WO2011069951A1 - Imidazolidinedione derivatives - Google Patents

Imidazolidinedione derivatives Download PDF

Info

Publication number
WO2011069951A1
WO2011069951A1 PCT/EP2010/068946 EP2010068946W WO2011069951A1 WO 2011069951 A1 WO2011069951 A1 WO 2011069951A1 EP 2010068946 W EP2010068946 W EP 2010068946W WO 2011069951 A1 WO2011069951 A1 WO 2011069951A1
Authority
WO
WIPO (PCT)
Prior art keywords
oxy
pyridinyl
methyl
phenyl
ethyl
Prior art date
Application number
PCT/EP2010/068946
Other languages
English (en)
French (fr)
Inventor
Giuseppe Alvaro
Anne Decor
Stefano Fontana
Dieter Hamprecht
Charles Large
Agostino Marasco
Original Assignee
Glaxo Group Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0921760A external-priority patent/GB0921760D0/en
Priority claimed from GBGB1012924.5A external-priority patent/GB201012924D0/en
Priority to ES10788314.2T priority Critical patent/ES2575215T3/es
Priority to BR112012015868A priority patent/BR112012015868A2/pt
Priority to CA2781685A priority patent/CA2781685C/en
Priority to JP2012542487A priority patent/JP5788404B2/ja
Priority to KR1020127018080A priority patent/KR101735675B1/ko
Priority to AU2010330048A priority patent/AU2010330048B9/en
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to DK10788314.2T priority patent/DK2509961T3/en
Priority to MX2012006615A priority patent/MX2012006615A/es
Priority to CN201080056084.0A priority patent/CN102753533B/zh
Priority to EA201290310A priority patent/EA019970B8/ru
Priority to US13/515,097 priority patent/US8722695B2/en
Priority to EP10788314.2A priority patent/EP2509961B1/en
Publication of WO2011069951A1 publication Critical patent/WO2011069951A1/en
Priority to DK11805571.4T priority patent/DK2649066T3/en
Priority to ES11805571.4T priority patent/ES2560304T3/es
Priority to US13/991,486 priority patent/US9346790B2/en
Priority to CN201180058712.3A priority patent/CN103328467B/zh
Priority to EA201390609A priority patent/EA023768B1/ru
Priority to BR112013013914-5A priority patent/BR112013013914B1/pt
Priority to AU2011340258A priority patent/AU2011340258C1/en
Priority to EP11805571.4A priority patent/EP2649066B1/en
Priority to MX2013006343A priority patent/MX338489B/es
Priority to CA2817205A priority patent/CA2817205C/en
Priority to KR1020137017537A priority patent/KR101862375B1/ko
Priority to SG2013035357A priority patent/SG190203A1/en
Priority to PL11805571T priority patent/PL2649066T3/pl
Priority to PCT/GB2011/052414 priority patent/WO2012076877A1/en
Priority to JP2013542606A priority patent/JP5913357B2/ja
Priority to ZA2012/03233A priority patent/ZA201203233B/en
Priority to IL219628A priority patent/IL219628A/en
Priority to HK13103330.8A priority patent/HK1176353A1/zh
Priority to IL226256A priority patent/IL226256A0/en
Priority to US14/226,988 priority patent/US9216967B2/en
Priority to HK14103468.1A priority patent/HK1190395A1/xx
Priority to US14/935,939 priority patent/US20160058737A1/en
Priority to JP2016023519A priority patent/JP6118927B2/ja
Priority to US15/093,004 priority patent/US20160251340A1/en
Priority to US15/348,091 priority patent/US9849131B2/en
Priority to US15/621,400 priority patent/US10265316B2/en
Priority to IL253102A priority patent/IL253102B/en
Priority to IL253104A priority patent/IL253104A0/en
Priority to US15/722,623 priority patent/US10058551B2/en
Priority to US16/049,230 priority patent/US10632118B2/en
Priority to US16/777,668 priority patent/US20200163964A1/en
Priority to US16/985,160 priority patent/US11197859B2/en
Priority to US17/517,620 priority patent/US11583527B2/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • 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
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C07D213/643—2-Phenoxypyridines; Derivatives thereof

Definitions

  • This invention relates to novel compounds, pharmaceutical compositions containing them and their use in therapy, in particular as antipsychotic agents.
  • the Kv3 voltage-gated potassium channel family includes four members, Kv3.1 , Kv3.2, KV3.3, and Kv3.4. Genes for each of these subtypes can generate multiple isoforms by alternative splicing, producing versions with different C-terminal domains. Thirteen isoforms have been identified in mammals to date, but the currents expressed by these variants appear identical (Rudy and McBain, 2001 , Trends in Neurosciences 24, 517-526). Kv3 channels are activated by depolarisation of the plasma membrane to voltages more positive than -20mV; furthermore, the channels deactivate rapidly upon repolarisation of the membrane.
  • Kv3 channels open towards the peak of the depolarising phase of the neuronal action potential to initiate repolarisation. Rapid termination of the action potential mediated by Kv3 channels allows the neuron to recover more quickly to reach sub-threshold membrane potentials from which further action potentials can be triggered.
