WO2019126842A1 - Composés thérapeutiques et leurs utilisations - Google Patents

Composés thérapeutiques et leurs utilisations Download PDF

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WO2019126842A1
WO2019126842A1 PCT/AU2018/051409 AU2018051409W WO2019126842A1 WO 2019126842 A1 WO2019126842 A1 WO 2019126842A1 AU 2018051409 W AU2018051409 W AU 2018051409W WO 2019126842 A1 WO2019126842 A1 WO 2019126842A1
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Prior art keywords
optionally substituted
alkyl
heterocyclyl
haloalkyl
aryl
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PCT/AU2018/051409
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English (en)
Inventor
Courtney HOLLIS
Nathan Kuchel
Rajinder Singh
Andrew Harvey
Thomas Avery
Florence CHERY
Jean-Marie Contreras
Julie GAY
Laetitia JUNG
Celine Michaut-Simon
Christophe Morice
Alexandre STEFFEN
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Bionomics Limited
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Priority claimed from AU2017905204A external-priority patent/AU2017905204A0/en
Application filed by Bionomics Limited filed Critical Bionomics Limited
Publication of WO2019126842A1 publication Critical patent/WO2019126842A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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

Definitions

  • the present invention relates to compounds useful in the modulation of ion channel activity in cells.
  • the invention also relates to use of these compounds in the treatment of pain, and pharmaceutical compositions containing these compounds and methods for their preparation.
  • Voltage gated sodium channels are essential for the initiation and propagation of action potentials in excitable tissues such as muscle and nerve.
  • 10 subtypes have been identified: Navl. l, Navl.2, Navl.3 and Navl.6 which occur in the CNS (and PNS), Navl.4 which is specific to skeletal muscle, Navl.5 in cardiac muscle and Navl.7-l.9 which are largely found in sensory neurones.
  • Increased Navl.x channel activity leads to nerve hyper excitability and underlies a number of pathological conditions including: epilepsy (Navl.l and Navl.2), cardiac arrhythmia (Navl.5), myotonia (Navl.4) and chronic pain (Navl.7-Navl.9).
  • Sodium channel blockers are commonly used as analgesics and are represented across three drug classes: local anaesthetics, class I antiarrhythmic and antiepileptic drugs. Although generally well tolerated, these drugs exhibit poor Navl.x subtype selectivity and have a limited dose range due to side effects expected of interfering with CNS, cardiac and skeletal muscle sodium channel function including convulsions, ataxia, motor impairment, arrhythmias and paralysis. Despite their poor Navl.x selectivity, these drugs are nevertheless tolerated due to their relatively low potency for Navl.x channels in the resting (closed) state and greater potency for the inactivated state which commonly presides in Navl.x channels mediating pain signals.
  • Navl.x blockers can exhibit functional selectivity as well as subtype selectivity.
  • Navl.7 has recently gained much attention as a pain target due to genetic evidence linking mutations of this channel to pain syndromes. Gain of function mutations of Navl.7 are linked to two painful conditions, inherited erythromelalgia and paroxysmal extreme pain syndrome. On the other hand, rare loss of function mutations of Navl.7 result in congenital insensitivity to pain and anosmia.
  • Navl.7 is distributed primarily in the peripheral nervous system in dorsal root and sympathetic ganglia where it plays a role in setting the threshold for action potential firing thus controlling sensory neuron sensitivity to incoming stimuli.
  • the largely peripheral distribution of this channel contributes to its attractiveness as a pain target due to the added safety of not requiring CNS penetrance and hence lowering the potential for CNS related side effects.
  • the present invention provides compounds of formula (I) and pharmaceutical compositions thereof.
  • compounds of formula (I) have utility in the treatment of pain disorders.
  • the invention provides compounds of formula (I)
  • R 1 and R 2 are independently selected from hydrogen, optionally substituted Ci_ 6 alkyl, Ci_ 6 haloalkyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted C 5 -C 12 aryl, optionally substituted C 2 -C 12 heterocyclyl; or R and R , together with the N to which they are attached, form an optionally substituted C 2 -C 12 heterocyclyl or optionally substituted C 2 -C 12 heteroaryl;
  • R is selected from hydrogen, optionally substituted Ci_C 6 alkyl, optionally substituted Ci_ C 6 haloalkyl, optionally substituted Ci_C 6 alkoxy, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted C 3 -C 7 cycloalkenyl, optionally substituted acyl, optionally substituted C 2 -C 12 heterocyclyl or optionally substituted aryl;
  • Y is a divalent linker group selected from C 1 -C 5 alkylene, -(CH 2 ) x -0-(CH 2 ) y -, -(CH 2 ) X -S- (03 ⁇ 4) g -, wherein x and y are each integers independently selected from 0, 1, 2, and 3; each R 4 is independently selected from hydroxy, acyl, acyloxy, amino, thio, halogen, cyano, optionally substituted Ci_C 6 alkyl, optionally substituted Ci_C 6 haloalkyl, optionally substituted -OCi_C 6 alkyl, optionally substituted -OCi_C 6 haloalkyl, optionally substituted Ci_C 6 alkyl amino, optionally substituted Ci_C 6 dialkyl amino, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted C 2 -C 12 heterocyclyl, optionally substituted aryl; or optionally substituted aryloxy
  • R 5 is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted heterocyclylalkyl; and n is an integer selected from 0, 1, and 2.
  • the invention provides compounds of formula (la):
  • R 1 , R 2 , R 3 , R 4 , Y and n are each as defined for compounds of formula (I) and; each R 6 is independently selected from hydroxy, acyl, acyloxy, halogen, amino, thio, cyano, nitro, nitrile, silyl, optionally substituted Ci_C 6 alkyl, optionally substituted Ci_C 6 haloalkyl, optionally substituted -OCi_C 6 alkyl, optionally substituted -OCi_C 6 haloalkyl, optionally substituted Ci_C 6 alkyl amino, optionally substituted Ci_C 6 dialkyl amino, optionally substituted acylamino, optionally substituted oxyacyl, optionally substituted sulfamoyl, optionally substituted sulfonyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted C 2 -C 12 heterocyclyl, optionally substituted aryl, optionally substituted
  • each R is independently selected from hydroxy, acyl, acyloxy, halogen, amino, thio, cyano, nitro, nitrile, silyl, optionally substituted Ci_C 6 alkyl, optionally substituted Ci_C 6 haloalkyl, optionally substituted -OCi_C 6 alkyl, optionally substituted -OCi_C 6 haloalkyl, optionally substituted Ci_C 6 alkyl amino, optionally substituted Ci_C 6 dialkyl amino, optionally substituted acylamino, optionally substituted oxyacyl, optionally substituted sulfamoyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted C 2 -C 12 heterocyclyl, optionally substituted aryl, optionally substituted aryloxy, and optionally substituted heteroaryl; or
  • R 6 and R 7 together form a group selected from C 3 -C 12 cycloalkenyl, C 5 -C 12 aryl, C 2 -C 12 heterocyclyl, C 2 -C 12 heteroaryl, each of which may be optionally substituted with one or more of Ci_C 6 alkyl, Ci-C 6 haloalkyl, OCi_C 6 alkyl, OCi_C 6 haloalkyl, C 3 -C 12 aryl, hydroxyl, alkoxy, acyl, acyloxy, acylamino, sulfamoyl, nitro, amino, thio, halogen, and cyano; p is an integer selected from 0, 1, 2 and 3; and m is an integer selected from 0, 1 and 2.
  • Y is -CH 2 CH 2 -.
  • Y is -CH 2 CH 2 CH 2 -.
  • R 1 is H and R 2 is H.
  • Y is -CH 2 CH 2 - and R 1 and R 2 are both H.
  • Y is -CH 2 CH 2 CH 2 - and R 1 and R 2 are both H.
  • the present invention relates to pharmaceutical compositions comprising of at least one compound provided herein and a pharmaceutical carrier, excipient or diluent.
