WO2010091721A1 - 3 -substituted 1-arylsulfonylpiperidine derivatives for the treatment of pain - Google Patents

3 -substituted 1-arylsulfonylpiperidine derivatives for the treatment of pain Download PDF

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Publication number
WO2010091721A1
WO2010091721A1 PCT/EP2009/051534 EP2009051534W WO2010091721A1 WO 2010091721 A1 WO2010091721 A1 WO 2010091721A1 EP 2009051534 W EP2009051534 W EP 2009051534W WO 2010091721 A1 WO2010091721 A1 WO 2010091721A1
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Prior art keywords
piperidinyl
sulfonyl
pyrrolidinone
trifluoromethyl
phenyl
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PCT/EP2009/051534
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French (fr)
Inventor
Paul John Beswick
Robert James Gleave
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Glaxo Group Limited
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Priority to PCT/EP2009/051534 priority Critical patent/WO2010091721A1/en
Publication of WO2010091721A1 publication Critical patent/WO2010091721A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to novel piperidine derivatives with affinity for Ca v 2.2 calcium channels and which are capable of interfering with Ca v 2.2 calcium channels; to processes for their preparation; to pharmaceutical compositions containing them; and to the use of such compounds in therapy.
  • Presynaptic Ca v 2.2 (N-type) voltage-gated calcium channels in the dorsal horn of the spinal cord modulate the release of key pro-nociceptive neurotransmitters such as glutamate, substance P (SP) and calcitonin-gene-related peptide (CGRP), indicating the potential therapeutic use of Ca v 2.2 calcium channel blockers as analgesics.
  • pro-nociceptive neurotransmitters such as glutamate, substance P (SP) and calcitonin-gene-related peptide (CGRP)
  • Peptidic ⁇ -conotoxins isolated from the venom of cone snails, are selective for Ca v 2.2 calcium channels and can block SP release in the spinal cord (Smith et al. (2002) Pain, 96: 119-127). Moreover, they are antinociceptive in animal models of chronic pain following intrathecal administration (Bowersox et al. (1996) Journal of Pharmacology and Experimental Therapeutics, 279: 1243-1249; Smith et al. (2002) supra), and are effective analgesics in clinical use, particularly in the treatment of neuropathic pain (Brose et al. (1997) Clinical Journal of Pain, 13: 256-259).
  • Ca v 2.2 calcium channels are also important for normal neuronal function. Therefore, the aim is to identify novel molecules that preferentially block Ca v 2.2 under conditions of increased neuronal excitability, so-called use-dependent blockers, as is the case in chronic pain syndromes (Winquist et al. (2005) Biochemical Pharmacology, 70: 489-499).
  • WO2005/068448 (lonix Pharmaceuticals Limited) describes a series of sulfonamides which are claimed to be useful in the treatment or prevention of a condition mediated by N-type calcium channels, such as pain.
  • the present invention provides compounds with affinity for Ca v 2.2 calcium channels and which are capable of interfering with the effects of these channels.
  • R 1 represents benzofuran-2-yl, benzothien-2-yl (benzothiophen-2-yl), 3- trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, A- chlorophenyl, 2-chloro-4-cyanophenyl, 2-chloro-4-trifluoromethylphenyl, 6- trifluoromethylpyridin-3-yl or 3,5-dichlorophenyl; and R 2 represents a group of formula (i), (ii) or (iii):
  • R 1 represents benzofuran-2-yl, benzothien-2-yl (benzothiophen- 2-yl), 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, A- chlorophenyl, 2-chloro-4-cyanophenyl or 2-chloro-4-trifluoromethylphenyl.
  • R 1 represents 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, A- trifluoromethoxyphenyl, 4-chlorophenyl, 2-chloro-4-trifluoromethylphenyl, 6- trifluoromethylpyridin-3-yl or 3,5-dichlorophenyl.
  • R 1 represents 4-trifluoromethoxyphenyl.
  • R 2 represents a group of formula (i) or (iii), particularly a group of formula (i).
  • R 1 represents benzofuran-2-yl, benzothien-2-yl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, A- trifluoromethoxyphenyl, 4-chlorophenyl, 2-chloro-4-cyanophenyl, 2-chloro-4- trifluoromethylphenyl, 6-trifluoromethylpyridin-3-yl or 3,5-dichlorophenyl.
  • R 1 represents benzofuran-2-yl, benzothien-2-yl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, A- trifluoromethoxyphenyl, 4-chlorophenyl, 2-chloro-4-cyanophenyl or 2-chloro-4- trifluoromethylphenyl.
  • R 1 represents 3- trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, A- chlorophenyl, 2-chloro-4-trifluoromethylphenyl, 6-trifluoromethylpyridin-3-yl or 3,5- dichlorophenyl.
  • R 1 when R 2 represents a group of formula (ii), R 1 represents A- trifluoromethylphenyl. In one embodiment, when R 2 represents a group of formula (Ni), R 1 represents 4- trifluoromethylphenyl or 4-trifluoromethoxyphenyl, in particular 4- trifluoromethoxyphenyl.
  • R 1 represents benzofuran-2-yl, benzothien-2-yl, 3-trifluoromethylphenyl, 4- trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-chlorophenyl, 2-chloro-4- cyanophenyl or 2-chloro-4-trifluoromethylphenyl.
  • a compound of formula (I) or a salt thereof is selected from:
  • a compound of formula (I) or a salt thereof is selected from: 1-(1- ⁇ [2-Chloro-4-(trifluoromethyl)phenyl]sulfonyl ⁇ -3-piperidinyl)-2-pyrrolidinone (E1 ); 1-((3R)-1- ⁇ [4-(Trifluoromethyl)phenyl]sulfonyl ⁇ -3-piperidinyl)-2-pyrrolidinone (E2); 1-[1-( ⁇ 4-[(Trifluoromethyl)oxy]phenyl ⁇ sulfonyl)-3-piperidinyl]-2-pyrrolidinone (E3); 1-(1- ⁇ [3-(Trifluoromethyl)phenyl]sulfonyl ⁇ -3-piperidinyl)-2-pyrrolidinone (E4); 1- ⁇ (3S)-1-[(4-Chlorophenyl)sulfonyl]-3-piperidinyl ⁇ -2-pyrrolidinone (E1
  • a compound of formula (I) or a salt thereof is selected from:
  • a compound of formula (I) or a salt thereof is selected from: 1-((3R)-1- ⁇ [4-(Trifluoromethyl)phenyl]sulfonyl ⁇ -3-piperidinyl)-2-pyrrolidinone (E2); 1-[(3/?)-1-( ⁇ 4-[(Trifluoromethyl)oxy]phenyl ⁇ sulfonyl)-3-piperidinyl]-2-pyrrolidinone (E12); and
  • a compound of formula (I) or a salt thereof is selected from: 1-((3R)-1- ⁇ [4-(Trifluoromethyl)phenyl]sulfonyl ⁇ -3-piperidinyl)-2-pyrrolidinone (E2);
  • the compound of formula (I) is 1-((3R)-1- ⁇ [4-
  • the compound of formula (I) is 1-[(3R)-1-( ⁇ 4- [(Trifluoromethyl)oxy]phenyl ⁇ sulfonyl)-3-piperidinyl]-2-pyrrolidinone (E12), or a salt thereof.
  • the compound of formula (I) is 1-[1-( ⁇ 4- [(Trifluoromethyl)oxy]phenyl ⁇ sulfonyl)-3-piperidinyl]-2-imidazolidinone (E16); or a salt thereof, in particular the fast running enantiomer of Example 16 (E16A).
  • salts of compounds of formula (I) are preferably pharmaceutically acceptable.
  • Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse , J. Pharm. ScL, 1977, 66, 1-19.
  • pharmaceutically acceptable salts includes salts prepared from pharmaceutically acceptable acids, including inorganic and organic acids.
  • Such acids include acetic, p-aminobenzoic, ascorbic, aspartic, benzenesulfonic, benzoic, bismethylenesalicylic, camphorsulfonic, citric, cyclohexylsulfamic, ethanesulfonic, ethanedisulfonic, fumaric, gluconic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, itaconic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, palmitic, pamoic, pantothenic, phosphoric, propionic, salicylic, stearic, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • Certain compounds of formula (I) are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
  • the different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
  • the invention also extends to any tautomeric forms and mixtures thereof.
  • the compound of formula (I) is a compound of formula
  • the compound of formula (I) is a compound of formula
  • the subject invention also includes isotopically-labeled compounds, which are identical to those recited in formula (I) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, fluorine, such as 3 H, 11 C, 14 C and 18 F.
  • Compounds of the present invention and salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention.
  • Isotopically-labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H, 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. 11 C and 8 F isotopes are particularly useful in PET (positron emission tomography). PET is useful in brain imaging.
  • lsotopically labeled compounds of formula (I) and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • the compounds of formula (I) or salts thereof are not isotopically labelled.
  • the present invention also provides a process for the preparation of a compound of formula (I) or a salt thereof, which process comprises:
  • Process (a) typically comprises reacting the intermediates in a suitable solvent, such as dichloromethane, in the presence of a base, for example triethylamine, at a temperature between O 0 C and ambient (e.g. O 0 C).
  • a suitable base for example triethylamine
  • the conversion may be carried out using a suitable base as a solvent (for example pyridine).
  • Suitable amine protecting groups include sulfonyl (e.g. tosyl), acyl (e.g. acetyl, 2',2',2'-trichloroethoxycarbonyl, benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g. benzyl), which may be removed by hydrolysis (e.g. using an acid such as hydrochloric acid) or reductively (e.g.
  • Suitable amine protecting groups include trifluoroacetyl (- COCF 3 ) which may be removed by base catalysed hydrolysis or a solid phase resin bound benzyl group, such as a Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker), which may be removed by acid catalysed hydrolysis, for example with trifluoroacetic acid.
  • Process (c) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, nucleophilic or electrophilic aromatic substitution or amide bond formation.
  • an intermediate of formula (V) is prepared by reacting a compound of formula (III) with acid halide of formula (IV) in a solvent, such as dichloromethane, in the presence of a suitable base, such as triethylamine, at a temperature between O 0 C and ambient temperature (for example addition of acid halide at O 0 C).
  • a solvent such as dichloromethane
  • a suitable base such as triethylamine
  • step (ii) may be achieved by treatment with a suitable base, for example sodium hydride, in an inert solvent, such as tetrahydrofuran or dimethylformamide, at a temperature between O 0 C and ambient (for example addition of the base at O 0 C).
  • a suitable base for example sodium hydride
  • an inert solvent such as tetrahydrofuran or dimethylformamide
  • Step (iii) typically comprises a deprotection reaction of intermediate (Vl) to yield a compound of formula (ll) a .
  • P 1 represents t-butoxycarbonyl
  • deprotection may be conveniently carried out by treatment with an acid, for example hydrochloric acid or trifluroroacetic acid in a solvent (such as 1 ,4-dioxane or a mixture of methanol and 1 ,4-dioxane).
  • L 4 and L 5 represent suitable leaving groups such as a halogen atom and P 2 represents a suitable protecting group, such as benzyl.
  • an intermediate of formula (VIII) is prepared by reacting a compound of formula (VII) with ethanolamine in a solvent, such as methanol, in the presence of a suitable acid and a reducing agent, such as acetic acid and sodium triacetoxyborohydride.
  • a suitable acid and a reducing agent such as acetic acid and sodium triacetoxyborohydride.
  • the reaction may be carried out at a temperature between O 0 C and ambient temperature (for example room temperature).
  • step (ii) The transformation of intermediate (VIII) to a compound of formula (IX) in step (ii) may be achieved by treatment with compound of formula (Xl), for example chloroacetylchloride, and a suitable base, for example potassium carbonate, in an inert solvent, such as ⁇ /, ⁇ /-dimethylformamide, at a temperature between ambient and 12O 0 C (for example room temperature then heating to 100°C).
  • compound of formula (Xl) for example chloroacetylchloride
  • a suitable base for example potassium carbonate
  • an inert solvent such as ⁇ /, ⁇ /-dimethylformamide
  • Step (iii) typically comprises a deprotection reaction of intermediate (IX) to yield a compound of formula (ll) b .
  • P 2 represents benzyl
  • such deprotection may be conveniently carried out by treatment with hydrogen in the presence of a catalyst suitable for hydrogenation, for example 10% palladium on carbon, in a solvent (such as ethanol).
  • L 6 and L 7 represent suitable leaving groups such as imidazole and P 3 and P 4 represents suitable orthogonal protecting groups, such as t-butoxycarbonyl and benzyloxycarbonyl.
  • an intermediate of formula (XIII) is prepared by reacting a compound of formula (XII) with a compound of formula (XVII) in a solvent, such as methanol, in the presence of a suitable acid and a reducing agent, such as acetic acid and sodium triacetoxyborohydride.
  • a solvent such as methanol
  • a suitable acid and a reducing agent such as acetic acid and sodium triacetoxyborohydride.
  • the reaction may be carried out at a temperature between O 0 C and ambient temperature (for example room temperature).
  • Step (ii) typically comprises a deprotection reaction of intermediate (XIII) to yield a compound of formula (XIV).
  • P 4 represents t-butoxycarbonyl
  • such deprotection may be conveniently carried out by treatment with an acid, for example hydrochloric acid or trifluroroacetic acid in a solvent (such as 1 ,4-dioxane or a mixture of methanol and 1 ,4-dioxane).