  • Kv3.1-3 subtypes are predominant in the CNS, whereas Kv3.4 channels are found predominantly in skeletal muscle and sympathetic neurons (Weiser et al., 1994, J. Neurosci. 14, 949-972).
  • Kv3.1-3 channel subtypes are differentially expressed by sub-classes of interneurons in cortical and hippocampal brain areas (e.g. Chow et al., 1999, J. Neurosci. 19, 9332-9345; Martina et al., 1998, J. Neurosci. 18, 81 1 1 -8125; McDonald and Mascagni, 2006, Neurosci. 138, 537- 547, Chang et al., 2007, J. Comp. Neurol. 502, 953-972), in the thalamus (e.g. Kasten et al., 2007, J.Physiol. 584, 565-582), cerebellum (e.g. Sacco et al., 2006, Mol. Cell. Neurosci. 33, 170-179), and auditory brain stem nuclei (Li et al., 2001 , J. Comp. Neurol. 437, 196-218).
  • thalamus e.g. Kasten et al.,
  • mice in which one or more of the Kv3 subtypes has been deleted shows that the absence of Kv3.1 gives rise to increased locomotor activity, altered electroencephalographic activity, and a fragmented sleep pattern (Joho et al., 1999, J.Neurophysiol. 82, 1855-1864).
  • the deletion of Kv3.2 leads to a reduction in seizure threshold and altered cortical electroencephalographic activity (Lau et al., 2000, J. Neurosci. 20, 9071-9085).
  • Deletion of Kv3.3 is associated with mild ataxia and motor deficits (McMahon et al., 2004, Eur. J. Neurosci. 19, 3317-3327).
  • Double deletion of Kv3.1 and Kv3.3 gives rise to a severe phenotype characterised by spontaneous seizures, ataxia, and an increased sensitivity to the effects of ethanol (Espinosa et al., 2001 , J.Neurosci. 21 , 6657-6665; Espinosa et al., 2008, J.Neurosci. 28, 5570-5581 ).
  • TAA Tetraethylammonium
  • BDS blood-depressing substance
  • Bipolar disorder, schizophrenia, anxiety, and epilepsy are serious disorders of the central nervous system that have been associated with reduced function of inhibitory interneurons and gamma-amino butyric acid (GABA) transmission
  • GABA gamma-amino butyric acid
  • Parvalbumin positive basket cells that express Kv3 channels in the cortex and hippocampus play a key role in generating feedback inhibition within local circuits (Markram et al., 2004, Nat. Rev. Neurosci. 5, 793-807). Given the relative dominance of excitatory synaptic input over inhibitory input to glutamatergic pyramidal neurons in these circuits, fast-firing of interneurons supplying inhibitory input is essential to ensure balanced inhibition.
  • Kv3.2 channels have been shown to be expressed by neurons of the superchiasmatic nucleus (SCN) the main circadian pacemaker in the CNS (Schuiz and Steimer, 2009, CNS Drugs 23 Suppl 2, 3-13).
  • SCN superchiasmatic nucleus
  • Kv3.2 channels varies over a 24 hour period; thus Kv3.2 channel expression may contribute to changes in the firing properties of neurons in the SCN and thus influence circadian rhythm. Consequently, drugs that modulate the activity of Kv3.2 channels could influence circadian rhythm and thus be useful in the treatment of related disorders.
  • Voltage-gated ion channels of the Kv3 family are expressed at high levels in auditory brainstem nuclei (Li et al., 2001 , J. Comp. Neurol. 437, 196-218) where they permit the fast firing of neurons that transmit auditory information from the cochlear to higher brain regions. Loss of Kv3.1 channel expression in central auditory neurons is observed in hearing impaired mice (von Hehn et al., 2004, J.
  • Kv3.1 a decline in Kv3.1 expression may be associated with loss of hearing in aged mice
  • pathological plasticity of auditory brainstem networks is likely to contribute to symptoms of tinnitus that are experienced by many people suffering from hearing loss of different types.
  • Recent studies have shown that regulation of Kv3.1 channel function and expression has a major role in controlling auditory neuron excitability (Kaczmarek et al., 2005, Hearing Res. 206, 133-145), suggesting that this mechanism could account for some of the plastic changes that give rise to tinnitus.
  • Fragile X syndrome and autism are frequently associated with hypersensitivity to sensory input, including auditory stimuli.
  • the invention provides a compound of formula (la)
  • R 1 is halo, C 1-4 alkyl, C 1-4 alkoxy, halo-C 1-4 alkyl, halo-C 1-4 alkoxy, or cyano;
  • R 2 is H, halo, cyano, d -4 alkyl or Ci -4 alkoxy; with the proviso that when R 2 is H, Ri is not in the para position;
  • X is C or N
  • Y is C or N
  • R 3 is C 1-4 alkyl
  • R 4 is H, deuterium, or C 1-4 alkyl; or R 3 and R 4 can be fused to form a C 3 . 4 spiro carbocyclyl group;
  • R 1 is halo, C1-4 alkyl or C1-4 alkoxy, halo-Ci -4 alkoxy, cyano;
  • R 2 is H, halo, Ci -4 alkyl and Ci -4 alkoxy; with the proviso that when R 2 is H, R-i is not in the para position;
  • X is C or N
  • Y is C or N
  • R 3 is C 1-4 alkyl
  • R 4 is H, deuterium, Ci -4 alkyl; or R 3 and R 4 can be fused to form a C 3-4 spiro carbocycly group;
  • the invention provides a compound of formula (Ic)
  • R 1 is halo, C1-4 alkyl or C1-4 alkoxy
  • R 2 is H, halo, C1-4 alkyl and Ci -4 alkoxy; with the proviso that when R 2 is H, R-i is not in the para position;
  • X is C or N
  • Y is C or N
  • R 3 is C1-4 alkyl
  • R 4 is H, deuterium, Ci -4 alkyl; or R 3 and R 4 can be fused to form a C 3-4 spiro carbocycly group;
  • Form (I) means any one of Formula (la), (lb), or (Ic).