  • the pharmaceutical composition can comprise one or more compounds described herein. It will be understood that compounds provided herein, useful in the pharmaceutical compositions and treatment methods disclosed below, can be pharmaceutically acceptable as prepared and used.
  • the invention provides or relates to methods for preventing, treating or ameliorating a condition from among those listed herein, particularly pain disorders (including pain associated with cancer, surgery, and bone fracture, acute pain, inflammatory pain and neuropathic pain).
  • Pain disorders for which the compounds of the invention may be useful include neuropathic pain (such as postherpetic neuralgia, nerve injury, the "dynias", e.g., vulvodynia, phantom limb pain, root avulsions, painful diabetic neuropathy, painful traumatic mononeuropathy, painful polyneuropathy); central pain syndromes (potentially caused by virtually any lesion at any level of the nervous system); postsurgical pain syndromes (eg, postmastectomy syndrome, postthoracotomy syndrome, stump pain); bone and joint pain (osteoarthritis), repetitive motion pain, dental pain (e.g., toothache), cancer pain, myofascial pain (muscular injury, fibromyalgia); perioperative pain (general surgery, gynecological), chronic pain, dysmennorhea, as well as pain associated with angina, and inflammatory pain of varied origins (e.g.
  • neuropathic pain such as postherpetic neuralgia,
  • osteoarthritis rheumatoid arthritis, rheumatic disease, teno- synovitis and gout
  • headache migraine and cluster headache
  • primary hyperalgesia secondary hyperalgesia
  • primary allodynia secondary allodynia
  • migraine and cluster headache primary hyperalgesia
  • secondary hyperalgesia primary allodynia
  • secondary allodynia secondary allodynia
  • the invention provides methods for treating or preventing pain disorders, said method including the step of administering to a patient a compound of either formula (I) or formula (la) or the embodiments mentioned hereinbefore or after.
  • the invention relates to the treatment of chronic pain.
  • the invention relates to the treatment of neuropathic pain.
  • the invention relates to the treatment of inflammatory pain.
  • the invention relates to the treatment of cancer pain.
  • the invention relates to the treatment of trigeminal neuralgia, lower back pain, post- operative pain, toothache, arthritic pain (rheumatoid, osteoarthritis, gout), pain from irritable bowel, inherited erythromelalgia, paroxysmal extreme pain syndrome, post herpetic neuralgia (shingles), musculoskeletal pain, multiple sclerosis, sciatica, diabetic neuropathy, and HIV related neuropathy.
  • the invention provides compounds to treat or prevent conditions resulting from membrane hyperexcitablility mediated by aberrant Nav channel activity for state and use- dependent Nav blockers; including:
  • ⁇ CNS conditions for instance, epilepsy, anxiety, depression, bipolar
  • Cardiac conditions for instance, arrhythmias, atrial and ventricular fibrillation
  • ⁇ Muscular for instance, restless leg, tetanus
  • the present invention extends to the use of any of the compounds of the invention in the preparation of medicaments that may be administered for such treatments, as well as to such compounds for the treatments disclosed and specified.
  • the present invention is directed to methods for synthesising the compounds described herein, with representative synthetic protocols and pathways described below.
  • the invention provides compounds that can treat or alleviate maladies or symptoms of same, such as pain, that may be causally related to the activation of a sodium channel.
  • the invention provides a method for treating or preventing conditions that may be casually related to the activation of at least one sodium channel, said method including the step of administering to a patient a compound of either formula (I) or formula (la) or the embodiments mentioned hereinbefore.
  • the compounds of the present invention display subtype and/or functional selectivity in relation to Navl.7 inhibition.
  • alkyl refers to a straight or branched chain saturated hydrocarbon group.
  • the term "Ci-12 alkyl” refers to such a group containing from one to twelve carbon atoms and "lower alkyl” refers to Ci_ 6 alkyl groups containing from one to six carbon atoms, such as methyl ("Me”), ethyl ("Et”), n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl and the like.
  • cycloalkyl refers to non-aromatic, saturated non-aromatic carbocycles.
  • C4- 9 cycloalkyl refers to such a group having from 4 to 9 carbon atoms. Examples include cyclobutyl, cyclopentyl and cyclohexyl.
  • alkenyl refers to a straight or branched hydrocarbon containing one or more double bonds, preferably one or two double bonds.
  • C2-12 alkenyl refers to such a group containing from two to twelve carbon atoms.
  • alkenyl examples include allyl, 1- methylvinyl, butenyl, iso-butenyl, l,3-butadienyl, 3-methyl-2-butenyl, l,3-butadienyl, 1,4- pentadienyl, l-pentenyl, l-hexenyl, 3-hexenyl, l,3-hexadienyl, 1 ,4-hexadienyl and 1,3,5- hexatrienyl.
  • cycloalkenyl refers to cyclic alkenyl groups having a single cyclic ring or multiple condensed rings, and at least one point of internal unsaturation, preferably incorporating 4 to 11 carbon atoms.
  • suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclohex-4-enyl, cyclooct-3-enyl, indenyl and the like.
  • alkynyl refers to a straight or branched hydrocarbon containing one or more triple bonds, preferably one or two triple bonds.
  • C2-12 alkynyl refers to such a group containing from two to twelve carbon atoms. Examples include 2-propynyl and 2- or 3- butynyl.
  • alkoxy refers to a straight or branched chain alkyl group covalently bound via an oxygen linkage (-0-) and the terms "Ci_ 6 alkoxy” and “lower alkoxy” refer to such groups containing from one to six carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and the like.
  • aryl refers to carbocyclic (non -heterocyclic) aromatic rings or ring systems.
  • the aromatic rings may be mono- or bi-cyclic ring systems.
  • the aromatic rings or ring systems are generally composed of 5 to 10 carbon atoms. Examples of suitable aryl groups include but are not limited to phenyl, biphenyl, naphthyl, tetrahydronaphthyl, and the like.
  • Aryl groups include phenyl, naphthyl, indenyl, azulenyl, fluorenyl or anthracenyl.
  • heteroaryl refers to a monovalent aromatic carbocyclic group, preferably of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring. Preferably the heteroatom is nitrogen.
  • heteroaryl groups can have a single ring (e.g., pyridyl, pyrrolyl or furyl) or multiple condensed rings (e.g., indolizinyl, benzothienyl, or benzofuranyl).
  • heterocyclyl refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, preferably from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur, oxygen, selenium or phosphorous within the ring.
  • Examples of 5-membered monocyclic heterocyclyl and heteroaryl groups include furyl, thienyl, pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, (including 1,2,3 and 1,2,4- oxadiazolyls) thiazolyl, isoxazolyl, furazanyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, triazolyl (including 1,2,3- and l,3,4-triazolyls), tetrazolyl, thiadiazolyl (including 1,2,3- and l,3,4-thiadiazolyls).
  • 6-membered monocyclic heterocyclyl and heteroaryl groups include pyridyl, pyrimidinyl, pyridazinyl, pyranyl, pyrazinyl, piperidinyl, l,4-dioxanyl, morpholinyl, 1,4- dithianyl, thiomorpholinyl, piperazinyl, l,3,5-trithianyl and triazinyl.
  • Examples of 8, 9 and lO-membered bicyclic heterocyclyl and heteroaryl groups include 1H thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, uridinyl, purinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzotriazinyl, naphthyridinyl, pteridinyl and the like.
  • halo and halogen refers to fluoro, chloro, bromo and iodo groups.
  • halo alkyl group has one or more of the hydrogen atoms on an alkyl group replaced with halogens. Notable examples are -CF 3 or -CF2H.
  • aryloxy refers to an aryl group as earlier described linked to the parent structure via an oxygen linkage (-0-).
  • phenoxy e.g., phenoxy
  • heteroaryloxy e.g., a heteroaryl group as earlier described linked to the parent structure via an oxygen group.