  • transformation of intermediate (XIV) to a compound of formula (XV) in step (iii) may be achieved by treatment with compound of formula (XVIII), for example carbonyldiimidazole, in an inert solvent, such as ⁇ /, ⁇ /-dimethylformamide, at a temperature between 0° and ambient (for example addition of reagents at O 0 C then warming to room temperature).
  • compound of formula (XVIII) for example carbonyldiimidazole
  • an inert solvent such as ⁇ /, ⁇ /-dimethylformamide
  • Step (iv) typically comprises a deprotection reaction of intermediate (XV) to yield a compound of formula (ll) c .
  • P 3 represents benzyloxycarbonyl
  • deprotection may be conveniently carried out by treatment with hydrogen in the presence of a catalyst suitable for hydrogenation, for example 10% palladium on carbon, in a solvent (such as ethanol).
  • a catalyst suitable for hydrogenation for example 10% palladium on carbon
  • Compounds of formula (III), (IV), (VII), (Xl), (XII), (XVII) and (XVIII) are either commercially available, or may be prepared by known methods.
  • a further process of the invention is the preparation of salts of compounds of formula (I), particularly pharmaceutically acceptable salts.
  • Compounds with affinity for Ca v 2.2 calcium channels may be useful in the treatment of pain, including acute pain, chronic pain, chronic articular pain, musculoskeletal pain, neuropathic pain, inflammatory pain, visceral pain, pain associated with cancer, pain associated with migraine, tension headache and cluster headaches, pain associated with functional bowel disorders, lower back and neck pain, pain associated with sprains and strains, sympathetically maintained pain; myositis, pain associated with influenza or other viral infections such as the common cold, pain associated with rheumatic fever, pain associated with myocardial ischemia, post operative pain, cancer chemotherapy, headache, toothache and dysmenorrhea.
  • 'Chronic articular pain' conditions include rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis.
  • 'Pain associated with functional bowel disorders' includes non-ulcer dyspepsia, non- cardiac chest pain and irritable bowel syndrome.
  • 'Neuropathic pain' syndromes include: diabetic neuropathy, sciatica, non-specific lower back pain, trigeminal neuralgia, multiple sclerosis pain, fibromyalgia, HIV- related neuropathy, post-herpetic neuralgia, trigeminal neuralgia, and pain resulting from physical trauma, amputation, phantom limb syndrome, spinal surgery, cancer, toxins or chronic inflammatory conditions.
  • neuropathic pain conditions include pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch
  • hypoesthesia painful sensation following innocuous stimulation (dynamic, static, thermal or cold allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).
  • neurodegenerative diseases and neurodegeneration include neurodegenerative diseases and neurodegeneration, neurodegeneration following trauma, tinnitus, dependence on a dependence- inducing agent such as opiods (e.g. morphine), CNS depressants (e.g. ethanol), psychostimulants (e.g. cocaine) and nicotine;
  • opiods e.g. morphine
  • CNS depressants e.g. ethanol
  • psychostimulants e.g. cocaine
  • nicotine nicotine
  • Neurodegenerative diseases include dementia, particularly degenerative dementia (including senile dementia, dementia with Lewy bodies, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt-Jakob disease, ALS, motor neuron disease); vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection, meningitis and shingles); metabolism; toxins; anoxia and vitamin deficiency; and mild cognitive impairment associated with ageing, particularly Age Associated Memory Impairment.
  • degenerative dementia including senile dementia, dementia with Lewy bodies, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt-Jakob disease, ALS, motor neuron disease
  • vascular dementia including multi-infarct dementia
  • dementia associated with intracranial space occupying lesions trauma
  • infections and related conditions including HIV infection, meningitis and shingles
  • the compounds of formula (I) may also be useful for neuroprotection and in the treatment of neurodegeneration following trauma such as stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like.
  • a method of treatment of any of the disorders herein, in particular pain in mammals comprises the administration to the mammal in need of such treatment, an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof.
  • treatment includes the treatment of established disorders and also includes the prophylaxis thereof.
  • prophylaxis is used herein to mean preventing symptoms in an already afflicted subject or preventing recurrence of symptoms in an afflicted subject and is not limited to complete prevention of an affliction.
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, adapted for use in human or veterinary medicine.
  • the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.
  • a pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusable solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
  • Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colourants.
  • fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • the composition may contain from 0.1% to 99% by weight, preferably from 10% to 60% by weight, of the active material, depending on the method of administration.
  • the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks, months, years or even life.
  • a further aspect to the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising 0.05 to
  • the compound was purified by silica chromatography (Biotage SP4, eluting with 20% EtOAc in hexane (5 column volumes), 20-50% (over 10 column volumes)) to yield the title compound as a white solid (1.5Og, 57%)
  • reaction was diluted with dichloromethane (10OmL) and the solution washed with 1 N hydrochloric acid (100ml), water (50ml), saturated sodium bicarbonate solution (10OmL), passed through a hydrophobic frit and reduced in vacuo to yield a yellow oil.
  • reaction was diluted with dichloromethane (10OmL) and the solution washed with 1 N hydrochloric acid (100ml), water (50ml), saturated sodium bicarbonate solution (100ml), passed through a hydrophobic frit and reduced in vacuo to yield a yellow oil.
  • Phenylmethyl 3-oxo-i-piperidinecarboxylate (5 g, 21.44 mmol) was dissolved in a mixture of methanol (200 ml) and acetic acid (1.227 ml, 21.44 mmol).
  • 1 ,1- dimethylethyl (2-aminoethyl)carbamate (10.30 g, 64.3 mmol) was added and sodium triacetoxyborohydride (11.36 g, 53.6 mmol) was also added after stirring for 1 hour.
  • the reaction mixture was allowed to stir for a further 4 hours.
  • Sodium bicarbonate (9.00 g, 107 mmol) was added to the reaction and the resulting mixture was concentrated in vacuo.
  • the resulting residue was redissolved using DCM and water.
  • the mixture was basified to pH 14 using 2M NaOH and the aqueous layer was extracted with DCM.
  • the combined organic extracts was passed through a hydrophobic frit and concentrated in vacuo.
  • the resulting residue was purified by silica column chromatography (Biotage SP4, eluting with a gradient from 0-20% MeOH in DCM) to give the title compound as a yellow oil (7.85 g, 20.80 mmol, 97 % yield).
  • the product was purified by silica chromatography (Biotage SP4, eluting 60% EtOAc in iso-hexanes (5 column volumes), a gradient from 60-100% EtOAc in iso-hexanes
  • the crude product was purified by silica chromatography (Biotage SP4, eluting 60% EtOAc in iso-hexanes (5 column volumes), a gradient from 60- 100% EtOAc in iso-hexanes (over 2 column volumes) then EtOAc (8 column volumes).
  • the crude product was purified by silica chromatography (Biotage SP4, eluting with 65% ethyl acetate in iso-hexanes (3 column volumes), a gradient from 65% to 100% (over 10 column volumes) then ethyl acetate (5 column volumes)) to yield the title compound as a white solid (112mg, 50%)
  • the DCM layers were combined, passed through a hydrophobic frit and evaporated to dryness in vacuo.
  • the residue was purified by silica chromatography (Biotage SP4, eluting 70% ethyl acetate in iso-hexanes (3 column volumes), a gradient form 70-100% ethyl acetate (over 9 column volumes) then ethyl acetate (3 column volumes)) to yield the title compound as a white solid (0.755g, 79%).
  • the crude product was purified by silica chromatography (Biotage SP4, eluting with 60% ethyl acetate in iso-hexanes (3 column volumes), a gradient from 60% to 100% ethyl acetate in iso-hexanes (over 10 column volumes) then ethyl acetate (3 column volumes)) to yield the title compound as a white solid (0.1 19g, 65%).
  • the column used is a Waters Acquity BEH UPLC C18, the dimensions of which are
  • the stationary phase particle size is 1.7 ⁇ m.
  • Aqueous solvent Water + 0.05% Formic Acid
  • the generic method used has a 2 minute runtime.
  • the above method has a flow rate of 1 ml/min.
  • the injection volume for the generic method is 0.5ul
  • the column temperature is 40deg
  • the UV detection range is from 220 to 330nm
  • Biotage - SP4® is an automated purification system. It uses preloaded silica gel columns. The user applies their material to the top of the column and selects solvents, gradients, flow rates, column size, collection method and eluting volumes.
  • Phase separators are a range of ISOLUTE® columns fitted with an optimized frit material that easily separates aqueous phase from chlorinated solvents under gravity.
  • Aqueous solvent Water + 0.1% Formic Acid
  • HEK293 human embryonic kidney cells.
  • HEK293 cells were cultured in Dulbecco's modified Eagles media/F12 media (Invitrogen, Cat # 041 -95750V) containing 10% fetal bovine serum, with added L-glutamine (2 mM; Invitrogen, Cat #
  • HEK293 cells were transfected with two plasmid vectors for expression of the hCa v 2.2 ⁇ subunit (pCIN5- hCa v 2.2 which carries a neomycin resistance marker) and the hCa v ⁇ 3 subunit (pCIH-hCa v ⁇ 3 which carries a hygromycin resistance marker).
  • This cell line was transfected with a plasmid vector for expression of the human ⁇ 2 ⁇ 1 subunit (pCIP- ⁇ 2 ⁇ 1 which carries a puromycin resistance marker) and clonal cell lines isolated following selection in media containing 0.62 ⁇ g ml "1 puromycin (Sigma, Cat # P-7255), in addition to 0.4 mg ml "1 Geneticin G418 and 0.1 mg ml "1 hygromycin.
  • pCIP- ⁇ 2 ⁇ 1 which carries a puromycin resistance marker
  • clonal cell lines isolated following selection in media containing 0.62 ⁇ g ml "1 puromycin (Sigma, Cat # P-7255), in addition to 0.4 mg ml "1 Geneticin G418 and 0.1 mg ml "1 hygromycin.
  • Several cell lines were identified that gave robust levels of Ca v 2.2 ⁇ / ⁇ 3/ ⁇ 2 ⁇ 1 -mediated current expression and one of these was selected for compound profiling.
  • Test pulses stepping from the holding potential (V H ) of -90 mV to +10 mV were applied for 20 ms and repeated 10 times at a frequency of 10 Hz.
  • the test pulse protocol was performed in the absence (pre-read) and presence (post-read) of a compound. Pre- and post-reads were separated by a compound addition followed by a 3-3.5 min incubation.
  • the intracellular solution contained the following (in mlW): K-gluconate 120, KCI 2OmM, MgCI 2 5, EGTA 5, HEPES 10, adjusted to pH 7.3.
  • Amphotericin was prepared as 30 mg/ml stock solution and diluted to a final working concentration of 0.2 mg ml "1 in intracellular buffer solution.
  • the extracellular solution contained the following (in m ⁇ f): Na-gluconate 120, NaCI 20, MgCI 2 1 , HEPES 10, BaCI 2 5, adjusted to pH 7.4.
  • the recordings were analysed and filtered using seal resistance (>40 M ⁇ ), resistance reduction (>35%) and peak current amplitude (>200pA) in the absence of compound to eliminate unsuitable cells from further analysis. Paired comparisons between pre-compound and post-compound additions were used to determine the inhibitory effect of each compound.
  • concentrations of compounds required to inhibit current elicited by the 1 st depolarising pulse by 50% (tonic plC50) were determined by fitting of the Hill equation to the concentration response data.
  • the use-dependent inhibitory properties of the compounds were determined by assessing the effect of compounds on the 10 th versus 1 st depolarising pulse.
  • the ratio of the 10 th over 1 st pulse was determined in the absence and presence of drug and the % use-dependent inhibition calculated.
  • the data was fitted using the same equation as for the tonic plC 5 o and the concentration producing 30% inhibition (use- dependent pUD 30 ) determined.

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Abstract

The present invention relates to novel piperidine derivatives of formula (I), wherein R1 represents benzofuran-2-yl, benzothien-2-yl, 3-trifluoromethylphenyl, 4- trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-chlorophenyl, 2-chloro-4- cyanophenyl, 2-chloro-4-trifluoromethylphenyl, 6-trifluoromethylpyridin-3-yl or 3,5- dichlorophenyl; and R2 represents a group of formula (i), (ii) or (iii): with affinity for Ca,2.2 calcium channels and which are capable of interfering with Ca,2.2 calcium channels; to processes for their preparation; to pharmaceutical compositions containing them; and to the use of such compounds in the treatment of pain.

Description

3 -SUBSTITUTED 1-ARYLSULFONYLPIPERIDINE DERIVATIVES FOR THE TREATMENT OF PAIN
The present invention relates to novel piperidine derivatives with affinity for Cav2.2 calcium channels and which are capable of interfering with Cav2.2 calcium channels; to processes for their preparation; to pharmaceutical compositions containing them; and to the use of such compounds in therapy.
Presynaptic Cav2.2 (N-type) voltage-gated calcium channels in the dorsal horn of the spinal cord modulate the release of key pro-nociceptive neurotransmitters such as glutamate, substance P (SP) and calcitonin-gene-related peptide (CGRP), indicating the potential therapeutic use of Cav2.2 calcium channel blockers as analgesics.