  • R 1 is Ci -4 alkoxy. In another embodiment of the invention R 1 is methoxy. In one embodiment of the invention R 1 is C 1-4 alkyl. In another embodiment of the inventon R 1 is methyl. In a further embodiment of the invention R 1 is ethyl. In a yet further embodiment of the invention R 1 is propyl. In a yet further embodiment of the invention R 1 is butyl.
  • R 1 is halo. In another embodiment of the invention R 1 is chloro. In a further embodiment of the invention R 1 is fluoro.
  • R 1 is halo-C 1-4 alkoxy. In another embodiment of the invention R 1 is trifluoromethoxy.
  • R 1 is halo-C 1-4 alkyl. In another embodiment of the invention R 1 is trifluoromethyl.
  • R 1 is cyano
  • R 2 is H.
  • R 2 is C 1-4 alkyl. In another embodiment of the invention R 2 is methyl.
  • R 2 is halo. In another embodiment of the invention, R 2 is chloro. In a further embodiment of the invention R 2 is fluoro.
  • R 2 is C 1-4 alkyl.
  • R 2 is cyano
  • X is C and Y is C.
  • X is N and Y is C.
  • X is N and Y is N.
  • R 3 is methyl. In another embodiment of the invention R 3 is ethyl. In a further embodiment of the invention R 3 is propyl. In a yet further embodiment of the invention R 3 is butlyl.
  • R 4 is H.
  • R 4 is deuterium
  • R 4 is C 1-4 alkyl. In another embodiment of the invention R 4 is methyl.
  • R 3 and R 4 together form a C 3-4 spiro carbocyl. In anther embodiment of the invention R 3 and R 4 together form a C 3 spiro carbocycyl. In a further embodiment of the invention R 3 and R 4 together form a C 4 spiro carbocycyl.
  • R 3 is C 1-4 alkyl
  • R 4 is H
  • the absolute configuration of the stereogenic centre is R.
  • R 1 is C 1-4 alkyl, C 1-4 alkoxy, or halo-C 1-4 alkoxy;
  • R 2 is H, cyano or alkyl;
  • X is N, Y is N or C,
  • R 3 is C 1-4 alkyl, and
  • R 4 is C 1-4 alkyl or H; or a pharmacuetically acceptable salt thereof.
  • R-i is propyl, butyl, methoxy, propoxy, or trifluoromethoxy;
  • R 2 is H, cyano or methyl;
  • X is N, Y is N or C,
  • R 3 is ethyl, and
  • R 4 is methyl or H; or a pharmaceutically acceptable salt thereof.
  • R 1 is methoxy and R 2 is methyl. In another embodiment of the invention R 1 is methoxy in the meta position and R 2 is methyl in the para position. In a further embodiment of the invention R 1 is methoxy in the meta position, R 2 is methyl in the para position, R 3 is C 1-4 alkyl, R 4 is H, R 3 is in the R configuration. In a yet further embodiment of the invention R 1 is methoxy in the meta position, R 2 is methyl in the para position, X is N, Y is C, R 3 is C 1-4 alkyl, R 4 is H and the absolute configuration of the stereogenic centre is R,.
  • R 1 is methoxy in the meta position
  • R 2 is methyl in the para position
  • X is N
  • Y is C
  • R 3 is ethyl
  • R 4 is H
  • the absolute configuration of the stereogenic centre is R.
  • the compound is selected from the group consisting of:
  • 'halo' or 'halogen' refers to a fluorine, chlorine, bromine or iodine atom.
  • the alkyl group may be straight chain, branched, cyclic, or a combination thereof.
  • Examples of (Ci -4 )alkyl are methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl and cyclobutyl.
  • An example of (Ci -4 )alkoxy is methoxy.
  • An example of halo-C 1-4 alky is trifluoromethyl.
  • An example of halo-C 1-4 alkoxy is trifluromethoxy.
  • salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse J.Pharm.Sci (1977) 66, pp 1-19. Such pharmaceutically acceptable salts include acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid and organic acids e.g.
  • succinic maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.
  • Other salts e.g. oxalates or formates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention.
  • Certain of the compounds of formula (I) may form acid addition salts with one or more equivalents of the acid.
  • the present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.
  • the compounds of formula (I) may be prepared in crystalline or non-crystalline form and, if crystalline, may optionally be solvated, eg. as the hydrate.