  • a notable example is a 4, 6 or 7-benzo[b]furanyloxy group.
  • acyl refers to groups H-C(O)-, alkyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl- C(O)- and heterocyclyl-C(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are described herein.
  • oxyacyl refers to groups HOC(O)-, alkyl-OC(O)-, cycloalkyl-OC(O)-, aryl-OC(O)-, heteroaryl-OC(O)-, and heterocyclyl-OC(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • alkylene refers to divalent alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. Examples of such alkylene groups include methylene (-CH 2 -), ethylene (-CH2CH2-), and the propylene isomers (e.g., -CH2CH2CH2- and - CH(CH 3 )CH 2 -), and the like.
  • sulfamoyl refers to the group -S(0)2NR”R” where each R” is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • sulfonyl refers to the group -S(0) 2 R” where R” is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.
  • a group may include one or more substituents.
  • One or more hydrogen atoms on the group may be replaced by substituent groups independently selected from halogens (for example halo alkyl such as -CF3 or -CF 2 H), Ci_ 6 alkyl, C 2-6 alkenyl, C2-6 alkynyl, -(CH2) V C3_ 7 cycloalkyl, -(CH2) V C4_ 7 cycloalkenyl, -(CH 2 ) V aryl, -(CH 2 ) V heterocyclyl, -(CH 2 ) V heteroaryl, -C 6 H 4 S(0) q Ci_ 6 alkyl, -C(Ph) 3 , -CN, -OR, -0-(CH 2 ) 1-6 -R, -O- (CH 2 ) I -6-OR, -0C(0)R, -C(0)R, -C(0)0R, -0C(0)NR'
  • each R, R' and R" is independently selected from H, Ci_ 6 alkyl, C2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, aryl, heterocyclyl, heteroaryl, Ci_ 6 alkylaryl, Ci_ 6 alkylheteroaryl, and Ci_ 6 alkylheterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, Ci_ 6 alkylaryl, Ci_ 6 alkylheteroaryl, or Ci_ 6 alkylheterocyclyl, may be optionally substituted with one to six of same or different groups selected from halogen, hydroxy, lower alkyl, lower alkoxy, -C0 2 H, CF3, CN, phenyl, NH 2
  • the invention provides compounds of formula (I)
  • R 1 and R 2 are independently selected from hydrogen, optionally substituted Ci_ 6 alkyl, Ci_ 6 haloalkyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted C 5 -C 12 aryl, optionally substituted C 2 -C 12 heterocyclyl; or R and R , together with the N to which they are attached, form an optionally substituted C 2 -C 12 heterocyclyl or optionally substituted C 2 -C 12 heteroaryl;
  • R is selected from hydrogen, optionally substituted Ci_C 6 alkyl, optionally substituted Ci_ C 6 haloalkyl, optionally substituted Ci_C 6 alkoxy, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted C 3 -C 7 cycloalkenyl, optionally substituted acyl, optionally substituted C 2 -C 12 heterocyclyl or optionally substituted aryl;
  • Y is a divalent linker group selected from C 1 -C 5 alkylene, -(CH 2 ) x -0-(CH 2 ) y -, -(CH 2 ) X -S- (03 ⁇ 4) g -, wherein x and y are each integers independently selected from 0, 1, 2, and 3; each R 4 is independently selected from hydroxy, acyl, acyloxy, amino, thio, halogen, cyano, optionally substituted Ci_C 6 alkyl, optionally substituted Ci_C 6 haloalkyl, optionally substituted -OCi_C 6 alkyl, optionally substituted -OCi_C 6 haloalkyl, optionally substituted Ci_C 6 alkyl amino, optionally substituted Ci_C 6 dialkyl amino, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted C 2 -C 12 heterocyclyl, optionally substituted aryl; or optionally substituted aryloxy
  • R 5 is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted heterocyclylalkyl; and n is an integer selected from 0, 1, and 2.
  • Y is a divalent linker group selected from, C 1 -C 5 alkylene, -(CH 2 ) x -0-(CH 2 ) y - and, -(CH 2 ) x -S-(CH 2 ) y -.
  • x and y are each integers independently selected from 0, 1, 2, and 3.
  • x is 0.
  • x is 1.
  • x is 2.
  • x is 3.
  • y 0.
  • y is 1.
  • y is 2.
  • y is 3.
  • Y is a divalent linker selected from C 1 -C 3 alkylene, for instance, -CH 2 -, -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -.
  • Y is -(CH 2 )-0-(CH 2 )-.
  • Y is -(CH 2 )-0-(CH 2 ) 2 -.
  • Y is -S-(CH 2 )-.
  • R and R are independently selected from hydrogen, optionally substituted Ci_ 6 alkyl, Ci_ 6 haloalkyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted C 5 -C 12 aryl, optionally substituted C 2 -C 12 heterocyclyl, or R and R together with the N to which they are attached, form an optionally substituted C 2 -C 12 heterocyclyl or optionally substituted C 2 -C 12 heteroaryl.
  • R and R are H.
  • R and R are methyl.
  • R 1 is H and R2 is methyl.
  • R 1 is propan-2-yl and
  • R 2 is H.
  • R 1 and R2 together with the N to which they are attached, form an azetidine.
  • R is selected from hydrogen, optionally substituted Ci_C 6 alkyl, optionally substituted Ci_C 6 haloalkyl, optionally substituted Ci_C 6 alkoxy, optionally substituted acyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted C 3 -C 7 cycloalkenyl, optionally substituted C 2 -C 12 heterocyclyl or optionally substituted aryl;
  • R is H.
  • R 3 is Ci_C 6 alkyl.
  • R 3 is C 3 -C 7 cycloalkyl.
  • R is substituted Ci_C 6 alkyl.
  • each R 4 (when present) is independently selected from the group consisting of hydroxy, acyl, acyloxy, amino, thio, halogen, cyano, optionally substituted Ci_C 6 alkyl, optionally substituted Ci_C 6 haloalkyl, optionally substituted -OCi_C 6 alkyl, optionally substituted -OCi_C 6 haloalkyl, optionally substituted Ci_C 6 alkyl amino, optionally substituted Ci_ C 6 dialkyl amino, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted C2-C12 heterocyclyl, optionally substituted aryl, or optionally substituted aryloxy.
  • R 4 is Ci-C 6 alkyl.
  • R 4 is halo.
  • n is selected from 0, 1, 2 and 3. In an embodiment, n is 0 (that is, unsubstituted). In another embodiment, n is 1. In another embodiment, n is 2. In another embodiment, n is 3.
  • R 5 is an optionally substituted heteroaryl-CH2-.
  • R 5 is an optionally substituted heterocyclyl-CH2-.
  • R 5 is an optionally substituted aryl-CH2-.
  • R 5 is an optionally substituted heteroaryl group. In another embodiment, R 5 is an optionally substituted heteroaryl group, wherein the heteroaryl group is 5-membered or 6- membered. In another embodiment, R 5 is an optionally substituted 5-membered heteroaryl group, selected from furan, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole and thiazole. In another embodiment, R 5 is an optionally substituted 6-membered heteroaryl group selected from pyridine, pyrazine, pyrimidine, pyridazine and triazine.
  • R 5 is an optionally substituted heteroaryl group, wherein the heteroaryl group is one or more fused 6- membered rings.
  • R 5 is an optionally substituted heteroaryl group selected from quinoline, isoquinoline, quinoxaline and quinazoline.
  • R 5 is an optionally substituted heteroaryl group, wherein the heteroaryl group has more than one heteroatom.
  • R 5 is a monosubstituted heteroaryl group.
  • R 5 is an optionally substituted heteroaryl group, wherein there is more than one substituent on the heteroaryl group.
  • R 5 is an unsubstituted heteroaryl group.