Peptidic ω-conotoxins, isolated from the venom of cone snails, are selective for Cav2.2 calcium channels and can block SP release in the spinal cord (Smith et al. (2002) Pain, 96: 119-127). Moreover, they are antinociceptive in animal models of chronic pain following intrathecal administration (Bowersox et al. (1996) Journal of Pharmacology and Experimental Therapeutics, 279: 1243-1249; Smith et al. (2002) supra), and are effective analgesics in clinical use, particularly in the treatment of neuropathic pain (Brose et al. (1997) Clinical Journal of Pain, 13: 256-259).
However, Cav2.2 calcium channels are also important for normal neuronal function. Therefore, the aim is to identify novel molecules that preferentially block Cav2.2 under conditions of increased neuronal excitability, so-called use-dependent blockers, as is the case in chronic pain syndromes (Winquist et al. (2005) Biochemical Pharmacology, 70: 489-499).
WO2005/068448 (lonix Pharmaceuticals Limited) describes a series of sulfonamides which are claimed to be useful in the treatment or prevention of a condition mediated by N-type calcium channels, such as pain.
The present invention provides compounds with affinity for Cav2.2 calcium channels and which are capable of interfering with the effects of these channels. In a first aspect there is provided a compound of formula (I), or a salt thereof:
Figure imgf000003_0001
(I) wherein R1 represents benzofuran-2-yl, benzothien-2-yl (benzothiophen-2-yl), 3- trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, A- chlorophenyl, 2-chloro-4-cyanophenyl, 2-chloro-4-trifluoromethylphenyl, 6- trifluoromethylpyridin-3-yl or 3,5-dichlorophenyl; and R2 represents a group of formula (i), (ii) or (iii):
Figure imgf000004_0001
(i) (ii) (iii)
In one embodiment, R1 represents benzofuran-2-yl, benzothien-2-yl (benzothiophen- 2-yl), 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, A- chlorophenyl, 2-chloro-4-cyanophenyl or 2-chloro-4-trifluoromethylphenyl.
In one embodiment, R1 represents 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, A- trifluoromethoxyphenyl, 4-chlorophenyl, 2-chloro-4-trifluoromethylphenyl, 6- trifluoromethylpyridin-3-yl or 3,5-dichlorophenyl.
In one embodiment, R1 represents 4-trifluoromethoxyphenyl.
In one embodiment, R2 represents a group of formula (i) or (iii), particularly a group of formula (i).
In one embodiment, when R2 represents a group of formula (i), R1 represents benzofuran-2-yl, benzothien-2-yl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, A- trifluoromethoxyphenyl, 4-chlorophenyl, 2-chloro-4-cyanophenyl, 2-chloro-4- trifluoromethylphenyl, 6-trifluoromethylpyridin-3-yl or 3,5-dichlorophenyl.
In a further embodiment, when R2 represents a group of formula (i), R1 represents benzofuran-2-yl, benzothien-2-yl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, A- trifluoromethoxyphenyl, 4-chlorophenyl, 2-chloro-4-cyanophenyl or 2-chloro-4- trifluoromethylphenyl.
In a further embodiment, when R2 represents a group of formula (i), R1 represents 3- trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, A- chlorophenyl, 2-chloro-4-trifluoromethylphenyl, 6-trifluoromethylpyridin-3-yl or 3,5- dichlorophenyl.
In one embodiment, when R2 represents a group of formula (ii), R1 represents A- trifluoromethylphenyl. In one embodiment, when R2 represents a group of formula (Ni), R1 represents 4- trifluoromethylphenyl or 4-trifluoromethoxyphenyl, in particular 4- trifluoromethoxyphenyl.
According to a further aspect there is provided a compound of formula (l)a, or a salt thereof:
Figure imgf000005_0001
(i)a
wherein R1 represents benzofuran-2-yl, benzothien-2-yl, 3-trifluoromethylphenyl, 4- trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-chlorophenyl, 2-chloro-4- cyanophenyl or 2-chloro-4-trifluoromethylphenyl.
In one embodiment, a compound of formula (I) or a salt thereof is selected from:
1-(1-{[2-Chloro-4-(trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E1 );
1-((3R)-1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E2);
1-[1-({4-[(Trifluoromethyl)oxy]phenyl}sulfonyl)-3-piperidinyl]-2-pyrrolidinone (E3);
1-(1-{[3-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E4); 1-{(3S)-1-[(4-Chlorophenyl)sulfonyl]-3-piperidinyl}-2-pyrrolidinone (E5);
1-((3S)-1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E6);
1-(1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E7);
1-[(3S)-1-(1-Benzothien-2-ylsulfonyl)-3-piperidinyl]-2-pyrrolidinone (E8);
3-Chloro-4-{[(3S)-3-(2-oxo-1 -pyrrolidinyl)-1 -piperidinyl]sulfonyl}benzonitrile (E9); 1-[(3S)-1-(1-Benzofuran-2-ylsulfonyl)-3-piperidinyl]-2-pyrrolidinone (E10);
1-((3/?)-1-{[6-(Trifluoromethyl)-3-pyridinyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone
(E1 1 );
1-[(3/?)-1-({4-[(Trifluoromethyl)oxy]phenyl}sulfonyl)-3-piperidinyl]-2-pyrrolidinone
(E12); 1-{(3R)-1-[(3,5-Dichlorophenyl)sulfonyl]-3-piperidinyl}-2-pyrrolidinone (E13);
4-(1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-3-morpholinone (E14);
1-(1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-imidazolidinone (E 15); and
1-[1-({4-[(Trifluoromethyl)oxy]phenyl}sulfonyl)-3-piperidinyl]-2-imidazolidinone (E16); or a salt thereof.
In one embodiment, a compound of formula (I) or a salt thereof is selected from: 1-(1-{[2-Chloro-4-(trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E1 ); 1-((3R)-1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E2); 1-[1-({4-[(Trifluoromethyl)oxy]phenyl}sulfonyl)-3-piperidinyl]-2-pyrrolidinone (E3); 1-(1-{[3-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E4); 1-{(3S)-1-[(4-Chlorophenyl)sulfonyl]-3-piperidinyl}-2-pyrrolidinone (E5);
1-((3S)-1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E6); 1-(1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E7); 1-[(3S)-1-(1-Benzothien-2-ylsulfonyl)-3-piperidinyl]-2-pyrrolidinone (E8); 3-Chloro-4-{[(3S)-3-(2-oxo-1 -pyrrolidinyl)-1 -piperidinyl]sulfonyl}benzonitrile (E9); and 1-[(3S)-1-(1-Benzofuran-2-ylsulfonyl)-3-piperidinyl]-2-pyrrolidinone (E10); or a salt thereof.
In a further embodiment, a compound of formula (I) or a salt thereof is selected from:
1-((3R)-1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E2); 1-((3S)-1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E6);
1-(1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E7);
1-[(3/?)-1-({4-[(Trifluoromethyl)oxy]phenyl}sulfonyl)-3-piperidinyl]-2-pyrrolidinone
(E12); and
1-[1-({4-[(Trifluoromethyl)oxy]phenyl}sulfonyl)-3-piperidinyl]-2-imidazolidinone (E16); or a salt thereof.
In a further embodiment, a compound of formula (I) or a salt thereof is selected from: 1-((3R)-1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E2); 1-[(3/?)-1-({4-[(Trifluoromethyl)oxy]phenyl}sulfonyl)-3-piperidinyl]-2-pyrrolidinone (E12); and
1-[1-({4-[(Trifluoromethyl)oxy]phenyl}sulfonyl)-3-piperidinyl]-2-imidazolidinone (E16); or a salt thereof.
In a further embodiment, a compound of formula (I) or a salt thereof is selected from: 1-((3R)-1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E2);
1-((3S)-1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E6); and 1-(1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E7); or a salt thereof.
In a further embodiment, the compound of formula (I) is 1-((3R)-1-{[4-
(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E2), or a salt thereof.
In a further embodiment, the compound of formula (I) is 1-[(3R)-1-({4- [(Trifluoromethyl)oxy]phenyl}sulfonyl)-3-piperidinyl]-2-pyrrolidinone (E12), or a salt thereof.
In a yet further embodiment, the compound of formula (I) is 1-[1-({4- [(Trifluoromethyl)oxy]phenyl}sulfonyl)-3-piperidinyl]-2-imidazolidinone (E16); or a salt thereof, in particular the fast running enantiomer of Example 16 (E16A).
Because of the potential use of compounds of formula (I) in medicine, salts of compounds of formula (I) are preferably pharmaceutically acceptable.
Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse , J. Pharm. ScL, 1977, 66, 1-19. The term "pharmaceutically acceptable salts" includes salts prepared from pharmaceutically acceptable acids, including inorganic and organic acids. Such acids include acetic, p-aminobenzoic, ascorbic, aspartic, benzenesulfonic, benzoic, bismethylenesalicylic, camphorsulfonic, citric, cyclohexylsulfamic, ethanesulfonic, ethanedisulfonic, fumaric, gluconic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, itaconic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, palmitic, pamoic, pantothenic, phosphoric, propionic, salicylic, stearic, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
It will be appreciated that certain compounds of formula (I), or their salts, may exist as solvates, such as hydrates. Where solvates exist, this invention includes within its scope stoichiometric and non-stoichiometric solvates.
It will be appreciated that certain compounds of formula (I), or their salts, may exist in more than one polymorphic form. The invention extends to all such forms whether in a pure polymorphic form or when admixed with any other material, such as another polymorphic form.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof. In particular, there is a chiral centre present within the compounds of formula (I) as shown by the asterisk below:
Figure imgf000007_0001
(I) Therefore, in one embodiment, the compound of formula (I) is a compound of formula
Figure imgf000008_0001
(IA) wherein R1 and R2 are as defined hereinbefore.
In an alternative embodiment, the compound of formula (I) is a compound of formula
Figure imgf000008_0002
(IB) wherein R1 and R2 are as defined hereinbefore.
The subject invention also includes isotopically-labeled compounds, which are identical to those recited in formula (I) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, fluorine, such as 3H, 11C, 14C and 18F. Compounds of the present invention and salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H, 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. 11C and 8F isotopes are particularly useful in PET (positron emission tomography). PET is useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances, lsotopically labeled compounds of formula (I) and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. In one embodiment, the compounds of formula (I) or salts thereof are not isotopically labelled.
Compounds of formula (I) can be prepared as set forth in the following Schemes and in the examples. The following processes form another aspect of the present invention.
The present invention also provides a process for the preparation of a compound of formula (I) or a salt thereof, which process comprises:
(a) reacting a compound of form
Figure imgf000009_0001
(H) or a protected derivative thereof, wherein R2 is as defined for compounds of formula (I), with a compound of formula R1-SO2-L1, wherein R1 is as defined for compounds of formula (I) and L1 represents a suitable leaving group such as a halogen (e.g. chloro); and optionally thereafter
(b) deprotecting a compound of formula (I) or converting groups which are protected; and optionally thereafter
(c) interconversion to other compounds of formula (I).
Process (a) typically comprises reacting the intermediates in a suitable solvent, such as dichloromethane, in the presence of a base, for example triethylamine, at a temperature between O0C and ambient (e.g. O0C). Alternatively the conversion may be carried out using a suitable base as a solvent (for example pyridine).
In process (b), examples of protecting groups and the means for their removal can be found in T. W. Greene 'Protective Groups in Organic Synthesis' (J. Wiley and Sons, 3rd Ed. 1999). Suitable amine protecting groups include sulfonyl (e.g. tosyl), acyl (e.g. acetyl, 2',2',2'-trichloroethoxycarbonyl, benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g. benzyl), which may be removed by hydrolysis (e.g. using an acid such as hydrochloric acid) or reductively (e.g. hydrogenolysis of a benzyl group or reductive removal of a 2',2',2'-trichloroethoxycarbonyl group using zinc in acetic acid) as appropriate. Other suitable amine protecting groups include trifluoroacetyl (- COCF3) which may be removed by base catalysed hydrolysis or a solid phase resin bound benzyl group, such as a Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker), which may be removed by acid catalysed hydrolysis, for example with trifluoroacetic acid.
Process (c) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, nucleophilic or electrophilic aromatic substitution or amide bond formation.
Compounds of formula (II) wherein R2 represents a group of formula (i) may be prepared in accordance with the following Scheme:
Figure imgf000010_0001
Step (MI)
Figure imgf000010_0002
wherein L2 and L3 represent suitable leaving groups such as a halogen atom and P1 represents a suitable protecting group, such as t-butoxycarbonyl.
In step (i) an intermediate of formula (V) is prepared by reacting a compound of formula (III) with acid halide of formula (IV) in a solvent, such as dichloromethane, in the presence of a suitable base, such as triethylamine, at a temperature between O0C and ambient temperature (for example addition of acid halide at O0C).
The transformation of intermediate (V) to a compound of formula (Vl) in step (ii) may be achieved by treatment with a suitable base, for example sodium hydride, in an inert solvent, such as tetrahydrofuran or dimethylformamide, at a temperature between O0C and ambient (for example addition of the base at O0C).
Step (iii) typically comprises a deprotection reaction of intermediate (Vl) to yield a compound of formula (ll)a. When P1 represents t-butoxycarbonyl, such deprotection may be conveniently carried out by treatment with an acid, for example hydrochloric acid or trifluroroacetic acid in a solvent (such as 1 ,4-dioxane or a mixture of methanol and 1 ,4-dioxane).
Compounds of formula (II) wherein R2 represents a group of formula (ii) may be prepared in accordance with the following Scheme:
Figure imgf000011_0001
(II)"
wherein L4 and L5 represent suitable leaving groups such as a halogen atom and P2 represents a suitable protecting group, such as benzyl.