  • This invention includes within its scope stoichiometric solvates (eg. hydrates) as well as compounds containing variable amounts of solvent (eg. water).
  • pharmaceutically acceptable derivatives include any pharmaceutically acceptable ester or salt of such ester of a compound of formula (I) which, upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.
  • the present invention encompasses all isomers of formula (I) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures). Where additional chiral centres are present in compounds of formula (I), the present invention includes within its scope all possible diastereoismers, including mixtures thereof.
  • the different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
  • the subject invention also includes isotopically-labeled compounds which are identical to those recited in formula (I) 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, oxygen, fluorine, iodine and chlorine such as 3 H, 11 C, 14 C, 18 F, 123 l or 125 l.
  • Isotopically labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H or 14 C have been incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, ie. 3 H, and carbon-14, ie. 14 C, isotopes are particularly preferred for their ease of preparation and detectability. 11 C and 18 F isotopes are particularly useful in PET (positron emission tomography).
  • the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions.
  • the compounds of formula (I) may be made according to the organic synthesis techniques known to those skilled in this field, as well as by the representative methods set forth in the Examples.
  • Compounds of formula (I) can be prepared by cyclization of compounds of formula (II) in a solvent e.g. dichloromethane with a carbonylating agent e.g. triphosgene preferentially prediluted in the same solvent and added in a second time at 0°C in presence of a base e.g. triethylamine. In some cases ethyl acetate could be used as a solvent. Optionally a catalytic amount of DMAP can be added.
  • acidic conditions e.g. TFA
  • a solvent e.g. dichloromethane e.g. at 0°C, RT.
  • a base e.g. DIPEA
  • a coupling agent e.g. HATU, TBTU, HBTU in a solvent such as N,N- dimethylformamide.
  • N-Boc protected amino acids of formula (V) are commercially available e.g. /V- ⁇ [(1 ,1 -dimethylethyl)oxy]carbonyl ⁇ -2-methylalanine from for example Aldrich, N- ⁇ [(1 ,1 -dimethylethyl)oxy]carbonyl ⁇ -D-alanine from for example Aldrich, (2/?)-2-( ⁇ [(1 ,1 - dimethylethyl)oxy]carbonyl ⁇ amino)butanoic acid from for example Bachem UK Ltd, N- ⁇ [(1 ,1 -dimethylethyl)oxy]carbonyl ⁇ -D-isovaline from for example Nagase & Co Ltd.
  • N-protected amino acids of formula (V) can also be prepared from compounds of formula (VI) for example with Boc-anhydride in presence of a base e.g. aqueous NaHC03, aqueous sodium hydroxide in a solvent such as THF, methanol, dioxane.
  • a base e.g. aqueous NaHC03, aqueous sodium hydroxide in a solvent such as THF, methanol, dioxane.
  • anilines (IV) are commercially available, e.g. 4- ⁇ [3-(methyloxy)phenyl]oxy ⁇ aniline for example from ChemBridge Corporation.
  • Ci-4 alkoxy and (X,Y) ⁇ (N,N) can be prepared from the nitro compounds (Vila) with the conditions described on scheme 3 or with the following conditions:
  • the phenol (IX) can be pre-stirred in presence of the solvent and the base.
  • Phenols of formula (IXa), wherein R 1 and R 2 are groups compatible with typical nitrosation conditions, can be prepared using the corresponding anilines (X) with sodium nitrite in presence of an excess of acid such as sulphuric acid in a solvent such as water, at 0°C or 0°C- 5°C in a first time and under heating in a second time e.g. at 40°C - 90°C.
  • Anilines of formula (Xa) (wherein R 1 and R 2 are groups non sensitive to typical nitrosation conditions) can be prepared from the nitro derivatives of formula (XI) (wherein R 1 and R 2 are groups non sensitive to typical nitrosation conditions) using usual reduction conditions for example
  • nitro derivatives of formula (XI) are commercially available.
  • Some other nitro derivatives such as the compound of formula (Xla) wherein R 2 is an ethoxy group can be prepared from the corresponding nitro-phenol derivative of formula (XI I) by alkylation with for example ethyl iodide in presence of a base such as potassium carbonate in acetone with heating e.g. at reflux.
  • Phenols of formula (IXb), wherein R 1 is H and R 2 is a C 1-4 alkoxy group (R 5 is a C 1-4 alkyl group) can be prepared by monoalkylation from the compounds of formula (XIII) using for example the suitable iodo-alkyl in presence of a base such as potassium hydroxide in a solvent such as ethanol.
  • a base e.g. DIPEA
  • a solvent e.g. THF
  • Some isocyanates of formula (XV) are commercially available other ones can be prepared from anilines of formula (IVb) using triphosgene and optionally triethylamine in a solvent such as dichloromethane at room temperature.
  • the two steps (ii) and (iii) can be performed in a one pot fashion; in a first time, an addition of isocyanates (XV) over aminoacides of formula (VI) in presence of a base e.g. pyridine or trietylamine in a solvent e.g. N.N-dimethylformamide or a mixture dichloromethane/DMF (e.g. at 35°C), then in a second time addition of HCI with heating (e.g. at 100°C).
  • Isocyanates can be prediluted in a solvent or not e.g. in THF.