  • R 5 is an optionally substituted aryl group. In another embodiment, R 5 is an optionally substituted aryl group, wherein the aryl group is one or more fused 6-membered rings. In another embodiment, R 5 is a monosubstituted aryl group. In another embodiment, R 5 is an optionally substituted aryl group, wherein there is more than one substituent on the aryl group. In another embodiment, R 5 is an unsubstituted phenyl group. In another embodiment, R 5 is an optionally substituted phenyl group.
  • R 5 is an optionally substituted phenyl group, wherein the substituents are selected from H, halogen, haloalkyl, alkyl, alkenyl, alkynyl, alkoxy, acyl, acyloxy, amino, acylamino, nitro, nitrile, silyl, sulfamoyl, aryl and heteroaryl.
  • R 5 is an optionally substituted phenyl group, wherein the substituent is a halogen.
  • R 5 is an optionally substituted phenyl group, wherein the substituent is an optionally substituted -OCi_C 6 alkyl.
  • R 5 is an optionally substituted phenyl group, wherein the substituent is an optionally substituted haloalkyl. In another embodiment, R 5 is an optionally substituted phenyl group, wherein the substituent is in the para position. In another embodiment, R 5 is an optionally substituted phenyl group, wherein the substituent is in the meta position. In another embodiment, R 5 is an optionally substituted phenyl group, wherein the substituent is in the ortho position.
  • R 5 of Formula (I) is an optionally substituted phenyl group
  • R 1 , R 2 , R 3 , R 4 , Y and n are each as defined for compounds of formula (I) and; each R 6 is independently selected from hydroxy, acyl, acyloxy, halogen, amino, thio, cyano, nitro, nitrile, silyl, optionally substituted Ci_C 6 alkyl, optionally substituted Ci_C 6 haloalkyl, optionally substituted -OCi_C 6 alkyl, optionally substituted -OCi_C 6 haloalkyl, optionally substituted Ci_C 6 alkyl amino, optionally substituted Ci_C 6 dialkyl amino, optionally substituted acylamino, optionally substituted oxyacyl, optionally substituted sulfamoyl, optionally substituted sulfonyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted
  • R 6 and R 7 together form a group selected from C 3 -C 12 cycloalkenyl, C 5 -C 12 aryl, C 2 -C 12 heterocyclyl, C2-C12 heteroaryl, each of which may be optionally substituted with one or more of Ci_C 6 alkyl, Ci-C 6 haloalkyl, OCi_C 6 alkyl, OCi_C 6 haloalkyl, C 3 -C 12 aryl, hydroxyl, alkoxy, acyl, acyloxy, acylamino, sulfamoyl, nitro, amino, thio, halogen, and cyano; p is an integer selected from 0, 1, 2 and 3; and m is an integer selected from 0, 1 and 2.
  • each R 6 is independently selected from hydrogen, hydroxy, acyl, acyloxy, halogen, amino, thio, cyano, nitro, nitrile, silyl, optionally substituted Ci_C 6 alkyl, optionally substituted Ci_C 6 haloalkyl, optionally substituted -OCi_C 6 alkyl, optionally substituted -OCi_C 6 haloalkyl, optionally substituted Ci_C 6 alkyl amino, optionally substituted Ci_C 6 dialkyl amino, optionally substituted acylamino, optionally substituted oxyacyl, optionally substituted sulfamoyl, optionally substituted sulfonyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted C 2 -C 12 heterocyclyl, optionally substituted aryl, optionally substituted aryloxy, or optionally substituted heteroaryl.
  • each R is independently selected from hydrogen, hydroxy, acyl, acyloxy, halogen, amino, thio, cyano, nitro, nitrile, silyl, optionally substituted Ci_C 6 alkyl, optionally substituted Ci_C 6 haloalkyl, optionally substituted -OCi_C 6 alkyl, optionally substituted -OCi_C 6 haloalkyl, optionally substituted Ci_C 6 alkyl amino, optionally substituted Ci_C 6 dialkyl amino, optionally substituted acylamino, optionally substituted oxyacyl, optionally substituted sulfamoyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted C 2 -C 12 heterocyclyl, optionally substituted aryl, optionally substituted aryloxy, or optionally substituted heteroaryl.
  • R 6 and R 7 together form a group selected from C 3 -C 12 cycloalkenyl, C 5 - C 12 aryl, C 2 -C 12 heterocyclyl, C 2 -C 12 heteroaryl, each of which may be optionally substituted with one or more of Ci_C 6 alkyl, Ci-C 6 haloalkyl, OCi_C 6 alkyl, OCi_C 6 haloalkyl, C 3 -C 12 aryl, hydroxyl, alkoxy, acyl, acyloxy, acylamino, sulfamoyl, nitro, amino, thio, halogen, and cyano.
  • R 1 and R 2 are H;
  • R 1 and R 2 are methyl
  • R 1 is H and R 2 is methyl
  • R 1 is propan-2-yl and R 2 is H;
  • R 3 is H
  • R is methyl
  • R is ethyl
  • R 3 is propyl
  • R 3 is propan-2-yl
  • R 3 is cyclopropyl
  • R 4 is fluoro
  • R 4 is chloro
  • R 5 is phenyl
  • R 5 is fluoro phenyl
  • R 5 is 3-fluoro phenyl
  • R 5 is 2, 3 -difluoro phenyl
  • R 5 is 2, 5 -difluoro phenyl
  • R 5 is 2,6-difluoro phenyl
  • R 5 is 3, 5 -difluoro phenyl
  • R 5 is difluoromethyl phenyl
  • R 5 is 2-difluoromethyl phenyl
  • R 5 is trifluoromethyl phenyl
  • R 5 is 2- trifluoromethyl phenyl
  • R 5 is 3 -trifluoromethyl phenyl
  • R 5 is fluoro trifluoromethyl phenyl
  • R 5 is 4-fluoro-2-trifluoromethyl phenyl
  • R 5 is chloro phenyl
  • R 5 is 2-chloro phenyl
  • R 5 is 3 -chloro phenyl
  • R 5 is chloro fluoro phenyl
  • R 5 is 5-chloro-2-fluorophenyl
  • R 5 is 3-chloro-4-fluoro phenyl; or R 5 is 4-chloro-5-fluoro phenyl; or
  • R 5 is 2-chloro-6-fluoro-phenyl
  • R 5 is methoxy phenyl
  • R 5 is 2-methoxy phenyl
  • R 5 is 3 -methoxy phenyl
  • R 5 is trifluoromethoxy phenyl
  • R 5 is 2-trifluoromethoxy phenyl
  • R 5 is 3 -trifluoromethoxy phenyl
  • R 5 is 4-trifluoromethoxy phenyl
  • R 5 is difluoromethoxy phenyl
  • R 5 is 4-difluoromethoxy phenyl
  • R 5 is fluoro-(trifluoromethoxy) phenyl
  • R 5 is 5-fluoro-2-(trifluoromethoxy) phenyl
  • R 5 is hydroxy phenyl
  • R 5 is 3-hydroxy phenyl
  • R 5 is 2,6-difluoro phenyl
  • R 5 is methyl phenyl
  • R 5 is 2-methyl phenyl
  • R 5 is dimethyl phenyl
  • R 5 is 2,6-dimethyl phenyl
  • R 5 is propan-2-yl phenyl
  • R 5 is 2-(propan-2-yl) phenyl
  • R 5 is 3-(propan-2-yl) phenyl
  • R 5 is naphthyl
  • R 5 is 1 -naphthyl
  • R 5 is 2-naphthyl
  • R 5 is tetrahydronaphthyl
  • R 5 is 5,6,7,8-tetrahydronaphthyl
  • R 5 is thiophene
  • R 5 is 3 -thiophene
  • R 5 is phenol; or R 5 is 3 -phenol; or
  • R 5 is pyrazole
  • R 5 is N-methyl pyrazole
  • R 5 is 1 -N-methyl -4-pyrazole
  • R 5 is benzopyrazole
  • R 5 is N-methyl benzopyrazole
  • R 5 is 1 -N-methyl -7-benzopyrazole
  • R 5 is benzodioxyl
  • R 5 is difluorobenzodioxyl
  • R 5 is 2,2-difluorobenzodioxyl
  • R 5 is indazolyl
  • R 5 is lH-indazolyl
  • R 5 is methyl-indazolyl
  • R 5 is 1 -methyl- lH-indazol-7-yl
  • R 5 is sulfamoyl phenyl
  • R 5 is 4-sulfamoyl phenyl
  • R 5 is benzo-N-methylsulfamoyl
  • R 5 is 3-benzo-N-methylsulfamoyl
  • R 5 is methyl benzoate
  • R 5 is methyl-4-benzoate
  • R 5 is benzamide
  • R 5 is benz-3-amide
  • Y is -(CH 2 ) 3 -;
  • Y is -(CH 2 ) 4 -;
  • Y is -(CH 2 )-0-(CH 2 )-, or
  • Y is -(CH 2 )-0-(CH 2 ) 2 -, or
  • Y is -S-(CH 2 )-.