In step (i) an intermediate of formula (VIII) is prepared by reacting a compound of formula (VII) with ethanolamine in a solvent, such as methanol, in the presence of a suitable acid and a reducing agent, such as acetic acid and sodium triacetoxyborohydride. The reaction may be carried out at a temperature between O0C and ambient temperature (for example room temperature).
The transformation of intermediate (VIII) to a compound of formula (IX) in step (ii) may be achieved by treatment with compound of formula (Xl), for example chloroacetylchloride, and a suitable base, for example potassium carbonate, in an inert solvent, such as Λ/,Λ/-dimethylformamide, at a temperature between ambient and 12O0C (for example room temperature then heating to 100°C).
Step (iii) typically comprises a deprotection reaction of intermediate (IX) to yield a compound of formula (ll)b. When P2 represents benzyl, such deprotection may be conveniently carried out by treatment with hydrogen in the presence of a catalyst suitable for hydrogenation, for example 10% palladium on carbon, in a solvent (such as ethanol).
Compounds of formula (II) wherein R2 represents a group of formula (iii) may be prepared in accordance with the following Scheme:
Figure imgf000012_0001
(XIl) (XIII)
O
Step (ii
(XVlIl)
Figure imgf000012_0002
(ll)c
Figure imgf000012_0003
wherein L6 and L7 represent suitable leaving groups such as imidazole and P3 and P4 represents suitable orthogonal protecting groups, such as t-butoxycarbonyl and benzyloxycarbonyl.
In step (i) an intermediate of formula (XIII) is prepared by reacting a compound of formula (XII) with a compound of formula (XVII) in a solvent, such as methanol, in the presence of a suitable acid and a reducing agent, such as acetic acid and sodium triacetoxyborohydride. The reaction may be carried out at a temperature between O0C and ambient temperature (for example room temperature).
Step (ii) typically comprises a deprotection reaction of intermediate (XIII) to yield a compound of formula (XIV). When P4 represents t-butoxycarbonyl, such deprotection may be conveniently carried out by treatment with an acid, for example hydrochloric acid or trifluroroacetic acid in a solvent (such as 1 ,4-dioxane or a mixture of methanol and 1 ,4-dioxane).
The transformation of intermediate (XIV) to a compound of formula (XV) in step (iii) may be achieved by treatment with compound of formula (XVIII), for example carbonyldiimidazole, in an inert solvent, such as Λ/,Λ/-dimethylformamide, at a temperature between 0° and ambient (for example addition of reagents at O0C then warming to room temperature).
Step (iv) typically comprises a deprotection reaction of intermediate (XV) to yield a compound of formula (ll)c. When P3 represents benzyloxycarbonyl, such deprotection may be conveniently carried out by treatment with hydrogen in the presence of a catalyst suitable for hydrogenation, for example 10% palladium on carbon, in a solvent (such as ethanol). Compounds of formula (III), (IV), (VII), (Xl), (XII), (XVII) and (XVIII) are either commercially available, or may be prepared by known methods. A further process of the invention is the preparation of salts of compounds of formula (I), particularly pharmaceutically acceptable salts.
Compounds with affinity for Cav2.2 calcium channels may be useful in the treatment of pain, including acute pain, chronic pain, chronic articular pain, musculoskeletal pain, neuropathic pain, inflammatory pain, visceral pain, pain associated with cancer, pain associated with migraine, tension headache and cluster headaches, pain associated with functional bowel disorders, lower back and neck pain, pain associated with sprains and strains, sympathetically maintained pain; myositis, pain associated with influenza or other viral infections such as the common cold, pain associated with rheumatic fever, pain associated with myocardial ischemia, post operative pain, cancer chemotherapy, headache, toothache and dysmenorrhea.
'Chronic articular pain' conditions include rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis.
'Pain associated with functional bowel disorders' includes non-ulcer dyspepsia, non- cardiac chest pain and irritable bowel syndrome.
'Neuropathic pain' syndromes include: diabetic neuropathy, sciatica, non-specific lower back pain, trigeminal neuralgia, multiple sclerosis pain, fibromyalgia, HIV- related neuropathy, post-herpetic neuralgia, trigeminal neuralgia, and pain resulting from physical trauma, amputation, phantom limb syndrome, spinal surgery, cancer, toxins or chronic inflammatory conditions. In addition, neuropathic pain conditions include pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch
(hyperesthesia), painful sensation following innocuous stimulation (dynamic, static, thermal or cold allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).
Other conditions which could potentially be treated by compounds of the present invention include neurodegenerative diseases and neurodegeneration, neurodegeneration following trauma, tinnitus, dependence on a dependence- inducing agent such as opiods (e.g. morphine), CNS depressants (e.g. ethanol), psychostimulants (e.g. cocaine) and nicotine;
Neurodegenerative diseases include dementia, particularly degenerative dementia (including senile dementia, dementia with Lewy bodies, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease and Creutzfeldt-Jakob disease, ALS, motor neuron disease); vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection, meningitis and shingles); metabolism; toxins; anoxia and vitamin deficiency; and mild cognitive impairment associated with ageing, particularly Age Associated Memory Impairment.
The compounds of formula (I) may also be useful for neuroprotection and in the treatment of neurodegeneration following trauma such as stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like.
Thus according to one aspect of the invention there is provided a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for use in therapy.
According to another aspect of the invention there is provided a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of any of the disorders herein, in particular pain.
According to a further aspect of the invention there is provided a use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of any of the disorders herein, in particular pain.
According to a further aspect of the invention there is provided a method of treatment of any of the disorders herein, in particular pain in mammals, which method comprises the administration to the mammal in need of such treatment, an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof.
The term "treatment" or "treating" as used herein includes the treatment of established disorders and also includes the prophylaxis thereof. The term "prophylaxis" is used herein to mean preventing symptoms in an already afflicted subject or preventing recurrence of symptoms in an afflicted subject and is not limited to complete prevention of an affliction.
It is to be understood that reference to treatment includes both treatment of established symptoms and prophylactic treatment, unless explicitly stated otherwise.
In order to use a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Therefore in another aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, adapted for use in human or veterinary medicine.
In order to use the compounds of formula (I) in therapy, they will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice. The present invention also provides a pharmaceutical composition, which comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.
A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusable solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colourants.
For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound. The composition may contain from 0.1% to 99% by weight, preferably from 10% to 60% by weight, of the active material, depending on the method of administration. The dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks, months, years or even life.
A further aspect to the invention is a pharmaceutical composition comprising 0.05 to
IOOOmg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and 0 to 3 g more suitably 0 to 2g of at least one pharmaceutically acceptable carrier.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
Examples
The following Intermediates and Examples illustrate the preparation of compounds of the invention.
Intermediate 1 1,1-Dimethylethyl 3-[(4-bromobutanoyl)amino]-1 -piperidinecarboxylate (D1)
Figure imgf000016_0001
To a solution of 3-amino-1-Λ/-BOC-piperidine (1.5g, 7.49mmol) in dichloromethane (6OmL), cooled to O0C under argon, was added triethylamine (9.74mmol, 1.36ml_) followed by the dropwise addition of 4-bromobutyryl chloride (8.99mmol, 1.04ml_). The reaction was allowed to warm in temperature to 22 0C and stirred for 4 days and 5 hours. The reaction was diluted with dichloromethane (10OmL) and the solution washed with 1 N hydrochloric acid (10OmL), water (5OmL) and saturated sodium bicarbonate solution (5OmL). The organic layer was passed though a hydrophobic frit and reduced in vacuo to yield a colourless oil.
The compound was purified by silica chromatography (Biotage SP4, eluting with 20% EtOAc in hexane (5 column volumes), 20-50% (over 10 column volumes)) to yield the title compound as a white solid (1.5Og, 57%)
1H NMR (DMSO) δ 1.34 (1 H, m), 1.38 (9H, s), 1.67 (1 H, m), 1.76 (1 H, m), 1.93 (2H, m), 2.22 (2H, m), 2.89 (2H, br s), 3.54 (2H, br s), 3.63 (2H, t, J=7Hz), 3.74 (2H, br s), 7.83 (1 H, d, J=7Hz)
Intermediate 2
1,1-Dimethylethyl 3-(2-oxo-1 -pyrrolidinyl)-1 -piperidinecarboxylate (D2)
Figure imgf000017_0001
A solution of 1 ,1-dimethylethyl 3-[(4-bromobutanoyl)amino]-1-piperidinecarboxylate (D1 ) (0.5g, 1.432 mmol) in anhydrous tetrahydrofuran (THF) (2OmL) was cooled to O0C under argon before the portion wise addition of sodium hydride (0.063 g, 1.575 mmol). The reaction was gradually allowed to rise to room temperature and stirred under argon for 18 hours. The reaction was diluted with water (25mL) then extracted with ethyl acetate (2 x 5OmL). The organic extracts were combined, passed through a hydrophobic frit and reduced in vacuo.
The crude product was purified by silica chromatography (Biotage SP4, eluting 25% EtOAc in iso-hexane (3 column volumes) then a gradient from 25-80% (over 25 column volumes)) to yield the title compound as a colourless gum (0.312g)
1H NMR (CDCI3) δ 1.45 (9H, s), 1.58 (2H, m), 1.72 (1 H, m), 1.83 (1 H, m), 2.02 (2H, m), 2.39 (2H, td, J= 8, 2Hz), 2.66 (1 H, br s), 2.81 (1 H, dd, J= 13, 11 Hz), 3.38 (2H, m), 3.99 (3H, m)
Intermediate 3
1-(3-Piperidinyl)-2-pyrrolidinone hydrochloride (D3)
Figure imgf000017_0002
A solution of 1 ,1-dimethylethyl 3-(2-oxo-1-pyrrolidinyl)-1-piperidinecarboxylate (D2) (0.312 g, 1.163 mmol) in 4 molar hydrochloric acid in 1 ,4-dioxane (3OmL, 120 mmol) was stirred at room temperature for 18 hours. The reaction was reduced in vacuo and the residue was triturated with diethyl ether (1OmL) to yield the title compound as a white solid (0.234g, 98%, appears hygroscopic).
1H NMR (d6-DMSO) δ 1.70 (3H, m), 1.89 (3H, m), 2.22 (2H, m), 2.74 (1 H, m), 2.92 (1 H, m), 3.04 (1 H, m), 3.16 (1 H, m), 3.30 (2H, t, J= 7Hz), 4.10 (1 H, m), 9.14 (1 H, m), 9.56 (1 H, m).
Intermediate 4
1,1-Dimethylethyl (3R)-3-(2-oxo-1-pyrrolidinyl)-1 -piperidinecarboxylate (D4)
Figure imgf000018_0001
A solution of 1 ,1-dimethylethyl (3R)-3-amino-1-piperidinecarboxylate (3g, 14.98 mmol) in dichloromethane (DCM) (80 ml) was cooled in an ice-water bath before the addition of triethylamine (2.297 ml, 16.48 mmol) then dropwise 4-bromobutanoyl chloride (1.823 ml, 15.73 mmol). The reaction was gradually allowed to warm to room temperature and stirred for 18 hours.
The reaction was diluted with dichloromethane (10OmL) and the solution washed with 1 N hydrochloric acid (100ml), water (50ml), saturated sodium bicarbonate solution (10OmL), passed through a hydrophobic frit and reduced in vacuo to yield a yellow oil.
The oil was dissolved in anhydrous tetrahydrofuran (THF) (180 ml) and cooled under argon in an ice-water bath before the portion wise addition of sodium hydride (0.243 g, 6.08 mmol). The reaction was allowed to warm to room temperature and stirred for 4 hours. TLC (eluent 50% EtOAc in iso-hexane, visualisation KMnO4) indicated the reaction had gone to completion. The reaction was reduced in vacuo and the residue partitioned between EtOAc (40OmL) and water (20OmL). The aqueous layer was separated and extracted with ethyl acetate (200ml). The organic layers were combined, passed through a hydrophobic frit and reduced in vacuo. The crude product was purified by silica chromatography (Biotage SP4, eluting 75% EtOAc in iso-hexane (4 column volumes), 75-100% EtOAc in iso-hexane (over 3 column volumes) then EtOAc (8 column volumes)) to yield the title compound as a colourless oil (0.943g, 64% )
1H NMR (CDCI3) δ 1.45 (9H, s), 1.58 (2H, m), 1.72 (1 H, br s), 1.83 (1 H, m), 2.01 (2H, m), 2.39 (2H, td, J= 8, 2Hz), 2.66 (1 H, br s), 2.81 (1 H, dd, J= 13, 11 Hz), 3.38 (2H, m), 3.99 (3H, m)
Intermediate 5
1-[(3R)-3-Piperidinyl]-2-pyrrolidinone hydrochloride (D5)
Figure imgf000019_0001
To a solution of 1 ,1-dimethylethyl (3R)-3-(2-oxo-1-pyrrolidinyl)-1- piperidinecarboxylate (940mg, 3.50 mmol) in methanol (5ml_) was added 4M hydrochloric acid in 1 ,4-dioxane (8.76 ml_, 35.0 mmol). The reaction was stirred at room temperature for 6 hours. The reaction was reduced in vacuo to yield the title compound as a white sticky solid (1.02g, >100%, appears hygroscopic)
1H NMR (d6-DMSO) δ 1.70 (3H, m), 1.89 (3H, m), 2.23 (2H, m), 2.73 (1 H, m), 2.94 (1 H, m), 3.04 (1 H, m), 3.17 (1 H, m), 3.31 (2H, t, J= 7Hz), 4.09 (1 H, m), 9.10 (1 H, m), 9.52 (1 H, m).