  • amino ester of formula (XVI) can be N-protected by a Boc group by reaction with Boc-anhydride in presence of a base e.g. DMAP in a solvent e.g. dichloromethane.
  • this solution can react with anilines (IVb) with heating e.g. at 35°C and in a third time the cyclization can be promoted by addition of HCI and heating e.g. at 100°C.
  • This reaction uses the corresponding phenol of formula (IXc), a fluoro compound of formula (XVII) in presence of a base e.g. potassium carbonate heating e.g. at 120°C in a high boiling point solvent e.g. DMF.
  • a base e.g. potassium carbonate heating e.g. at 120°C in a high boiling point solvent e.g. DMF.
  • Fluoro compound of formula (XVII) can be prepared by N-arylation of 5,5- dimethyl-2,4-imidazolidinedione (XVIII) with the arylboronic acid (XIX), promoted for example by copper (II) acetate using a base e.g. pyridine and a solvent such as dichloromethane e.g. at room temperature, open to air.
  • a base e.g. sodium methoxide heating e.g. at 65°C in solvent such as methanol.
  • a base such as triethylamine in a solvent such as EtOAc
  • a carbonylating agent such as triphosgene in a solvent such as EtOAc e.g. at 0°C
  • ester (XXIa) can be pre-dissolved in a solvent such as EtOAc, the triethylamine being added to this pre-solution.
  • a solvent such as EtOAc
  • some additional triethylamine and ester (XXIa) or some additional triphosgene can be added.
  • the needed ester (XXIa) can be prepared from the corresponding aminoacid, using methanol, heating the reaction mixture e.g. at reflux, after thionyl chloride addition.
  • a base e.g. sodium methoxide heating e.g. at 65°C in solvent such as methanol.
  • a base such as triethylamine or diisopropylethy
  • ester (XXIb) can be pre-dissolved in a solvent such as EtOAc or dichloromethane, the triethylamine or diisopropylethylamine being added to this pre-solution.
  • a solvent such as EtOAc or dichloromethane
  • some additional triethylamine or diisopropylethylamine and ester (XXIb) or some additional triphosgene can be added.
  • the needed ester (XXIb) can be prepared from the corresponding aminoacid, using methanol, heating the reaction mixture e.g. at reflux, after thionyl chloride addition.
  • the organozinc intermediate can be prepared by addition of a solution of zinc dichloride on the suitable alkyl magnesium bromide solution or by reverse addition of the alkyl magnesium bromide solution on the zinc dichloride solution e.g. at -15 °C, 0°C or r.t. in solvents such as THF, diethyl ether.
  • a solution of the bromo compound (XXIII) e.g. in THF can be added e.g. at 0°C to the organozinc intermediate or reversely the organozinc intermediate solution can be added to a solution of the bromo compound (XXIII) pre-warmed e.g. at 60°C.
  • some additional Pd(iBu 3 P) 2 or some additionnal pre-formed organozinc intermediate can be added.
  • Bromo compound of formula (XXIII) can be prepared from compounds of formula (XXIV) by benzylation with benzylhalide e.g. benzyl bromide in presence of a base e.g. potassium carbonate, in a solvent such as acetone heating e.g. at 50°C.
  • benzylhalide e.g. benzyl bromide
  • a base e.g. potassium carbonate
  • the organozinc intermediate can be prepared by addition of a solution of zinc dichloride on the suitable alkyl magnesium bromide solution or by reverse addition of the alkyl magnesium bromide solution on the zinc dichloride solution e.g. at -15 °C, 0°C or room temperature in solvents such as THF, diethyl ether.
  • a solution of the halo compound (Vlld) e.g. in THF can be added e.g. at 0°C to the organozinc intermediate or reversely the organozinc intermediate solution can be added to a solution of the halo compound (VI Id) pre-warmed e.g. at 60°C.
  • some additional Pd(iBu 3 P) 2 or some additionnal pre-formed organozinc intermediate can be added.
  • step i Compound of formula (XXVII) can be prepared by a Reimer-Tiemann formylation starting from compound of formula (XXVIII) in a solvent such as a mixture MeOH/water, using an hydroxide base such as sodium hydroxide in water, heating e.g. at 60°C and adding chloroform.
  • a solvent such as a mixture MeOH/water
  • an hydroxide base such as sodium hydroxide in water
  • Phenol of formula (IXe) can be prepared from compound of formula (XXXI), using a demethylating agent such a BBr 3 , in a solvent such as dichlorometane or dichloroethane at a suitable temperature ranging from r.t. to 100°C optionally under microwave irradiation.
  • a catalyst such as Pd/C
  • step ii, i Compounds of formula (XXXII) can be prepared in 2 steps from nitro compounds of formula (XXXIII) using a similar way to the one described on schemes 3, 2 (e.g. reduction with Fe/ ammonium chloride and coupling).
  • a base such as potassium triphosphate
  • a system containing a palladium catalyst and a ligand such as (Pd(OAc) 2 / PCy 3 ) or (Pd(iBu 3 )2) in a solvent such as DMF heating e.g. at 1 10°C optionally under microwave irradiation.
  • the present invention provides compounds of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.