  • R 1 R , and R 3 are as defined for compounds of formula (I) and;
  • R 4 is H
  • R 6 is selected from hydroxy, acyl, acyloxy, halogen, amino, thio, cyano, nitro, nitrile, silyl, optionally substituted Ci_C 6 alkyl, optionally substituted Ci_C 6 haloalkyl, optionally substituted -OCi_C 6 alkyl, optionally substituted -OCi_C 6 haloalkyl, optionally substituted Ci_C 6 alkyl amino, optionally substituted Ci_C 6 dialkyl amino, optionally substituted acylamino, optionally substituted oxyacyl, optionally substituted sulfamoyl, optionally substituted sulfonyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted C 2 - C 12 heterocyclyl, optionally substituted aryl, optionally substituted aryloxy, and optionally substituted heteroaryl; and
  • R is selected from hydrogen, hydroxy, acyl, acyloxy, halogen, amino, thio, cyano, nitro, nitrile, silyl, optionally substituted Ci_C 6 alkyl, optionally substituted Ci_C 6 haloalkyl, optionally substituted -OCi_C 6 alkyl, optionally substituted -OCi_C 6 haloalkyl, optionally substituted Ci_C 6 alkyl amino, optionally substituted Ci_C 6 dialkyl amino, optionally substituted acylamino, optionally substituted oxyacyl, optionally substituted sulfamoyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted C 2 -C 12 heterocyclyl, optionally substituted aryl, optionally substituted aryloxy, and optionally substituted heteroaryl.
  • R 1 and R 2 are both H.
  • R 3 is H or CH 3 .
  • R 3 is H.
  • R 6 is halogen, Ci-C 6 haloalkyl, -OCi-C 6 -alkyl or Ci-C 6 alkyl.
  • R 6 is halogen, Ci-C 6 haloalkyl, or -OCi-C 6 -alkyl.
  • R 7 is H.
  • R 6 is halogen, Ci-C 6 haloalkyl, or -OCi-C 6 -alkyl
  • R 7 is H.
  • R 1 and R 2 are both H
  • R 3 is H or CH 3 ;
  • R 6 is halogen, Ci-C 6 haloalkyl, -OCi-C 6 -alkyl or Ci-C 6 alkyl;
  • R 7 is H.
  • salts of the compounds of the invention are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts.
  • pharmaceutically acceptable derivatives includes pharmaceutically acceptable esters, prodrugs, solvates and hydrates of the compounds of formula (I), or salts thereof.
  • Pharmaceutically acceptable derivatives may include any pharmaceutically acceptable hydrate or any other compound or prodrug which, upon administration to a subject, is capable of providing (directly or indirectly) a compound of formula (I), or an active metabolite or residue thereof.
  • the pharmaceutically acceptable salts include acid addition salts, base addition salts, and the salts of quaternary amines and pyridiniums.
  • the acid addition salts are formed from a compound of the invention and a pharmaceutically acceptable inorganic or organic acid including but not limited to hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, toluenesulphonic, benzenesulphonic, acetic, propionic, ascorbic, citric, malonic, fumaric, maleic, lactic, salicylic, sulfamic, or tartaric acids.
  • the counter ion of quaternary amines and pyridiniums include chloride, bromide, iodide, sulfate, phosphate, methansulfonate, citrate, acetate, malonate, fumarate, sulfamate, and tartrate.
  • the base addition salts include but are not limited to salts such as sodium, potassium, calcium, lithium, magnesium, ammonium and alkylammonium.
  • basic nitrogen-containing groups may be quaternised with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.
  • the salts may be made in a known manner, for example by treating the compound with an appropriate acid or base in the presence of a suitable solvent.
  • the compounds of the invention may be in crystalline form and/or as solvates (e.g. hydrates) and it is intended that both forms be within the scope of the present invention.
  • solvate is a complex of variable stoichiometry formed by a solute (in this invention, a compound of the invention) and a solvent. Such solvents should not interfere with the biological activity of the solute. Solvents may be, by way of example, water, ethanol or acetic acid. Methods of solvation are generally known within the art.
  • pro-drug is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, for example, compounds where a free hydroxy group is converted into an ester derivative or a ring nitrogen atom is converted to an N-oxide. Examples of ester derivatives include alkyl esters, phosphate esters and those formed from amino acids, preferably valine. Any compound that is a prodrug of a compound of the invention is within the scope and spirit of the invention.
  • pharmaceutically acceptable ester includes biologically acceptable esters of a compound of the invention such as sulphonic, phosphonic and carboxylic acid derivatives.
  • a prodrug or pharmaceutically acceptable ester of a compound of the invention or of a salt thereof is provided.
  • the compounds of the invention may have at least one asymmetric centre, and therefore are capable of existing in more than one stereoisomeric form.
  • the invention extends to each of these forms individually and to mixtures thereof, including racemates.
  • the isomers may be separated conventionally by chromatographic methods or by using a resolving agent.
  • the individual isomers may be prepared by asymmetric synthesis using chiral intermediates.
  • the compound has at least one carbon-carbon double bond, it may occur in Z- and E- forms with all isomeric forms of the compounds being included in the present invention.
  • alicyclic compounds can also display cis trans isomerism.
  • the compounds of formula (I) comprise a pyrrolidine which is capable of existing in more than one stereoisomeric form.
  • the substituents about the pyrrolidine may be in a c/.v-form.
  • the substituents about the pyrrolidine may be in a trans- form.
  • the compound of formula (I) may be a mixture of cis- and trans- isomers.
  • the asymmetric centres of an alicyclic compound, such as a pyrrolidine for example may also (or as an alternative) be assigned as R- or 5- to denote the relative stereochemistry.
  • the invention also includes where possible a salt or pharmaceutically acceptable derivative such as a pharmaceutically acceptable ester, solvate and/or prodrug of the aforementioned embodiments of the invention.
  • a pharmaceutical composition that comprises a therapeutically effective amount of one or more of the aforementioned compounds or pharmaceutically acceptable salts thereof, including pharmaceutically acceptable derivatives thereof, and optionally a pharmaceutically acceptable carrier or diluent.
  • the present invention provides pharmaceutical compositions for use as a sodium ion channel modulators, more particularly as pain relief agents, the composition comprising an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, including a pharmaceutically acceptable derivative thereof, and optionally a pharmaceutically acceptable carrier or diluent.
  • composition is intended to include the formulation of an active ingredient with encapsulating material as carrier, to give a capsule in which the active ingredient (with or without another carrier) is surrounded by carriers.
  • compositions or formulations include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • the compounds of the invention may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • Formulations containing ten (10) milligrams of active ingredient or, more broadly, 0.1 to one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
  • the compounds of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of the invention or a pharmaceutically acceptable salt of a compound of the invention.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispensable granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilisers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid that is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from five or ten to about seventy percent of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
  • a low melting wax such as an admixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions.
  • parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
  • Sterile liquid form compositions include sterile solutions, suspensions, emulsions, syrups and elixirs.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both.
  • the compounds according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, eg. sterile, pyrogen-free water, before use.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
  • solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilising agents, and the like.
  • the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
  • Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
  • the formulations may be provided in single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomising spray pump.
  • the compounds according to the invention may be encapsulated with cyclodextrins, or formulated with other agents expected to enhance delivery and retention in the nasal mucosa.
  • Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • CFC chlorofluorocarbon
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by provision of a metered valve.
  • the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • a powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
  • the compound In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 5 to 10 microns or less. Such a particle size may be obtained by means known in the art, for example by micronisation.
  • formulations adapted to give sustained release of the active ingredient may be employed.
  • the pharmaceutical preparations are preferably in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the invention also includes the compounds in the absence of carrier where the compounds are in unit dosage form.
  • the amount of the compound of the invention to be administered may be in the range from about 10 mg to 2000 mg per day, depending on the activity of the compound and the disease to be treated.
  • Liquids or powders for intranasal administration, tablets or capsules for oral administration and liquids for intravenous administration are the preferred compositions.
  • the pharmaceutical preparations of the compounds according to the present invention may be co-administered with one or more other active agents in combination therapy.
  • the pharmaceutical preparation of the active compound may be co-administered (for example, separately, concurrently or sequentially), with one or more other agents used to treat cognitive impairment or mood disorders such as acetylcholine esterase inhibitors, antipsycho tics, and antidepressants.
  • NMR Agilent DD2 (500 MHz), Aglient DD2 (600 MHz) or Varian DD2 (300 MHz) using residual signal of deuterated solvent as internal reference.
  • LCMS Agilent Technologies LC/MS (1260 Infinity, 6120 Quadrupole LC/MS), column Zorbax SB-C8, 4.6 x l50mm, 5m, with mobile phase 80% ACN, 15% H 2 0, 5% buffer (3: 1 MeOH/H 2 0, 315 mg HC0 2 NH 4 , 1 mL AcOH) and MS detection (ESI method).
  • Analytical thin-layer chromatography was performed on Merck silica gel 60F254 aluminium-backed plates which were visualised using fluorescence quenching under UV light or using an acidic anisaldehyde or a basic potassium permanganate dip. Flash chromatography was performed using either a Teledyne Isco CombiFlash Rf purification system using standard RediSep® cartridges or classically using conventional chromatographic equipment and techniques. Microwave irradiation was achieved using a CEM Explorer 48 Microwave Reactor. All reactions carried out using microwave irradiation were stirred.
  • anhydrous solvents were prepared using a Glascontour purification system or purchased from Sigma- Aldrich.
  • Scheme A outlines the synthesis of four isomeric intermediates, 7, 9, 10 and 11, which are accessible utilising enantiomerically pure lactam 1 or its enantiomer.
  • Bromophenols of type 2 can be protected via treatment with TBDMSC1 in the presence of imidazole in DCE. It is conceivable that other bases and solvents can also be used such as TEA and DCM to affect TBDMS protection of the phenol.
  • the resultant phenyl bromides, 3, can be treated with nBuLi in THF to yield substituted phenyl lithium intermediates which when reacted with lactams of type 1 give ketones of type 4.
  • ketones of type 4 can be accessed via treatment of phenyl bromides of type 3 with magnesium in THF to give phenyl magnesium bromide intermediates which are then reacted with lactams of type 1.
  • Subsequent cyclisation via imine formation can be affected by treatment with TFA in DCM to give imines of type 5 and 6.
  • Foss of the TBDMS protecting group is occasionally observed at this point or following the subsequent reduction, which eliminates the requirement for the final deprotection step.
  • Imines of type 5 and 6 can be reduced via hydrogenation in the presence of Pt0 2 in MeOH to give pyrrolidines of type 7 and 8. The reduction can also be performed via treatment with NaB3 ⁇ 4 in MeOH.
  • TBDMS protecting group is still in place after the previous two steps it can be cleaved via treatment of 8 with TBAF in DCM to give pyrrolidines of type 7 and 9.
  • Other methods of cleaving TBDMS protected phenols could be used and are outlined in Greene’s Protective Groups in Organic Synthesis (Fourth Edition) by Wuts P G M and Greene T W, New Jersey, John Wiley & Sons, Inc., 2007.
  • Scheme B outlines the synthesis of compounds of Formula (I).
  • Amines of type 12, where R 5 is optionally substituted aryl, heteroaryl or heterocyclyl can be converted to azides of type 14 via diazotization with NaN0 2 and HC1 in THF at low temperatures followed by treatment with NaN 3 .
  • Azides of type 14 can also be accessed via copper mediated azide displacement of bromides of type 13, where R 5 is as defined above, in the presence of sodium ascorbate and N,N’-DMED in EtOH/H 2 0.
  • Other bases and ligands can also be used such as NaOH and L- proline.
  • Neat azides can be reacted with p-toluene sulfonyl cyanide at l00°C in a pressure vessel to give sulfonyl tetrazoles of type 15.
  • sulfonyl tetrazoles of type 15 can be generated from isothiocyanates. Reaction of isothiocyanates of type 16, where R 5 is optionally substituted aryl, heteroaryl or heterocyclyl, with NaN 3 in EtOH yields thiotetrazoles of type 17.
  • Reaction of thiotetrazoles of type 17 with 4-iodotoluene in the presence of CuCl, K 2 C0 3 , and ethylenediamine in DMF yields p-toluene thiotetrazoles of type 18.
  • Subsequent oxidation of p- toluene thiotetrazoles of type 18 with mCPBA in DCM gives sulfonyl tetrazoles of type 15.
  • Other oxidants could also be used such as H 2 0 2 , NaOCl, dimethyldioxirane, Oxone® or KMn0 4 .
  • Sulfonyl tetrazoles of type 15 can be coupled with phenols of type 7, 9, 10 or 11 in the presence of a base to generate ethers of type 24.
  • K 2 C0 3 in DMF is indicated in Scheme B, however, alternative bases such as NaH or potassium /-butoxide could be used, as well as other solvents such as THF, to affect the transformation.
  • Ethers of type 24 can be converted to compounds of Formula (I) via treatment with NH 3 in MeOH to produce primary amides or with methylamine or dimethylamine in THF to produce secondary and tertiary amides respectively.
  • ethers of type 24 can be converted to compounds of Formula (I) by reaction with dimethylaluminium amides, which are easily prepared via treatment of primary or secondary amines with AlMe 3 , in DCM to form secondary and tertiary amides.
  • Compounds of Formula (I) can also be accessed via bromotetrazoles of type 19.
  • Reaction of isothiocyanates of type 16, where R 5 is optionally substituted aryl, heteroaryl or heterocyclyl, with NaN 3 in EtOH yields thiotetrazoles of type 17.
  • Treatment of the thiotetrazoles of type 17 with ZnBr and AcOOH in AcOH gives bromotetrazoles of type 19.
  • Subsequent coupling of bromotetrazoles of type 19 with phenols of type 7, 9, 10 or 11 in a similar manner as described above for sulfonyl tetrazoles of type 15 generates ethers of type 24, which in turn are converted to compounds of Formula (I).
  • Compounds of Formula (I) can also be accessed via chlorotetrazoles of type 23.
  • Reaction of amines of type 12, where R 5 is optionally substituted aryl, heteroaryl or heterocyclyl, with formic acid in the presence of I 2 yields formamides of type 20.
  • ethyl formate can be used in exchange for I 2 in the formation of formamides.
  • Treatment of formamides of type 20 with S0 2 Cl 2 in SOCl 2 generates isocyanide dichlorides of type 22.