Intermediate 6
1,1-Dimethylethyl (3S)-3-(2-oxo-1 -pyrrolidinyl)-1-piperidinecarboxylate (D6)
Figure imgf000019_0002
A solution of 1 ,1-dimethylethyl (3S)-3-amino-1-piperidinecarboxylate (3g, 14.98 mmol) in dichloromethane (DCM) (80 ml) was cooled in an ice-water bath before the addition of triethylamine (2.297 ml, 16.48 mmol) then dropwise 4-bromobutanoyl chloride (1.823 ml, 15.73 mmol). The reaction was gradually allowed to warm to room temperature and stirred for 18 hours. The reaction was diluted with dichloromethane (10OmL) and the solution washed with 1 N hydrochloric acid (100ml), water (50ml), saturated sodium bicarbonate solution (100ml), passed through a hydrophobic frit and reduced in vacuo to yield a yellow oil.
The oil was dissolved in anhydrous tetrahydrofuran (THF) (180 ml) and cooled under argon in an ice-water bath before the portionwise addition of sodium hydride (0.587 g, 14.68 mmol). The reaction was allowed to warm to room temperature and stirred for 4 hours. TLC (eluent 50% EtOAc in iso-hexane, visualisation KMnO4 solution) indicated the reaction had gone to completion. The reaction was reduced in vacuo and the residue partitioned between EtOAc (40OmL) and water (20OmL). The aqueous layer was separated and extracted with ethyl acetate (200ml). The organic layers were combined, passed through a hydrophobic frit and reduced in vacuo. The crude product was purified by silica chromatography (Biotage SP4, eluting 50% EtOAc in iso-hexane (3 column volumes), 50-100% EtOAc in iso-hexane (over 10 column volumes) then EtOAc (6 column volumes)) to yield the title compound as a colourless oil (2.97g, 74%)
1H NMR (CDCI3) δ 1.45 (9H, s), 1.58 (2H, m), 1.72 (1 H, br s), 1.83 (1 H, m), 2.02 (2H, m), 2.39 (2H, td, J= 8, 2Hz), 2.66 (1 H, br s), 2.81 (1 H, dd, J= 13, 11 Hz), 3.38 (2H, m), 3.99 (3H, m)
Intermediate 7
1-[(3S)-3-Piperidinyl]-2-pyrrolidinone hydrochloride (D7)
Figure imgf000020_0001
A solution of 1 ,1-dimethylethyl (3S)-3-(2-oxo-1-pyrrolidinyl)-1-piperidinecarboxylate (2.97g, 1 1.07 mmol) in 4 molar hydrochloric acid in 1 ,4-dioxane (100ml, 400 mmol) was stirred at room temperature for 18 hours. TLC indicated the reaction to have gone to completion and was therefore reduced in vacuo to yield the title compound as a white solid (2.52g, yield > 100%, appears hygroscopic).
1H NMR (d6-DMSO) δ 1.70 (3H, m), 1.89 (3H, m), 2.21 (2H, m), 2.74 (1 H, m), 2.94 (1 H, m), 3.05 (1 H, m), 3.17 (1 H, m), 3.31 (2H, t, J= 7Hz), 4.10 (1 H, m), 9.10 (1 H, br s), 9.52 (1 h, br s).
Intermediate 8
2-{[1 -(Phenylmethyl)-3-piperidinyl]amino}ethanol (D8)
Figure imgf000021_0001
1-(Phenylmethyl)-3-piperidinone (10 g, 44.3 mmol) was dissolved in methanol (80 ml). Then ethanolamine (10.7 ml, 177 mmol) was added followed by sodium triacetoxyborohydride (30.7 g, 145 mmol) and acetic acid (2.54 ml, 44.3 mmol). The reaction was stirred at room temperature for 17 hours. At this point 2M HCI was added and the reaction was stirred for 30 minutes. The mixture was concentrated in vacuo then dissolved in H2O (200 ml) before the addition of sodium hydroxide until a basic pH was achieved. The product was extracted with DCM (7 x 100 ml) and concentrated in vacuo to yield the title compound (9.2g, 89%).
1H NMR (400 MHz, MeOD) δ ppm 1.2 (m, 1 H) 1.6 (m, 1 H) 1.7 (m, 1 H) 1.9 (m, 2 H) 2.1 (m, 1 H) 2.7 (m, 4 H) 2.9 (m, 1 H) 3.5 (d, J=1.8 Hz, 2 H) 3.6 (t, J=5.6 Hz, 2 H) 7.3 (m, 1 H) 7.3 (m, 4 H)
Intermediate 9 (D9)
Figure imgf000021_0002
A solution of 2-{[1-(phenylmethyl)-3-piperidinyl]amino}ethanol (D8) (9.23 g, 39.4 mmol) in ethanol (77 ml) and water (35 ml) was cooled to 0 0C and chloroacetyl chloride (7.89 ml, 99 mmol) and NaOH were added. After stirring for 48 hours chloroacetyl chloride (7.89 ml, 99 mmol) was added. After stirring for a further 24 hours, the reaction mixture was concentrated in vacuo, dissolved in H2O (300 ml) and 2M NaOH was added until pH 14 was reached. The mixture was extracted with DCM (4 x 150 ml) and concentrated in vacuo.
The mixture was dissolved in dichloromethane (DCM) (60 ml). Triethylamine (8.79 ml, 63.0 mmol) was added followed by chloroacetyl chloride (2.78 ml, 34.7 mmol). The mixture was stirred for 5 days and 17 hours. The mixture was then washed with 1 M NaOH. The organic phase was separated and the aqueous extracted with DCM (3 x 80 ml). The organics were combined, passed through a hydrophobic frit and concentrated in vacuo. The residue was dissolved in Λ/,Λ/-Dimethylformamide (70.0 ml) and potassium carbonate (6.53 g, 47.3 mmol) was added. After stirring at room temperature for 5 days, the mixture was heated to 100 0C and stirred for 6 h before concentrating in vacuo. The resulting residue was dissolved in H2O (150 ml), extracted with DCM (100 ml x 6), the organic layer was passed through a hydrophobic frit and concentrated in vacuo. Purification was carried out by silica column chromatography (Biotage SP4, gradient elution: 0-40% MeOH in DCM) to give the title compound as a brown oil (4.11 g, 46% yield).
1H NMR (400 MHz, MeOD) δ ppm 1.7 (m, 4 H) 1.9 (m, 1 H) 2.1 (t, J=10.9 Hz, 1 H) 2.8 (m, 2 H) 3.3 (m, integration obscured by solvent, assume 1 H) 3.4 (m, 1 H) 3.5 (d, J=12.9 Hz, 1 H) 3.6 (d, J=12.9 Hz, 1 H) 3.8 (m, 2 H) 4.1 (s, 2 H) 4.5 (m, 1 H) 7.2 (m, 1 H) 7.3 (m, 4 H)
MS ES+ve m/z 275 (M+H)
Intermediate 10 4-(3-Piperidinyl)-3-morpholinone (D10)
Figure imgf000022_0001
4-[1-(Phenylmethyl)-3-piperidinyl]-3-morpholinone (D9) (4.1 1 g, 14.98 mmol) was dissolved in ethanol (300 ml). Palladium on carbon (500 mg, 4.70 mmol) was added and the mixture was stirred under a hydrogen atmosphere for 5 days. The catalyst was filtered off and the solution concentrated in vacuo. It was then redissolved in methanol and passed through a 50 g SCX ion exchange column eluting with MeOH/NH3 to give the title compound as a yellow oil (2,58g, 93%).
1H NMR (400 MHz, MeOD) δ ppm 1.6 (m, 1 H) 1.8 (m, 3 H) 2.4 (td, J=12.6, 2.4 Hz, 1 H) 2.7 (dd, J=11.6 Hz, 1 H) 2.9 (m, 2 H) 3.3 (m, 2 H) 3.4 (m, 1 H) 3.8 (m, 2 H) 4.1 (s, 2 H) 4.3 (m, 1 H)
Intermediate 11
Phenylmethyl 3-{[2-({[(1 ,1-dimethylethyl)oxy]carbonyl}amino)ethyl]amino}-1 - piperidinecarboxylate (D11)
Figure imgf000023_0001
Phenylmethyl 3-oxo-i-piperidinecarboxylate (5 g, 21.44 mmol) was dissolved in a mixture of methanol (200 ml) and acetic acid (1.227 ml, 21.44 mmol). 1 ,1- dimethylethyl (2-aminoethyl)carbamate (10.30 g, 64.3 mmol) was added and sodium triacetoxyborohydride (11.36 g, 53.6 mmol) was also added after stirring for 1 hour. The reaction mixture was allowed to stir for a further 4 hours. Sodium bicarbonate (9.00 g, 107 mmol) was added to the reaction and the resulting mixture was concentrated in vacuo. The resulting residue was redissolved using DCM and water. The mixture was basified to pH 14 using 2M NaOH and the aqueous layer was extracted with DCM. The combined organic extracts was passed through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by silica column chromatography (Biotage SP4, eluting with a gradient from 0-20% MeOH in DCM) to give the title compound as a yellow oil (7.85 g, 20.80 mmol, 97 % yield).
MS ES+ve m/z 275 (M+H)
1H NMR (400 MHz, DMSO-D6) δ ppm 1.2 (m, 1 H) 1.4 (m, 1 H) 1.4 (s, 9 H) 1.6 (m, 2 H) 1.8 (m, 1 H) 2.4 (m, 1 H) 2.6 (m, 2 H) 2.7 (m, 1 H) 2.9 (m, 3 H) 3.7 (m, 1 H) 3.8 (m, 1 H) 5.1 (s, 2 H) 6.7 (m, 1 H) 7.3 (m, 5 H)
Intermediate 12
Phenylmethyl 3-[(2-aminoethyl)amino]-1 -piperidinecarboxylate dihydrochloride
Figure imgf000023_0002
To a solution of phenylmethyl 3-{[2-({[(1 ,1- dimethylethyl)oxy]carbonyl}amino)ethyl]amino}-1-piperidinecarboxylate (D11 ) (1g, 2.65 mmol) in methanol (2 ml) was added 4M HCI in 1 ,4-dioxane (6.62 ml, 26.5 mmol). The reaction was stirred at room temperature for 6 hours. The reaction was concentrated in vacuo to yield the title compound as a colourless gum (0.94g, 100%)
MS ES+ve m/z 278 (M+H)
Intermediate 13 Phenylmethyl 3-(2-oxo-1-imidazolidinyl)-1 -piperidinecarboxylate (D13)
Figure imgf000024_0001
A solution of phenylmethyl 3-[(2-aminoethyl)amino]-1-piperidinecarboxylate dihydrochloride (D12) (0.735 g, 2.65mmol) and triethylamine (0.813 ml, 5.83 mmol) in Λ/,Λ/-Dimethylformamide (20 ml) was cooled in an ice-water bath before the portionwise addition of CDI (0.430 g, 2.65 mmol). The reaction was allowed to warm to room temperature and stirred for 17 hours.
The reaction was concentrated in vacuo and the residue partitioned between EtOAc (10OmL) and 1 N HCI (5OmL). The organic layer was separated, passed though a hydrophobic frit and concentrated in vacuo to yield the title compound as a colourless gum (0.479g, 60%)
1H NMR (400 MHz, Chloroform-D) δ ppm 1.6 (m, 2 H) 1.7 (m, 2 H) 1.8 (m, 1 H) 1.9 (m, 1 H) 2.7 (m, 1 H) 2.9 (m, 1 H) 3.4 (m, 2 H) 3.5 (m, 1 H) 3.8 (m, 1 H) 4.1 (m, 1 H) 4.6 (s, 1 H) 5.1 (m, 2 H) 7.3 (m, 5 H)
Intermediate 14 1-(3-Piperidinyl)-2-imidazolidinone (D14)
Figure imgf000024_0002
To a solution of phenylmethyl 3-(2-oxo-1-imidazolidinyl)-1-piperidinecarboxylate (D13) (0.479 g, 1.579 mmol) in ethanol (15 ml) was added 10% Pd/C (0.168 g, 0.158 mmol) and the reaction placed under a hydrogen atmosphere. The reaction was stirred at room temperature for 72 hours. The reaction was filtered and concentrated in vacuo to yield the title compound as a yellow gum (0.244g, 91%).
1H NMR (400 MHz, Chloroform-D) δ ppm 1.6 (m, 2 H) 1.8 (m, 2 H) 2.5 (m, 1 H) 2.6 (m, 1 H) 3.0 (m, 3 H) 3.4 (m, 3 H) 3.7 (m, 1 H) 5.6 (s, 1 H).
Example 1
1-(1-{[2-Chloro-4-(trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2- pyrrolidinone (E1)
Figure imgf000025_0001
To a solution of 1-(3-piperidinyl)-2-pyrrolidinone hydrochloride (D3) (100mg, 0.489 mmol) and triethylamine (0.143 ml, 1.026 mmol) in dichloromethane (DCM) (3ml) was added 2-chloro-4-(trifluoromethyl)benzenesulfonyl chloride (150 mg, 0.537 mmol). The reaction was shaken at room temperature for 18 hours. To the reaction was added DCM (3ml_) and water (3ml). The organic layer was collected via a hydrophobic frit and the solvent removed under a stream of argon.