  • the compounds of formula (I) or their pharmaceutically acceptable salts may be of use for the treatment or prophylaxis of a disease or disorder where a modulator of the Kv3.1 or Kv3.2 or Kv3.1 and Kv3.2 channels is required.
  • a modulator of Kv3.1 or Kv3.2 or Kv 3.1 and Kv3.2 is a compound which alters the properties of these channels, either positively or negatively.
  • Kv3.1 and/or Kv3.1 channels Diseases or conditions that may be mediated by modulation of Kv3.1 and/or Kv3.1 channels may be selected from the list below.
  • the numbers in brackets after the listed diseases below refer to the classification code in Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, published by the American Psychiatric Association (DSM- IV) and/or the International Classification of Diseases, 10th Edition (ICD-10).
  • the compounds of formula (I) or their pharmaceutically acceptable salts may be of use for the treatment or prophylaxis of depression and mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (31 1 ); Bipolar Disorders including Bipolar I Disorder, Bipolar II Disorder (Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80); Other Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, With Manic Features and With Mixed Features), Substance- Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and With Mixed Features) and Mood Disorder Not Otherwise Specified (296.90); Seasonal affective disorder.
  • the compounds of formula (I) or their pharmaceutically acceptable salts may be of use for the treatment or prophylaxis of schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1 ) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition including the subtypes With Delusions and With Hallucinations; Substance-Induced Psychotic Disorder including the subtypes With Delusions (293.81 ) and With Hallucinations (293.82); and Psychotic Disorder Not
  • the compounds of formula (I) or their pharmaceutically acceptable salts may be of use for the treatment or prophylaxis of anxiety disorders including Panic Attack; Panic Disorder including Panic Disorder without Agoraphobia (300.01 ) and Panic Disorder with Agoraphobia (300.21 ); Agoraphobia; Agoraphobia Without History of Panic Disorder (300.22), Specific Phobia (300.29, formerly Simple Phobia) including the subtypes Animal Type, Natural Environment Type, Blood-lnjection-lnjury Type, Situational Type and Other Type), Social Phobia (Social Anxiety Disorder, 300.23), Obsessive-Compulsive Disorder (300.3), Posttraumatic Stress Disorder (309.81 ), Acute Stress Disorder (308.3), Generalized Anxiety Disorder (300.02), Anxiety Disorder Due to a General Medical Condition (293.84), Substance-Induced Anxiety Disorder, Separation Anxiety Disorder (309.21 ), Adjustment Disorders with Anxiety (309.24) and Anxiety Disorder Not Otherwise Specified (300.00
  • the compounds of formula (I) or their pharmaceutically acceptable salts may be of use for the treatment or prophylaxis of substance-related disorders including Substance Use Disorders such as Substance Dependence, Substance Craving and Substance Abuse; Substance-Induced Disorders such as Substance Intoxication, Substance Withdrawal, Substance-Induced Delirium, Substance-Induced Persisting Dementia, Substance-Induced Persisting Amnestic Disorder, Substance-Induced Psychotic Disorder, Substance-Induced Mood Disorder, Substance-Induced Anxiety Disorder, Substance- Induced sexual Dysfunction, Substance-Induced Sleep Disorder and Hallucinogen Persisting Perception Disorder (Flashbacks); Alcohol-Related Disorders such as Alcohol Dependence (303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00), Alcohol Withdrawal (291 .81 ), Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol- Induced Persisting
  • the compounds of formula (I) or their pharmaceutically acceptable salts may be of use for the treatment or prophylaxis of enhancement of cognition including the treatment of cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment, e.g. Alzheimer's disease.
  • the compounds of formula (I) or their pharmaceutically acceptable salts may be of use for the treatment or prophylaxis of sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition, in particular sleep disturbances associated with such diseases as neurological disorders, neuropathic pain, restless leg syndrome, heart and lung diseases; and Substance-Induced Sleep Disorder including the subtypes Insomnia
  • the compounds of formula (I) or their pharmaceutically acceptable salts may be of use for the treatment or prophylaxis of eating disorders such as Anorexia Nervosa (307.1 ) including the subtypes Restricting Type and Binge-Eating/Purging Type; Bulimia Nervosa (307.51 ) including the subtypes Purging Type and Nonpurging Type; Obesity; Compulsive Eating Disorder; Binge Eating Disorder; and Eating Disorder Not Otherwise Specified (307.50):
  • the compounds of formula (I) or their pharmaceutically acceptable salts may be of use for the treatment or prophylaxis of Autism Spectrum Disorders including Autistic Disorder (299.00), Asperger's Disorder (299.80), Rett's Disorder (299.80), Childhood Disintegrative Disorder (299.10) and Pervasive Disorder Not Otherwise Specified (299.80, including Atypical Autism).
