DCM (1 :4) to give the title compound (149 mg, 74% yield).
  • Step 4 To a solution of the free base obtained in Step 3 (149 mg, 0.42 mmol) in anhydrous diethyl ether (2 ml_), HCI (2 M solution in diethyl ether, 0.25 ml_, 0.5 mmol) was added, and the mixture was stirred at r.t. for 1 h. The solids were filtered, washed with cold diethyl ether and dried under vacuum to give the title hydrochloride salt (133 mg, 81 % yield).
  • Example 7 (/?)-9-(2-(2,5-Difluorophenyl)ethyl-1 ,1 -c/ 2 )-4-(ethyl-c/ 5 )-2-methyl-1 -oxa- 4,9-diazaspiro[5.5]undecan-3-one
  • Example 7 The seven deuterated examples (Ex. 1 to Ex. 7) synthesized as described above were tested in this test of biological activity for their In vitro metabolic stability in liver microsomes.
  • Example 7 the non-deuterated Example 70 ((R)-9-(2,5- difluorophenethyl)-4-ethyl-2-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one) described in the PCT publication WO2015/185209 was used.

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Abstract

La présente invention concerne des dérivés deutérés de 9-(2,5-difluorophénéthyl)-4-éthyl-2-méthyl-1-oxa-4,9-diazaspiro[5.5]undécan-3-one ayant une activité pharmacologique, des procédés de préparation de ces composés, des compositions pharmaceutiques les comprenant, ainsi que leur utilisation thérapeutique, en particulier pour traiter la douleur.
PCT/EP2019/053646 2018-02-16 2019-02-14 Dérivés deutérés de 9-(2,5-difluorophénéthyl)-4-éthyl-2-méthyl-1-oxa-4,9-diazaspiro[5.5]undécan-3-one Ceased WO2019158634A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015185209A1 (fr) 2014-06-02 2015-12-10 Laboratorios Del Dr. Esteve, S.A. Dérivés alkyles de composés de 1-oxa-4,9-diazaspiro-undécane ayant une activité multimodale contre la douleur
WO2017105881A1 (fr) * 2015-12-15 2017-06-22 NeuForm Pharmaceuticals, Inc. Composés deutérés pour traiter la douleur

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015185209A1 (fr) 2014-06-02 2015-12-10 Laboratorios Del Dr. Esteve, S.A. Dérivés alkyles de composés de 1-oxa-4,9-diazaspiro-undécane ayant une activité multimodale contre la douleur
WO2017105881A1 (fr) * 2015-12-15 2017-06-22 NeuForm Pharmaceuticals, Inc. Composés deutérés pour traiter la douleur

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Title
DI, L.; KERNS, E. H.; HONG, Y.; KLEINTOP T. A.; MCCONNELL, O. J.; HURYN, D. M.: "Optimization of a higher throughput microsomal stability screening assay for profiling drug discovery candidates", J. BIOMOL SCREEN., vol. 8, 2003, pages 453 - 462, XP002670661, DOI: doi:10.1177/1087057103255988
GOLDBERG DS; MCGEE SJ: "Pain as a global public health priority", vol. 11, 2011, BMC PUBLIC HEALTH, pages: 770
J.ORG.CHEM., vol. 35, 1970, pages 4256
KROGSGAARD-LARSEN ET AL.: "Textbook of Drug design and Discovery", April 2002, TAYLOR & FRANCIS
KUSHNER DJ ET AL: "Pharmacological uses and perspectives of heavy water and deuterated compounds", CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACO, OTTAWA, ONT, CA, vol. 77, no. 2, 1 February 1999 (1999-02-01), pages 79 - 88, XP009086918 *
MARTIN I BLAKE ET AL: "Studies with Deuterated drugs", JOURNAL OF PHARMACEUTICAL SCIENCES, AMERICAN PHARMACEUTICAL ASSOCIATION, US, vol. 64, no. 3, 1 March 1975 (1975-03-01), pages 367 - 391, XP009090019, ISSN: 0022-3549, DOI: 10.1002/JPS.2600640306 *
OBACH, R. S.: "Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: an examination of in vitro half-life approach and nonspecific binding to microsomes", AM. SOC. PHARMACOL. EXP. THER., vol. 27, 1999, pages 1350 - 1359
THOMAS G. GANT: "Using Deuterium in Drug Discovery: Leaving the Label in the Drug", JOURNAL OF MEDICINAL CHEMISTRY, vol. 57, no. 9, 8 May 2014 (2014-05-08), pages 3595 - 3611, XP055139522, ISSN: 0022-2623, DOI: 10.1021/jm4007998 *
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