The residue was purified by silica chromatography (Biotage SP4, eluting with 60% EtOAc in iso-hexane (3 column volumes), a gradient from 60-100% EtOAc in iso- hexane (4 column volumes) and EtOAc (8 column volumes)) to yield the title compound as a white solid (108mg, 54%)
1H NMR (CDCI3) δ 1.55-1.91 (4H, m), 2.01 (2H, m), 2.37 (2H, m), 2.83 (1 H, m), 2.98 (1 H, dd, J=12,11 Hz), 3.38 (2H, m), 3.76 (2H, m), 4.00 (1 H, m), 7.65 (1 H, m), 7.79 (1 H, d, J= 1 Hz), 8.20 (1 H, d, J =9Hz)
MS ES+ve m/z 41 1 , 413 (M+H)
Example 2 1-((3R)-1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E2)
Figure imgf000026_0001
To a solution of 1-[(3R)-3-piperidinyl]-2-pyrrolidinone hydrochloride (D5) (150mg, 0.733 mmol) in dichloromethane (DCM) (3 ml) was added triethylamine (0.225 ml, 1.612 mmol) and 4-(trifluoromethyl)benzenesulfonyl chloride (197 mg, 0.806 mmol). The reaction was stirred at room temperature for 18 hours. To the reaction was added DCM (2ml) and water (2ml_) and then the organic layer collected via a hydrophobic frit and reduced in vacuo. The residue was purified by silica chromatography (Biotage SP4, eluting 60% EtOAc in iso-hexane (3 column volumes), 60 -100% (over 10 column volumes) and 100% 3 column volumes)) to yield the title compound as a white solid (95mg, 34%)
1H NMR (CDCI3) δ 1.52-1.87 (4H, m), 2.02 (2H, m), 2.38 (2H, m), 2.48 (1 H, td, J = 11 , 3Hz), 2.62 (1 H, dd, J =11 , 10Hz), 3.37 (2H, m), 3.65 (2H, m), 4.01 (1 H, m), 7.81 (2H, d, J = 8Hz), 7.91 (2H, d, J = 8Hz)
MS ES+ve m/z 377 (M+H)
Example 3
1-[1-({4-[(Trifluoromethyl)oxy]phenyl}sulfonyl)-3-piperidinyl]-2-pyrrolidinone (E3)
Figure imgf000027_0001
To a solution of 1-(3-piperidinyl)-2-pyrrolidinone hydrochloride (D3) (100mg, 0.489 mmol) and triethylamine (0.143 ml, 1.026 mmol) in dichloromethane (DCM) (3ml) was added 4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (140 mg, 0.537 mmol). The reaction was shaken at room temperature for 18 hours. To the reaction was added DCM (3ml_) and water (3ml). The organic layer was collected via a hydrophobic frit and the solvent removed under a stream of argon.
The residue was purified by silica chromatography (Biotage SP4, eluting with 60% EtOAc in iso-hexane (3 column volumes), a gradient from 60-100% EtOAc in iso- hexane (4 column volumes) and EtOAc (8 column volumes)) to yield title compound as a white solid (142mg, 74%)
1H NMR (CDCI3) δ 1.50-1.88 (4H, m), 2.02 (2H, m), 2.38 (2H, m), 2.48 (1 H, m), 2.64 (1 H, dd, J=11 ,10Hz), 3.38 (2H, m), 3.61 (2H, m), 4.01 (1 H, m), 7.37 (2H, m), 7.83 (2H, m)
MS ES+ve m/z 393 (M+H)
Example 4
1 -(1 -{[3-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E4)
Figure imgf000028_0001
To a solution of 1-(3-piperidinyl)-2-pyrrolidinone hydrochloride (D3) (100mg, 0.489 mmol) and triethylamine (0.143 ml, 1.026 mmol) in dichloromethane (DCM) (3ml) was added 3-(trifluoromethyl)benzenesulfonyl chloride (0.086 ml, 0.537 mmol). The reaction was shaken at room temperature for 18 hours. To the reaction was added DCM (3ml_) and water (3ml). The organic layer was collected via a hydrophobic frit and the solvent removed under a stream of argon.
The residue was purified by silica chromatography (Biotage SP4, eluting with 60% EtOAc in iso-hexane (3 column volumes), a gradient from 60-100% EtOAc in iso- hexane (4 column volumes) and EtOAc (8 column volumes)) to yield the title compound as a white solid (117mg, 64%)
1H NMR (CDCI3) δ 1.54-1.89 (4H, m), 2.02 (2H, m), 2.38 (2H, m), 2.49 (1 H, m), 2.63 (1 H, dd, J=11 ,10Hz), 3.37 (2H, m), 3.63 (2H, m), 4.01 (1 H, m), 7.37 (2H, t, J=8Hz), 7.87 (2H, d, J=8Hz), 7.97 (2H, d, J= 8Hz), 8.03 (1 H, s)
MS ES+ve m/z 377 (M+H)
Example 5
1 -{(3S)-1 -[(4-Chlorophenyl)sulfonyl]-3-piperidinyl}-2-pyrrolidinone (E5)
Figure imgf000028_0002
To a solution of 1-[(3S)-3-piperidinyl]-2-pyrrolidinone hydrochloride (D7) (150 mg, 0.733 mmol) in Dichloromethane (DCM) (3 ml) was added triethylamine (0.214 ml, 1.539 mmol) and 4-chlorobenzenesulfonyl chloride (170 mg, 0.806 mmol). The reaction was shaken at room temperature for 18 hours. To the reaction was added DCM (2ml) and water (2ml_) and then the organic layer collected via a hydrophobic frit and reduced in vacuo. The residue was purified by silica chromatography (Biotage SP4, eluting 60% EtOAc in iso-hexane (3 column volumes), 60 -100% (over 10 column volumes) and 100% 3 column volumes)) to yield the title compound as a white solid (0.161g, 64%)
1H NMR (CDCI3) δ 1.51-1.85 (4H, m), 2.01 (2H, m), 2.37 (2H, m), 2.46 (1 H, td, J= 11 , 3Hz), 2.60 (1 H, d, J= 11 , 10Hz), 3.37 (2H, m), 3.59 (2H, m), 4.0 (1 H, m), 7.52 (2H, m), 7.71 (2H,m)
MS ES+ve m/z 343, 345 (M+H)
Example 6 1-((3S)-1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone
Figure imgf000029_0001
To a solution of 1-[(3S)-3-piperidinyl]-2-pyrrolidinone hydrochloride (D7) (150mg, 0.733 mmol) in pyridine (2 ml) was added 4-(trifluoromethyl)benzenesulfonyl chloride (197 mg, 0.806 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was reduced in vacuo and the residue partitioned between water (5ml_) and DCM (1OmL). The organic layer was collected via a hydrophobic frit and reduced in vacuo. The residue was purified by silica chromatography (Biotage SP4, eluting 60-100% EtOAc over 12 column volumes) to yield the title compound as a white solid (0.110g, 40%) 1H NMR (CDCI3) δ 1.51-1.88 (4H, m), 2.02 (2H, m), 2.38 (2H, m), 2.48 (1 H, m), 2.62 (1 H, dd, J=11 ,10Hz), 3.37 (2H, m), 3.65 (2H, m), 4.01 (1 H, m), 7.81 (2H, d, J=8Hz), 7.91 (2H, d, J=8Hz) MS ES+ve m/z 377 (M+H)
Example 7
1 -(1 -{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E7)
Figure imgf000030_0001
To a solution of 1-(3-piperidinyl)-2-pyrrolidinone hydrochloride (0.212 g, 1.036 mmol) (D3) in pyridine (4 ml) was added 4-(trifluoromethyl)benzenesulfonyl chloride (0.279 g, 1.139 mmol). The reaction was stirred at room temperature for 3 hours. The reaction was reduced in vacuo and the residue purified by silica chromatography (Biotage silica cartridge, eluting with a gradient from 0-25% ethyl acetate in iso- hexane (over 7 column volumes) then a gradient from 25-100% (3 column volumes) and ethyl acetate (5 column volumes)). Fractions containing the major product were combined and the solvent removed to yield a white solid which was dried under vacuum to yield the title compound (0.195g, 50%)
1H NMR (CDCI3) δ 1.52-1.88 (4H, m), 2.02 (2H, m), 2.38 (2H, m), 2.48 (1 H, m), 2.63 (1 H, m), 3.37 (2H, m), 3.65 (2H, m), 4.01 (1 H, m), 7.81 (2H, d, J=8Hz), 7.91 (2H, d, J=8Hz)
MS ES+ve m/z 377 (M+H)
Example 8
1 -[(3S)-1 -(1 -Benzothien-2-ylsulfonyl)-3-piperidinyl]-2-pyrrolidinone (E8)
Figure imgf000031_0001
To a solution of 1-[(3S)-3-piperidinyl]-2-pyrrolidinone hydrochloride (D7) (100mg, 0.489 mmol) and triethylamine (0.143 ml, 1.026 mmol) in dichloromethane (DCM) (3 ml) was added 1-benzothiophene-2-sulfonyl chloride (1.1 eq., 0.537mmol, 125mg). The reaction was shaken at room temperature for 18 hours. To the reaction was added water (1.5ml_). The organic layer was collected via a hydrophobic frit and reduced under a stream of argon.
The product was purified by silica chromatography (Biotage SP4, eluting 60% EtOAc in iso-hexanes (5 column volumes), a gradient from 60-100% EtOAc in iso-hexanes
(over 2 column volumes) then EtOAc (8 column volumes). Fractions containing the desired product were combined and the solvent removed to yield the title compound as a white solid (99mg, 56%)
1H NMR (CDCI3) δ 1.47-1.92 (4H, m), 2.01 (2H, m), 2.38 (2H, m), 2.61 (1 H, td, J= 11 , 3Hz), 2.74 (1 H, dd, J= 11 ,10Hz), 3.39 (2H, m), 3.69 (2H, m), 4.11 (1 H, m), 7.50
(2H, m), 7.81 (1 H, s), 7.90 (2H, m)
MS ES+ve m/z 365 (M+H)
Example 9
3-Chloro-4-{[(3S)-3-(2-oxo-1 -pyrrolidinyl)-1 -piperidinyl]sulfonyl}benzonitrile (E9)
Figure imgf000031_0002
To a solution of 1-[(3S)-3-piperidinyl]-2-pyrrolidinone hydrochloride (D7) (150 mg, 0.733 mmol) in dichloromethane (DCM) (3 ml) was added triethylamine (0.214 ml, 1.539 mmol) and 2-chloro-4-cyanobenzenesulfonyl chloride (232 mg, 0.981 mmol) . The reaction was shaken at room temperature for 18 hours. To the reaction was added DCM (2ml) and water (2ml_) and then the organic layer was collected via a hydrophobic frit and reduced in vacuo. The residue was purified by silica chromatography (Biotage SP4, eluting 60% EtOAc in iso-hexane (3 column volumes), 60 -100% (over 6 column volumes) and 100% 5 column volumes)) to yield the title compound as a white solid (0.165g, 50%)
1H NMR (CDCI3) δ 1.59-1.74 (2H, m), 1.85 (2H, m), 2.02 (2H, m), 2.36 (2H, t, J= 8.1 Hz), 2.83 (1 H, m), 2.97 (1 H, dd, J=12,11 Hz), 3.37 (2H, m), 3.76 (2H, m), 3.96 (1 H, m), 7.69 (1 H, dd, J=8, 2Hz), 7.82 (1 H, d, J=2Hz), 8.19 (1 H, d, J=8Hz)
MS ES+ve m/z 368, 370 (M+H)
Example 10
1 -[(3S)-1 -(1 -Benzofuran-2-ylsulfonyl)-3-piperidinyl]-2-pyrrolidinone (E10)
Figure imgf000032_0001
To a solution of 1-[(3S)-3-piperidinyl]-2-pyrrolidinone hydrochloride (D7) (100mg, 0.489 mmol) and triethylamine (0.143 ml, 1.026 mmol) in dichloromethane (DCM) (3 ml) was added 1-benzofuran-2-sulfonyl chloride (1.1 eq., 0.537mmol). The reaction was shaken at room temperature for 18 hours. To the reaction was added water (1.5ml_). The organic layer was collected via a hydrophobic frit and reduced under a stream of argon. The crude product was purified by silica chromatography (Biotage SP4, eluting 60% EtOAc in iso-hexanes (5 column volumes), a gradient from 60- 100% EtOAc in iso-hexanes (over 2 column volumes) then EtOAc (8 column volumes). Fractions containing the desired product were combined and the solvent removed to yield the title compound as a white solid (1 15mg, 68%) 1H NMR (CDCI3) δ 1.52-1.90 (4H, m), 2.01 (2H,m), 2.38 (2H, m), 2.76 (1 H ,m), 2.89 (1 H, dd, J= 12, 10Hz), 3.38 (2H, m), 2.80 (2H, m), 4.07 (1 H, m), 7.36 (2H, m), 7.48 (1 H, m), 7.59 (1 H, m), 7.70 (1 H, m)
MS ES+ve m/z 349 (M+H)
Example 11
1-((3/?)-1-{[6-(Trifluoromethyl)-3-pyridinyl]sulfonyl}-3-piperidinyl)-2- pyrrolidinone (E11)
Figure imgf000033_0001
To a solution of 1-[(3R)-3-piperidinyl]-2-pyrrolidinone hydrochloride (D5) (100mg, 0.594 mmol) and triethylamine (0.174 ml, 1.248 mmol) in anhydrous dichloromethane (3ml) was added 6-(trifluoromethyl)-3-pyridinesulfonyl chloride (146 mg, 0.594 mmol). The reaction was shaken at ambient temperature for 18 hours. To the reaction was added DCM (3ml) and water (3ml_). The organic layer was collected via a hydrophobic frit and the solvent removed under a stream of argon.