  • the compounds of formula (I) or their pharmaceutically acceptable salts may be of use for the treatment or prophylaxis of Attention-Deficit/Hyperactivity Disorder including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01 ), Attention- Deficit /Hyperactivity Disorder Predominantly Inattentive Type (314.00), Attention-Deficit /Hyperactivity Disorder Hyperactive-Impulse Type (314.01 ) and Attention-Deficit /Hyperactivity Disorder Not Otherwise Specified (314.9); Hyperkinetic Disorder; Disruptive Behaviour Disorders such as Conduct Disorder including the subtypes childhood-onset type (321 .81 ), Adolescent-Onset Type (312.82) and Unspecified Onset (312.89), Oppositional Defiant Disorder (313.81 ) and Disruptive Behaviour Disorder Not Otherwise Specified; and Tic Disorders such as Tourette's Disorder (307.23):
  • the compounds of formula (I) or their pharmaceutically acceptable salts may be of use for the treatment or prophylaxis of Personality Disorders including the subtypes Paranoid Personality Disorder (301.0), Schizoid Personality Disorder (301.20), Schizotypal Personality Disorder (301 ,22), Antisocial Personality Disorder (301 .7), Borderline Personality Disorder (301 ,83), Histrionic Personality Disorder (301 .50), Narcissistic Personality Disorder (301 ,81 ), Avoidant Personality Disorder (301.82), Dependent Personality Disorder (301.6), Obsessive-Compulsive Personality Disorder (301.4) and Personality Disorder Not Otherwise Specified (301.9).
  • Paranoid Personality Disorder (301.0
  • Schizoid Personality Disorder 301.20
  • Schizotypal Personality Disorder 301 ,22
  • Antisocial Personality Disorder 301 .7
  • Borderline Personality Disorder 301 ,83
  • Histrionic Personality Disorder 301 .50
  • Narcissistic Personality Disorder 301 ,81
  • the compounds of formula (I) or their pharmaceutically acceptable salts may be of use for the treatment or prophylaxis of Sexual dysfunctions including Sexual Desire Disorders such as Hypoactive Sexual Desire Disorder (302.71 ), and sexual Aversion Disorder (302.79); sexual arousal disorders such as Female sexual Arousal Disorder (302.72) and Male Erectile Disorder (302.72); orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) and Premature Ejaculation (302.75); sexual pain disorder such as Dyspareunia (302.76) and Vaginismus (306.51 ); Sexual Dysfunction Not Otherwise Specified (302.70); paraphilias such as Exhibitionism (302.4), Fetishism (302.81 ), Frotteurism (302.89), Pedophilia (302.2), Sexual Masochism (302.83), sexual Sadism (302.84), Transvestic Fetishism (302.3), Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9); gender identity disorders such as
  • the compounds of formula (I) or their pharmaceutically acceptable salts may be of use for the treatment or prophylaxis of Impulse control disorder" including: Intermittent Explosive Disorder (312.34), Kleptomania (312.32), Pathological Gambling (312.31 ), Pyromania (312.33), Trichotillomania (312.39), Impulse-Control Disorders Not Otherwise Specified (312.3), Binge Eating, Compulsive Buying, Compulsive sexual Behaviour and Compulsive Hoarding.
  • Impulse control disorder including: Intermittent Explosive Disorder (312.34), Kleptomania (312.32), Pathological Gambling (312.31 ), Pyromania (312.33), Trichotillomania (312.39), Impulse-Control Disorders Not Otherwise Specified (312.3), Binge Eating, Compulsive Buying, Compulsive sexual Behaviour and Compulsive Hoarding.
  • the compounds of formula (I) or their pharmaceutically acceptable salts may be of use for the treatment or prophylaxis of hearing disorders including auditory neuropathy, auditory processing disorder, hearing loss, which includes sudden hearing loss, noise induced hearing loss, substance-induced hearing loss, and hearing loss in adults over 60 (presbycusis), and tinnitus.
  • the compounds of formula (I) or their pharmaceutically acceptable salts may be of use for the treatment or prophylaxis of Meniere's disease, disorders of balance, and disorders of the inner ear.
  • the compounds of formula (I) or their pharmaceutically acceptable salts may be of use for the treatment or prophylaxis of hyperacusis and disturbances of loudness perception, including Fragile-X syndrome and autism.
  • the compounds of formula (I) or their pharmaceutically acceptable salts may be of use for the treatment or prophylaxis of Epilepsy, (including, but not limited to, localization- related epilepsies, generalized epilepsies, epilepsies with both generalized and local seizures, and the like), seizures associated with Lennox-Gastaut syndrome, seizures as a complication of a disease or condition (such as seizures associated with encephalopathy, phenylketonuria, juvenile Gaucher's disease, Lundborg's progressive myoclonic epilepsy, stroke, head trauma, stress, hormonal changes, drug use or withdrawal, alcohol use or withdrawal, sleep deprivation, fever, infection, and the like), essential tremor, restless limb syndrome, partial and generalised seizures (including tonic, clonic, tonic-clonic, atonic, myoclonic, absence seizures), secondarily generalized seizures, temporal lobe epilepsy, absence epilepsies (including childhood, juvenile, myoclonic, photo- and
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment or prophylaxis of depression and mood disorders, hearing disorders, schizopherenea, substance abuse disorders, sleep disorders or epilepsy.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment or prophylaxis of bipolar disorder or mania.
  • treatment includes the control, mitigation, reduction, or modulation of the disease state or its symptoms.
  • prophylaxis is used herein to mean preventing symptoms of a disease or disorder in a subject or preventing recurrence of symptoms of a disease or disorder in an afflicted subject and is not limited to complete prevention of an affliction.