  • isocyanide dichlorides of type 22 can be accessed through formamide dehydration of formamides of type 20 via treatment with POCl 3 and TEA in DCM to give isocyanides of type 21 and subsequent chlorination with S0 2 Cl 2 in DCM. Reaction of isocyanide dichlorides of type 22 with NaN 3 in acetone/water gives chlorotetrazoles of type 23. Alternatively, chlorotetrazoles of type 23 can be accessed via reaction of isocyanide dichlorides of type 22 with NaN 3 in a biphasic mixture of toluene and water in the presence of TBAB.
  • Scheme C outlines an alternative sequence of chemical transformations to achieve compounds of Formula (I).
  • Phenols of type 7, 9, 10 or 11 can be converted to amides of type 25 via treatment with NH 3 in MeOH to form primary amides or by reaction with dimethylaluminium amides, which are easily prepared via treatment of primary or secondary amines with AlMe 3 , in DCM to form secondary and tertiary amides.
  • Secondary and tertiary amides can also be produced via reaction of phenols of type 7, 9, 10 or 11 with methylamine or dimethylamine respectively in THF (Scheme B).
  • amides of type 25 can be coupled with tetrazoles of type 15, 19, or 23 in the presence of a base to generate compounds of Formula (I).
  • K 2 C0 3 in DMF is indicated in Scheme C, however, alternative bases such as NaH or potassium /-butoxide could be used, as well as other solvents such as THF, to affect the transformation.
  • Phenols of type 7, 9, 10 or 11 can also be Boc protected, to prevent degradation, via treatment with BocoO in the presence of NaHC0 3 and 'BLIOH in THF to give phenols of type 26. Subsequently, phenols of type 26 can be converted to amides in a similar manner as described above for phenols of type 7, 9, 10 or 11. Amides of type 27 can also be coupled with tetrazoles of type 15, 19, or 23 in the presence of a base to generate compounds of type 28 in a similar manner to amides of type 25 as described above. Finally, deprotection of compounds of type 28 via treatment with 4N HC1 in dioxane in MeOH leads to the formation of compounds of Formula
  • Methyl substitution can be affected via treatment of compounds of Formula (I) with formaldehyde, NaBH 3 CN, and AcOH in MeOH.
  • Ethyl substitution can be affected via treatment of compounds of Formula (I) with NaBH 4 in AcOH.
  • ethyl substituted compounds can be obtained via treatment of compounds of Formula (I) with iodoethane in the presence of K2CO3 in DMF.
  • Isopropyl substitution can be affected via treatment of compounds of Formula (I) with acetone, NaBH(OAc) 3 , and AcOH in DCE.
  • Cyclopropyl substituted compounds can be obtained via treatment of compounds of Formula (I) with ( 1 -ethoxycyclopropoxy)trimethylsilane in the presence of NaoSO ⁇ AcOH, and NaBH 3 CN in MeOH.
  • the reducing agents NaBH 3 CN, NaB3 ⁇ 4, and NaBH(OAc) 3 can potentially be used interchangeably across the four reductive alkylation reactions. Substitution on the basic nitrogen is also possible via amide bond formation.
  • Treatment of compounds of Formula (I) with acid chlorides, such as acetyl chloride, in the presence of TEA in DCM leads to the formation of tertiary amides.
  • Scheme E shows that substitution on the basic nitrogen can also be undertaken prior to the conversion of the terminal methyl ether group to an amide.
  • Reaction of ethers of type 24 with alkyl bromides, such as 2-bromoethyl methyl ether as depicted in Scheme E, in the presence of K 2 C0 3 in DMF leads to the formation of ethers of type 78.
  • Ethers of type 78 can then be converted to compounds of Formula (I) via treatment with NH 3 in MeOH to produce primary amides or with methylamine or dimethylamine in THF to produce secondary and tertiary amides respectively.
  • ethers of type 78 can be converted to compounds of Formula (I) by reaction with dimethylaluminium amides, which are easily prepared via treatment of primary or secondary amines with AlMe 3 , in DCM to form secondary and tertiary amides.
  • Scheme F
  • Scheme F outlines the synthesis of four phenols 37, 38, 39 and 40, which can be substituted for phenols 7, 9, 10 or 11 in Schemes B and C, previously described, to yield seven membered ring analogues.
  • Diacids of type 29 can be converted to azepines of type 30 via a three step synthesis as described in New J. Chem., 38(12), 5905-5917; 2014.
  • Azepines of type 30 are Boc protected via treatment with BocoO in the presence of NaHC0 3 and 'BuOH in THF to give azepines of type 31.
  • Bromophenols of type 2 can be protected via treatment with TBDMSC1 in the presence of imidazole in DCE.
  • ketones of type 32 can be accessed via treatment of phenyl bromides of type 3 with magnesium in THF to give phenyl magnesium bromide intermediates which are then reacted with azepines of type 31. Subsequent cyclisation via imine formation can be affected by treatment with TFA in DCM to give imines of type 33 and 34.
  • Imines of type 33 and 34 can be reduced via hydrogenation in the presence of Pt0 2 in MeOH to give azepines of type 35 and 36.
  • the reduction can also be performed via treatment with NaBH 4 in MeOH. If the TBDMS protecting group is still in place after the previous two steps it can be cleaved via treatment of 36 with TBAF in DCM to give phenols of type 35, which encapsulates isomers 37, 38, 39 and 40. Separation of isomers 37-40 could be achieved through classical separation methods where the isomers are diastereomers.
  • isomers are enantiomers chromatographic methods, such as chiral HPLC or SFC, could be employed.
  • classical methods such as derivatisation with chiral auxiliaries or the formation of chiral salts could be used. Separation of racemic mixtures 30 or 31 utilising the methods described above could also be achieved.
  • Scheme G outlines the synthesis of four phenols 49, 51, 52 and 53, which can be substituted for phenols 7, 9, 10 or 11 in Schemes B and C previously described to yield six membered morpholine ring analogues.
  • Amino acids of type 41 can undergo reductive amination with 4- methoxybenzaldehyde in the presence of NaOH in water, followed by treatment with NaB3 ⁇ 4, to give the para methoxy benzyl protected derivatives of type 42.
  • Compounds of type 42 undergo cyclisation when treated with 2-chloroacetyl chloride in the presence of NaOH in water. Subsequent treatment with SOCl 2 in MeOH gives methyl ester oxomorpholine derivatives of type 43.
  • Deprotection of compounds of type 43 is affected via treatment with ceric ammonium nitrate in a mixture of CH 3 CN and water to give oxomorpholines of type 44.
  • Oxomorpholines of type 44 are Boc protected via treatment with Boc 2 0 in the presence of NaHC0 3 and 'BuOH in THF to give oxomorpholines of type 45.
  • Bromophenols of type 2 can be protected via treatment with TBDMSC1 in the presence of imidazole in DCE.
  • Other bases and solvents can also be used such as TEA and DCM.
  • ketones of type 48 can be accessed via treatment of phenyl bromides of type 3 with magnesium in THF to give phenyl magnesium bromide intermediates which are then reacted with oxomorpholines of type 45.
  • Subsequent cyclisation via imine formation can be affected by treatment with TFA in DCM to give imines of type 47 and 48. Loss of the TBDMS protecting group is occasionally observed at this point or following the subsequent reduction, which eliminates the requirement for the final deprotection step.
  • Imines of type 47 and 48 can be reduced via hydrogenation in the presence of Pt0 2 in MeOH to give oxomorpholines of type 49 and 50.
  • the reduction can also be performed via treatment with NaB3 ⁇ 4 in MeOH. If the TBDMS protecting group is still in place after the previous two steps it can be cleaved via treatment of 50 with TBAF in DCM to give phenols of type 49 and 51.
  • Phenols 52 and 53 can be accessed via the use of the alternative isomer of amino acid 41 in the first step.
  • Scheme H outlines the synthesis of derivatives of compounds of Formula (I) which have an oxazepan ring.
  • Boc protected serine esters 55 can be reacted with propargyl bromides 54 in the presence of NaH in DMF to yield alkynes of type 56.