The crude product was purified by silica chromatography (Biotage SP4, eluting with 65% ethyl acetate in iso-hexanes (3 column volumes), a gradient from 65% to 100% (over 10 column volumes) then ethyl acetate (5 column volumes)) to yield the title compound as a white solid (112mg, 50%)
1H NMR (400 MHz, Choloroform-D) δ ppm 1.6 (m, 2 H) 1.8 (m, 2 H) 2.0 (m, 2 H) 2.4 (m, 2 H) 2.5 (m, 1 H) 2.6 (dd, J=11.3, 10.4 Hz, 1 H) 3.4 (m, 2 H) 3.7 (m, 2 H) 4.0 (m, 1 H) 7.9 (dd, J=8.2, 0.8 Hz, 1 H) 8.3 (m, 1 H) 9.1 (m, 1 H)
MS ES+ve m/z 378 (M+H)
Example 12
1-[(3/?)-1-({4-[(Trifluoromethyl)oxy]phenyl}sulfonyl)-3-piperidinyl]-2- pyrrolidinone (E12)
Figure imgf000034_0001
A solution of 1-[(3R)-3-piperidinyl]-2-pyrrolidinone hydrochloride (D5) (500 mg, 2.44 mmol) and triethylamine (0.749 ml, 5.37 mmol) in dichloromethane (DCM) (10 ml) was cooled in an ice-water bath under argon before the addition of 4- [(trifluoromethyl)oxy]benzenesulfonyl chloride (0.414 ml, 2.443 mmol). The reaction was allowed to warm to room temperature and stirred for 18 hours. The reaction was diluted with DCM (3OmL) and water (2OmL). The aqueous layer was separated and extracted with DCM (2OmL). The DCM layers were combined, passed through a hydrophobic frit and evaporated to dryness in vacuo. The residue was purified by silica chromatography (Biotage SP4, eluting 70% ethyl acetate in iso-hexanes (3 column volumes), a gradient form 70-100% ethyl acetate (over 9 column volumes) then ethyl acetate (3 column volumes)) to yield the title compound as a white solid (0.755g, 79%).
1H NMR (400 MHz, Choloroform -D) δ ppm 1.6 (m, 2 H) 1.8 (m, 2 H) 2.0 (m, 2 H) 2.4 (m, 2 H) 2.5 (m, 1 H) 2.6 (dd, J=11.0, 10.3 Hz, 1 H) 3.4 (m, 2 H) 3.6 (m, 2 H) 4.0 (m, 1 H) 7.4 (d, J=9.6 Hz, 2 H) 7.8 (m, 2 H)
MS ES+ve m/z 393 (M+H)
Example 13 1-{(3/?)-1-[(3,5-Dichlorophenyl nyl}-2-pyrrolidinone (E13)
Figure imgf000034_0002
To a solution of 1-[(3R)-3-piperidinyl]-2-pyrrolidinone hydrochloride (D5) (100mg, 0.489 mmol) and triethylamine (0.143 ml, 1.026 mmol) in anhydrous dichloromethane (DCM) (3ml) was added 3,5-dichlorobenzenesulfonyl chloride (120 mg, 0.489 mmol). The reaction was shaken at ambient temperature for 18 hours. To the reaction was added DCM (3ml) and water (3ml_). The organic layer was collected via a hydrophobic frit and the solvent removed under a stream of argon.
The crude product was purified by silica chromatography (Biotage SP4, eluting with 60% ethyl acetate in iso-hexanes (3 column volumes), a gradient from 60% to 100% ethyl acetate in iso-hexanes (over 10 column volumes) then ethyl acetate (3 column volumes)) to yield the title compound as a white solid (0.1 19g, 65%).
1H NMR (400 MHz, Choloroform -D) δ ppm 1.6 (m, 2 H) 1.8 (m, 2 H) 2.0 (m, 2 H) 2.4 (m, 2 H) 2.5 (m, 1 H) 2.6 (dd, J=11.3, 10.2 Hz, 1 H) 3.4 (m, 2 H) 3.6 (m, 2 H) 4.0 (m, 1 H) 7.59 (t, J=1.9 Hz, 1 H) 7.64 (d, J=2.0 Hz, 2 H)
MS ES+ve m/z 377, 379 (M+H)
Example 14 4-(1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-3-morpholinone (E14)
Figure imgf000035_0001
4-(3-Piperidinyl)-3-morpholinone (D10) (300 mg, 1.628 mmol) was dissolved in dichloromethane (20 ml) and triethylamine (0.454 ml, 3.26 mmol). 4- (trifluoromethyl)benzenesulfonyl chloride (438 mg, 1.791 mmol) was added and the mixture was stirred for 3 days. The reaction mixture was concentrated in vacuo, redissolved in a minimum amount of DCM and purified by silica column chromatography (Biotage SP4, eluting with 0 - 10% methanol in DCM) followed by further purification using MDAP to yield the title compound as a white solid (433mg, 66%).
1H NMR (400 MHz, DMSO-D6) δ ppm 1.6 (m, 3 H) 1.8 (m, 1 H) 2.3 (m, 1 H) 2.4 (m, 1 H) 3.2 (m, 2 H) 3.6 (m, 2 H) 3.8 (m, 2 H) 4.0 (m, 2 H) 4.3 (m, 1 H) 8.0 (d, J=8.3 Hz, 2 H) 8.0 (d, J=8.3 Hz, 2 H) MS ES+ve m/z 393 (M+H)
Example 15 1 -(1 -{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-imidazolidinone (E15)
Figure imgf000036_0001
To a solution of 1-(3-piperidinyl)-2-imidazolidinone (D14) (0.112 g, 0.662 mmol) and triethylamine (0.11 1 ml, 0.794 mmol) in dichloromethane (DCM) (3ml) was added 4- (trifluoromethyl)benzenesulfonyl chloride (0.170 g, 0.695 mmol) . The reaction was shaken at room temperature for 18 hours. The reaction was diluted with DCM (2ml) and water (2ml_) was added. The reaction was vigorously shaken then the organic layer collected via a hydrophobic frit and the solvent evaporated under a stream of argon.
The residue was purified by silica chromatography (Biotage SP4, eluting with 70% EtOAc in iso-hexane (3 column volumes) then a gradient from 70-100% (over 10 column volumes) then EtOAc (5 column volumes)) to yield the title compound as a white solid (214mg, 86%).
1H NMR (400 MHz, Chloroform-D) δ ppm 1.6 (m, 2 H) 1.8 (m, 2 H) 2.5 (td, J=11.2, 2.7 Hz, 1 H) 2.6 (dd, J=11.0, 10.1 Hz, 1 H) 3.4 (m, 3 H) 3.5 (m, 1 H) 3.6 (m, 1 H) 3.7 (m, 1 H) 3.8 (m, 1 H) 4.4 (s, 1 H) 7.8 (d, J=8.3 Hz, 2 H) 7.9 (d, J=8.1 Hz, 2 H)
MS ES+ve m/z 378 (M+H)
Example 16
1-[1-({4-[(Trifluoromethyl)oxy]phenyl}sulfonyl)-3-piperidinyl]-2-imidazolidinone
(E16)
Figure imgf000037_0001
To a solution of 1-(3-piperidinyl)-2-imidazolidinone (D14) (0.112 g, 0.662 mmol) and triethylamine (0.11 1 ml, 0.794 mmol) in dichloromethane (DCM) (3ml) was added 4- [(trifluoromethyl)oxy]benzenesulfonyl chloride (0.1 18 ml, 0.695 mmol). The reaction was shaken at room temperature for 18 hours. The reaction was diluted with DCM (2ml) and water (2ml_) added. The reaction was vigorously shaken then the organic layer collected via a hydrophobic frit and the solvent evaporated under a stream of argon.
The residue was purified by silica chromatography (Biotage SP4, eluting with 70% EtOAc in iso-hexane (3 column volumes) then a gradient from 70-100% (over 10 column volumes) then EtOAc (5 column volumes)) to yield the title compound as a white solid (208mg, 80%).
1H NMR (400 MHz, Chloroform-D) δ ppm 1.6 (m, 2 H) 1.8 (m, 2 H) 2.5 (td, J=11.2, 2.7 Hz, 1 H) 2.6 (dd, J=11.0, 10.1 Hz, 1 H) 3.4 (m, 3 H) 3.5 (m, 1 H) 3.6 (m, 1 H) 3.7 (m, 1 H) 3.8 (m, 1 H) 4.4 (s, 1 H) 7.4 (m, 2 H) 7.8 (m, 2 H)
MS ES+ve m/z 394 (M+H)
Example 16A
1-[1-({4-[(Trifluoromethyl)oxy]phenyl}sulfonyl)-3-piperidinyl]-2-imidazolidinone (E16A; faster running enantiom
Figure imgf000037_0002
Racemic 1-[1-({4-[(trifluoromethyl)oxy]phenyl}sulfonyl)-3-piperidinyl]-2- imidazolidinone (0.198g) (E16) was seperated using chiral preperative HPLC. The conditions used were as follows:
Preparative conditions:
Chiralpak IA (20mm x 250mm, 5μm)
Heptane : Absolute Ethanol 70:30 v/v pump-mixed
Flow rate = 17.0mls/min
U.V. Absorbance (S) 215nm
Autosampler injection (500μl of 50.0mgs/ml sample in DCM/Methanol (80:20)
lsocratic Run time = 23.0 minutes
Solubility = 50.0 mgs/ml in DCM/Methanol (80:20)
The faster running enantiomer was isolated and further purified by MDAP to yield the title compound as a white solid (44mg)
Chiral HPLC indicated a retention time of 7.26min
Analytical conditions:
Chiralpak IA (4.6mm x 250mm, 5μm)
Heptane : Absolute Ethanol 50:50 v/v pump-mixed
Flow rate = 1.Omls/min
U.V. Absorbance @ 215nm
Autosampler injection (1 Oμl of 1.0mgs/ml sample in Absolute ethanol on column)
lsocratic Run time = 15.0 minutes
Abbreviations
Figure imgf000039_0001
Liquid Chromatography / Mass Spectrometry
Analysis of the above Examples by Liquid Chromatography / Mass Spectrometry
(LC/MS) was carried out using the following apparatus and conditions:
Hardware
Waters Acquity Binary Solvent Manager
Waters Acquity Sample Manager
Waters Acquity PDA
Waters ZQ Mass Spectrometer
Sedere Sedex 75
Software
Waters MassLynx version 4.1
Column
The column used is a Waters Acquity BEH UPLC C18, the dimensions of which are
2.1 mm x 50mm. The stationary phase particle size is 1.7μ m.
Solvents
A : Aqueous solvent = Water + 0.05% Formic Acid
B : Organic solvent = Acetonitrile + 0.05% Formic Acid
Weak Wash = 1 :1 Methanol : Water
Strong Wash = Water
Method
The generic method used has a 2 minute runtime.
Figure imgf000040_0001
The above method has a flow rate of 1 ml/min. The injection volume for the generic method is 0.5ul The column temperature is 40deg The UV detection range is from 220 to 330nm
Biotage SP4®
Biotage - SP4® is an automated purification system. It uses preloaded silica gel columns. The user applies their material to the top of the column and selects solvents, gradients, flow rates, column size, collection method and eluting volumes.
Phase Separators (Hydrophobic frit)
Phase separators are a range of ISOLUTE® columns fitted with an optimized frit material that easily separates aqueous phase from chlorinated solvents under gravity.
Mass-directed automated HPLC/Mass-directed automated preparation (MDAP)
Where indicated in the above examples, purification by mass-directed automated HPLC was carried out using the following apparatus and conditions:
Hardware
Waters 2525 Binary Gradient Module
Waters 515 Makeup Pump
Waters Pump Control Module
Waters 2767 Inject Collect
Waters Column Fluidics Manager
Waters 2996 Photodiode Array Detector
Waters ZQ Mass Spectrometer
Gilson 202 fraction collector
Gilson Aspec waste collector
Software
Waters MassLynx version 4 SP2
Column The columns used are Waters Atlantis, the dimensions of which are 19mm x 100mm (small scale) and 30mm x 100mm (large scale). The stationary phase particle size is 5m.
Solvents
A : Aqueous solvent = Water + 0.1% Formic Acid
B : Organic solvent = Acetonitrile + 0.1 % Formic Acid
Make up solvent = Methanol : Water 80:20
Needle rinse solvent = Methanol
Methods
There are five methods used depending on the analytical retention time of the compound of interest. They have a 13.5-minute runtime, which comprises of a 10- minute gradient followed by a 3.5 minute column flush and re-equilibration step.
Large/Small Scale 1.0-1.5 = 5-30% B
Large/Small Scale 1.5-2.2 = 15-55% B
Large/Small Scale 2.2-2.9 = 30-85% B
Large/Small Scale 2.9-3.6 = 50-99% B Large/Small Scale 3.6-5.0 = 80-99% B (in 6 minutes followed by 7.5 minutes flush and re-equilibration)
Flow rate
All of the above methods have a flow rate of either 20mls/min (Small Scale) or 40mls/min (Large Scale).
Pharmacological data
Compounds of the invention may be tested for in vitro biological activity in the hCav2.2 assay in accordance with the following studies:
Methods
Cell biology
Stable cell lines expressing the human Cay2.2 α (α1 β) subunit, along with the human β3 and α2δ1 auxiliary subunits were created following sequential transfection and selection of human embryonic kidney (HEK293) cells. HEK293 cells were cultured in Dulbecco's modified Eagles media/F12 media (Invitrogen, Cat # 041 -95750V) containing 10% fetal bovine serum, with added L-glutamine (2 mM; Invitrogen, Cat #
25030-024) and non-essential amino acids (5%; Invitrogen, Cat # 1 1140-035).
Initially HEK293 cells were transfected with two plasmid vectors for expression of the hCav2.2 α subunit (pCIN5- hCav2.2 which carries a neomycin resistance marker) and the hCav β3 subunit (pCIH-hCav β3 which carries a hygromycin resistance marker).
Clonal cell lines were isolated following selection in media supplemented with 0.4 mg ml"1 Geneticin G418 (Invitrogen, Cat # 10131-027) and 0.1 mg ml"1 hygromycin (Invitrogen, Cat # 10687-010). These clonal cell lines were assessed for Cav2.2 α/ β3-mediated current expression using the IonWorks planar array electrophysiology technology (described below). A clonal line was identified that gave a reasonable level of functional Cav2.2 α/ β3 current expression. This cell line was transfected with a plasmid vector for expression of the human α2δ1 subunit (pCIP-α2δ1 which carries a puromycin resistance marker) and clonal cell lines isolated following selection in media containing 0.62 μg ml"1 puromycin (Sigma, Cat # P-7255), in addition to 0.4 mg ml"1 Geneticin G418 and 0.1 mg ml"1 hygromycin. Several cell lines were identified that gave robust levels of Cav2.2 α/ β3/α2δ1 -mediated current expression and one of these was selected for compound profiling. Expression of all three subunits within this cell line was continuously maintained by the inclusion of G418 (0.4 mg ml"1), hygromycin (0.1 mg ml"1) and puromycin (0.62 μg ml"1). Cells were maintained at 37°C in a humidified environment containing 5% CO2 in air. Cells were liberated from the T175 culture flasks for passage and harvesting using TrpLE (Invitrogen, Cat # 12604-013).
Cell preparation
Cells were grown to 30-60% confluence in T175 flasks and maintained at 300C for
24 hrs prior to recording. Cells were lifted by removing the growth media, washing with Ca2+ free PBS (Invitrogen, Cat #14190-094) and incubating with 3 ml of warmed (37°C) TrpLE (Invitrogen, Cat # 12604-013) for 6 minutes. Lifted cells were suspended in 10 ml of extracellular buffer. Cell suspension was then placed into a 15 ml tube and centrifuged for 2 minutes at 700 rpm. After centrifugation, the supernatant was removed and the cell pellet was resuspended in 4.5 ml of extracellular solution.
Electrophysiology
Currents were recorded at room temperature (21-23°C) using the IonWorks planar array electrophysiology technology (Molecular Devices Corp.). Stimulation protocols and data acquisition were carried out using a microcomputer (Dell Pentium 4). In order to determine planar electrode hole resistances (Rp), a 10 mV, 160 ms potential difference was applied across each hole. These measurements were performed before cell addition. After cell addition a seal test was performed prior to antibiotic (amphotericin) circulation to achieve intracellular access. Leak subtraction was conducted in all experiments by applying a 160 ms hyperpolarizing (10 mV) prepulse 200 ms before the test pulses to measure leak conductance. Test pulses stepping from the holding potential (VH) of -90 mV to +10 mV were applied for 20 ms and repeated 10 times at a frequency of 10 Hz. In all experiments, the test pulse protocol was performed in the absence (pre-read) and presence (post-read) of a compound. Pre- and post-reads were separated by a compound addition followed by a 3-3.5 min incubation.
Solutions and drugs The intracellular solution contained the following (in mlW): K-gluconate 120, KCI 2OmM, MgCI2 5, EGTA 5, HEPES 10, adjusted to pH 7.3. Amphotericin was prepared as 30 mg/ml stock solution and diluted to a final working concentration of 0.2 mg ml"1 in intracellular buffer solution. The extracellular solution contained the following (in mΛf): Na-gluconate 120, NaCI 20, MgCI2 1 , HEPES 10, BaCI2 5, adjusted to pH 7.4.
Compounds were prepared in DMSO as 1 OmM stock solutions and subsequent 1 :3 serial dilutions performed. Finally the compounds were diluted 1 :100 in external solution resulting in a final DMSO concentration of 1%.
Data analysis
The recordings were analysed and filtered using seal resistance (>40 MΩ), resistance reduction (>35%) and peak current amplitude (>200pA) in the absence of compound to eliminate unsuitable cells from further analysis. Paired comparisons between pre-compound and post-compound additions were used to determine the inhibitory effect of each compound. The concentrations of compounds required to inhibit current elicited by the 1 st depolarising pulse by 50% (tonic plC50) were determined by fitting of the Hill equation to the concentration response data. In addition the use-dependent inhibitory properties of the compounds were determined by assessing the effect of compounds on the 10th versus 1 st depolarising pulse. The ratio of the 10th over 1 st pulse was determined in the absence and presence of drug and the % use-dependent inhibition calculated. The data was fitted using the same equation as for the tonic plC5o and the concentration producing 30% inhibition (use- dependent pUD30) determined.
The compounds of Examples 1-16 and 16A were tested in the hCay2.2 assay and demonstrated the following pUD30 and plC50 values:
Figure imgf000043_0001
Figure imgf000044_0001

Claims

Claims
1. A compound of formula (I), or a salt thereof:
Figure imgf000045_0001
(I)
wherein R1 represents benzofuran-2-yl, benzothien-2-yl, 3-trifluoromethylphenyl, A- trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-chlorophenyl, 2-chloro-4- cyanophenyl, 2-chloro-4-trifluoromethylphenyl, 6-trifluoromethylpyridin-3-yl or 3,5- dichlorophenyl; and R2 represents a group of formula (i), (N) or (Ni):
Figure imgf000045_0002
(i) (Ii) (ill)
2. A compound or salt as defined in claim 1 wherein R1 is selected from benzofuran-2-yl, benzothien-2-yl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, A- trifluoromethoxyphenyl, 4-chlorophenyl, 2-chloro-4-cyanophenyl and 2-chloro-4- trifluoromethylphenyl.
3. A compound or salt as defined in claim 1 wherein R1 is selected from 3- trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, A- chlorophenyl, 2-chloro-4-trifluoromethylphenyl, 6-trifluoromethylpyridin-3-yl and 3,5- dichlorophenyl.
4. A compound or salt as defined in any one of claims 1 to 3 wherein R2 represents a group of formula (i) or (iii).
5. A compound or salt as defined in any one of claims 1 to 3 wherein R2 represents a group of formula (i).
6. A compound or salt as defined in claim 1 , selected from: 1-(1-{[2-Chloro-4-(trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E1 ); 1-((3R)-1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E2); 1-[1-({4-[(Trifluoromethyl)oxy]phenyl}sulfonyl)-3-piperidinyl]-2-pyrrolidinone (E3); 1-(1-{[3-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E4);
1-{(3S)-1-[(4-Chlorophenyl)sulfonyl]-3-piperidinyl}-2-pyrrolidinone (E5);
1-((3S)-1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E6);
1-(1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E7); 1-[(3S)-1-(1-Benzothien-2-ylsulfonyl)-3-piperidinyl]-2-pyrrolidinone (E8);
3-Chloro-4-{[(3S)-3-(2-oxo-1 -pyrrolidinyl)-1 -piperidinyl]sulfonyl}benzonitrile (E9);
1-[(3S)-1-(1-Benzofuran-2-ylsulfonyl)-3-piperidinyl]-2-pyrrolidinone (E10);
1-((3/?)-1-{[6-(Trifluoromethyl)-3-pyridinyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone
(E1 1 ); 1-[(3/?)-1-({4-[(Trifluoromethyl)oxy]phenyl}sulfonyl)-3-piperidinyl]-2-pyrrolidinone
(E12);
1-{(3R)-1-[(3,5-Dichlorophenyl)sulfonyl]-3-piperidinyl}-2-pyrrolidinone (E13);
4-(1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-3-morpholinone (E14);
1-(1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-imidazolidinone (E15); and 1-[1-({4-[(Trifluoromethyl)oxy]phenyl}sulfonyl)-3-piperidinyl]-2-imidazolidinone (E16); or a salt thereof.
7. A compound or salt as defined in claim 1 , selected from: 1-(1-{[2-Chloro-4-(trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E1 ); 1-((3R)-1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E2);
1-[1-({4-[(Trifluoromethyl)oxy]phenyl}sulfonyl)-3-piperidinyl]-2-pyrrolidinone (E3);
1-(1-{[3-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E4);
1-{(3S)-1-[(4-Chlorophenyl)sulfonyl]-3-piperidinyl}-2-pyrrolidinone (E5);
1-((3S)-1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E6); 1-(1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E7);
1-[(3S)-1-(1-Benzothien-2-ylsulfonyl)-3-piperidinyl]-2-pyrrolidinone (E8);
3-Chloro-4-{[(3S)-3-(2-oxo-1 -pyrrolidinyl)-1 -piperidinyl]sulfonyl}benzonitrile (E9); and
1-[(3S)-1-(1-Benzofuran-2-ylsulfonyl)-3-piperidinyl]-2-pyrrolidinone (E10); or a salt thereof.
8. A compound or salt as defined in claim 1 , selected from: 1-((3R)-1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E2); 1-((3S)-1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E6); 1-(1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E7); 1-[(3/?)-1-({4-[(Trifluoromethyl)oxy]phenyl}sulfonyl)-3-piperidinyl]-2-pyrrolidinone (E12); and
1-[1-({4-[(Trifluoromethyl)oxy]phenyl}sulfonyl)-3-piperidinyl]-2-imidazolidinone (E16); or a salt thereof.
9. A compound or salt as defined in claim 1 , selected from:
1-((3R)-1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E2);
1-[(3/?)-1-({4-[(Trifluoromethyl)oxy]phenyl}sulfonyl)-3-piperidinyl]-2-pyrrolidinone
(E12); and 1-[1-({4-[(Trifluoromethyl)oxy]phenyl}sulfonyl)-3-piperidinyl]-2-imidazolidinone (E16); or a salt thereof.
10. A compound or salt as defined in claim 1 , selected from: 1-((3R)-1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E2); 1-((3S)-1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E6); and 1-(1-{[4-(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E7); or a salt thereof.
11. A compound or salt as defined in claim 1 which is 1-((3R)-1 -{[4-
(Trifluoromethyl)phenyl]sulfonyl}-3-piperidinyl)-2-pyrrolidinone (E2), or a salt thereof.
12. A compound or salt as defined in claim 1 , which is 1-[(3R)-1-({4- [(Trifluoromethyl)oxy]phenyl}sulfonyl)-3-piperidinyl]-2-pyrrolidinone (E12), or a salt thereof.
13. A compound or salt as defined in claim 1 , which is 1-[1-({4- [(Trifluoromethyl)oxy]phenyl}sulfonyl)-3-piperidinyl]-2-imidazolidinone (E16), or a salt thereof, in particular the fast running enantiomer of Example 16 (E16A).
14. A compound or salt as defined in any one of claims 1 to 13 wherein the salt is a pharmaceutically acceptable salt.
15. A pharmaceutical composition which comprises a compound as defined in any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
16. A compound as defined in any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for use in therapy.
17. A method of treating a human or animal subject suffering from pain which method comprises administering to said subject an effective amount of a compound as defined in any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.
18. Use of a compound as defined in any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of pain.
19. A compound as defined in any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for use in the treatment of pain.
PCT/EP2009/051534 2009-02-11 2009-02-11 3 -substituted 1-arylsulfonylpiperidine derivatives for the treatment of pain WO2010091721A1 (en)

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WO2024084360A1 (en) 2022-10-18 2024-04-25 Pfizer Inc. Patatin-like phospholipase domain-containing protein 3 (pnpla3) modifiers
WO2024084363A1 (en) 2022-10-18 2024-04-25 Pfizer Inc. Use of patatin-like phospholipase domain-containing protein 3 compounds

Citations (2)

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WO2005068448A1 (en) * 2003-08-29 2005-07-28 Ionix Pharmaceuticals Limited Sulfonamides antagonising n-type calcium channels
WO2007125398A2 (en) * 2006-04-27 2007-11-08 Pfizer Japan Inc. : sulfonamide compounds as antagonists of the n-type calcium channel

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2005068448A1 (en) * 2003-08-29 2005-07-28 Ionix Pharmaceuticals Limited Sulfonamides antagonising n-type calcium channels
WO2007125398A2 (en) * 2006-04-27 2007-11-08 Pfizer Japan Inc. : sulfonamide compounds as antagonists of the n-type calcium channel

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024084360A1 (en) 2022-10-18 2024-04-25 Pfizer Inc. Patatin-like phospholipase domain-containing protein 3 (pnpla3) modifiers
WO2024084363A1 (en) 2022-10-18 2024-04-25 Pfizer Inc. Use of patatin-like phospholipase domain-containing protein 3 compounds

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