  • Chlorotetrazoles of type 23, previously described, can be coupled with bromophenols of type 57 to give ethers of type 58.
  • K 2 C0 3 in DMF is indicated in Scheme H, however, alternative bases such as NaH or potassium /-butoxide could be used, as well as other solvents such as THF, to affect the transformation.
  • Alkynes of type 56 and ethers of type 58 can then undergo Sonogashira coupling to produce alkynes of type 59.
  • Pd(PPli3)Cl2, Cul, and TEA in THF is indicated in Scheme H, however, alternative catalysts such as Pd(PPh 3)4 and Pd 2 (dba) 3 could be used, as well as other bases, such as DIPEA, and solvents such as dioxane and DMF, to affect the transformation.
  • Compounds of type 59 can then be Boc deprotected via treatment with a methanolic solution of HC1, in EtOAc, generated from acetyl chloride in MeOH, to produce compounds of type 60.
  • Compounds of type 60 can then undergo cyclisation via treatment with silver triflate in a suitable solvent such as DCM, THF or DMF to give cyclized compounds of type 61.
  • oxazepans of type 62 Reduction of compounds of type 61 via hydrogenation give oxazepans of type 62. 5% Pt/C and EtOAc are indicated in Scheme H, however, other catalysts, such as 5% Pd/C, and solvents, such as MeOH and EtOH, could be substituted.
  • oxazepans of type 62 with NH 3 in MeOH yields isomeric oxazepans 63 and 64.
  • Oxazepans 65 and 66 can be accessed via the use of the alternative isomer of Boc protected serine ester 55 in the first step.
  • Scheme I outlines the synthesis of four phenols 73, 75, 76 and 77, which can be substituted for phenols 7, 9, 10 or 11 in Schemes B and C, previously described, to yield six membered ring analogues.
  • Piperidine acids of type 67 can be converted to piperidine methyl esters of type 68 via treatment with SOCl 2 in MeOH.
  • Piperidines of type 68 are Boc protected via treatment with BocoO in the presence of TEA and DMAP in DCM to give piperidines of type 69.
  • Bromophenols of type 2 can be protected via treatment with TBDMSC1 in the presence of imidazole in DCE.
  • Other bases and solvents can also be used such as TEA and DCM.
  • ketones of type 70 can be accessed via treatment of phenyl bromides of type 3 with magnesium in THF to give phenyl magnesium bromide intermediates which are then reacted with piperidines of type 69.
  • Subsequent cyclisation via imine formation can be affected by treatment with TFA in DCM to give imines of type 71 and 72. Loss of the TBDMS protecting group is occasionally observed at this point or following the subsequent reduction, which eliminates the requirement for the final deprotection step.
  • Imines of type 71 and 72 can be reduced via hydrogenation in the presence of Pt0 3 in MeOH to give piperidines of type 73 and 74.
  • the reduction can also be performed via treatment with NaB3 ⁇ 4 in MeOH. If the TBDMS protecting group is still in place after the previous two steps it can be cleaved via treatment of 74 with TBAF in DCM to give phenols of type 73 and 75.
  • Phenols 76 and 77 can be accessed via the use of the alternative isomer of piperidine acid 67 in the first step.
  • Scheme J outlines a sequence of chemical transformations to achieve compounds of Formula (I) with piperidine ring systems.
  • Phenols of type 73, 75, 76 or 77 can be converted to amides of type 79 via treatment with NH 3 in MeOH to form primary amides or by reaction with dimethylaluminium amides, which are easily prepared via treatment of primary or secondary amines with AlMe 3 , in DCM to form secondary and tertiary amides.
  • amides of type 79 can be coupled with tetrazoles of type 15, 19, or 23 in the presence of a base to generate compounds of Formula (I).
  • protecting groups may require the use of protecting groups in order to obtain the desired compound.
  • Protecting groups can be installed and removed using standard techniques, well known in the industry, such as those described in Greene’s Protective Groups in Organic Synthesis (Fourth Edition) by Wuts P G M and Greene T W, New Jersey, John Wiley & Sons, Inc., 2007.
  • Pyrrolidines 7, 9, 10 and 11 and piperidines 73, 75, 76 and 77 should be stored below -4°C to prevent isomerisation.
  • reaction mixture was extracted with EtOAc and the organic extracts combined, dried (MgS0 4 ), filtered and concentrated in vacuo.
  • the crude residue was flushed through a short plug of silica (eluent 100% hexane or Et 2 0), dried in vacuo and used as such for the subsequent reaction.
  • hNavl.7, hNavl.2blb2, hNavl.4, hNavl.5, rNavl.6blb2 were stably expressed in human embryonic kidney cells and kept under constant antibiotic selection.
  • cells were maintained in appropriate growth medium at 37 °C and 5% CO 2 in a humidified incubator.
  • Navl.x expressing cells plated in T-25 flasks for 2-3 days prior to use and grown to 70-85% confluence were briefly trypsinized to obtain a single cell suspension of ⁇ 2-3 x 10 6 cells/ml. All electrophysiological recordings were performed at ambient temperature (21-23 °C) using automated patch clamp (Patchliner, Nanion Technologies GmbH) in the whole -cell configuration using the following solutions: Internal solution contained (in mM): CsCl (50), NaCl (10), CsF (60), EGTA (20), HEPES (10), pH 7.2 KOH, 285 mOsmol.Kg 1 .
  • External (bath) solution contained (in mM): NaCl (140), KC1 (4), MgCE (1), CaCE (2) D-Glucose monohydrate (5), HEPES (10), pH 7.4 NaOH, 298 mOsmol.kg 1 .
  • Cells were held at -120 mV and activated by 6 x 20 ms depolarising voltage pulses to -10 mV at a frequency of 0.1 Hz. Recordings were made initially in bath solution and 2-3 minutes after compound addition at increasing concentrations and steady state values were calculated from the 6 th pulse (P6). % resting state inhibition was calculated by (l-(P6drug/P6control))*l00%.
  • mice Male mice were injected subcutaneously (s.c.) with 25 m ⁇ of 2.5% formalin diluted in saline into the plantar surface of the left footpad and flinching (pain behaviour) was quantified using an automated nociception analyser from the university of California, San Diego (Yaksh et al 2001). A characteristic biphasic response in flinching behaviour was observed with Phase 1 flinching quantitated from 0-5 minutes and phase 2 flinching quantitated from 10 - 30 minutes post formalin. In general, animals were administered a single dose of compound 30 minutes prior to formalin via the oral route and treatment animals were scored for phase 1 and phase 2 cumulative flinching against appropriate vehicle treated controls.

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Abstract

La présente invention concerne des composés utiles dans la modulation de l'activité des canaux ioniques dans des cellules. L'invention concerne également l'utilisation de ces composés dans le traitement de la douleur, et des compositions pharmaceutiques contenant ces composés ainsi que leurs procédés de préparation.
PCT/AU2018/051409 2017-12-27 2018-12-24 Composés thérapeutiques et leurs utilisations WO2019126842A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012007836A1 (fr) * 2010-07-16 2012-01-19 Purdue Pharma .Lp. Composés pyridines comme bloqueurs des canaux sodiques
WO2014151393A2 (fr) * 2013-03-15 2014-09-25 Purdue Pharma L.P. Dérivés de carboxamide et leur utilisation
WO2015099841A1 (fr) * 2013-12-23 2015-07-02 Purdue Pharma L.P. Indazoles et leur utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012007836A1 (fr) * 2010-07-16 2012-01-19 Purdue Pharma .Lp. Composés pyridines comme bloqueurs des canaux sodiques
WO2014151393A2 (fr) * 2013-03-15 2014-09-25 Purdue Pharma L.P. Dérivés de carboxamide et leur utilisation
WO2015099841A1 (fr) * 2013-12-23 2015-07-02 Purdue Pharma L.P. Indazoles et leur utilisation

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