  • the invention also provides a method of treating or preventing a disease or disorder where a modulator of Kv3 is required, for example those diseases and disorders mentioned hereinabove, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of a disease or disorder where a modulator of Kv3 is required, for example those diseases and disorders mentioned hereinabove.
  • the invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder where a modulator of Kv3 is required, for example those diseases and disorders mentioned hereinabove.
  • the invention also provides a method of treating depression and mood disorders, schizopherenea, substance abuse disorders, sleep disorders or epilepsy, for example for those indications mentioned hereinabove, which comprises administering to a subject in need thereof an effective amount of a Kv3 modulator or a pharmaceutically acceptable salt thereof.
  • the compounds of the invention are usually administered as a pharmaceutical composition.
  • the invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the compounds of formula (I) or their pharmaceutically acceptable salts may be administered by any convenient method, e.g. by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration, and the pharmaceutical compositions adapted accordingly.
  • the compounds of formula (I) or their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids or solids, e.g. as syrups, suspensions, emulsions, tablets, capsules or lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the active ingredient in a suitable liquid carrier(s) e.g. an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • a suitable liquid carrier(s) e.g. an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
  • the formulation may also contain a suspending agent, preservative, flavouring and/or colouring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations, such as magnesium stearate, starch, lactose, sucrose and cellulose.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures, e.g. pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), e.g. aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • suitable pharmaceutical carrier(s) e.g. aqueous gums, celluloses, silicates or oils
  • Typical parenteral compositions consist of a solution or suspension of the active ingredient in a sterile aqueous carrier or parenterally acceptable oil, e.g. polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders.
  • Aerosol formulations typically comprise a solution or fine suspension of the active ingredient in a pharmaceutically acceptable aqueous or nonaqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container which can take the form of a cartridge or refill for use with an atomising device.
  • the sealed container may be a disposable dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve.
  • the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas e.g. air, or an organic propellant such as a fluorochloro- hydrocarbon or hydrofluorocarbon. Aerosol dosage forms can also take the form of pump-atomisers.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles where the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
  • a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
  • compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
  • compositions suitable for transdermal administration include ointments, gels and patches.
  • the composition is in unit dose form such as a tablet, capsule or ampoule.
  • the composition may contain from 0.1 % to 100% by weight, for example from 10 to 60% by weight, of the active material, depending on the method of administration.
  • the composition may contain from 0% to 99% by weight, for example 40% to 90% by weight, of the carrier, depending on the method of administration.
  • the composition may contain from 0.05mg to 1000mg, for example from 1.0mg to 500mg, of the active material, depending on the method of administration.
  • the composition may contain from 50 mg to 1000 mg, for example from 100mg to 400mg of the carrier, depending on the method of administration.
  • the dose of the compound 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 500mg, 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 or months.
  • the invention provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent or agents.
  • the compounds When the compounds are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route.
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • 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 infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
  • the present invention also provides Kv3 modulators, or their pharmaceutically acceptable salts, for use in the treatment or prophylaxis of depression and mood disorders, hearing disorders, schizopherenea, substance abuse disorders, sleep disorders or epilepsy.
  • Kv3 modulators or their pharmaceutically acceptable salts may be particularly useful in the treatment or prophylaxis of depression and mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (31 1 ); Bipolar Disorders including Bipolar I Disorder, Bipolar II Disorder (Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80); Other Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, With Manic Features and With Mixed Features), Substance-Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and With Mixed Features) and Mood Disorder Not Otherwise Specified (296.90), Seasonal affective disorder
  • the invention also provides a method of treating depression and mood disorders, hearing disorders, schizopherenea, substance abuse disorders, sleep disorders or epilepsy, including for example those disorders mentioned hereinabove, which comprises administering to a subject in need thereof an effective amount of Kv3 modulator or a pharmaceutically acceptable salt thereof.
  • the invention also provides a Kv3 modulator, or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of depression and mood disorders, hearing disorders, schizopherenea, substance abuse disorders, sleep disorders or epilepsy, including for example those disorders mentioned hereinabove.
  • the invention also provides the use of a Kv3 modulator, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of depression and mood disorders, hearing disorders, schizopherenea, substance abuse disorders, sleep disorders or epilepsy, including for example those disorders mentioned hereinabove.
  • the Kv3 modulators are usually administered as a pharmaceutical composition for example a composition comprising a Kv3 modulator or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for example a composition comprising a Kv3 modulator or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Such compositions, and methods of administration thereof, which compositions comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof, are described hereinabove.
  • Such compositions and methods of administration may also be used for other Kv3 modulators or pharmaceutically acceptable salts thereof, in the treatment of depression and mood disorders, hearing disorders, schizopherenea, substance abuse disorders, sleep disorders or epilepsy, including for example those disorders mentioned hereinabove.
  • Figure 1 a hKv3.2 currents recorded using the assay described in Example 89. Data shown are the individual currents over the period of the depolarising voltage step to - 15mV recorded from 4 different cells at two concentrations of the compound of Example 19. The data are fitted by a single exponential curve (solid lines) using the fitting procedure in Prism version 5 (Graphpad Software Inc).
  • Figure 2 Recordings made from identified "fast-firing" interneurons in the somatosensory cortex of the mouse.
  • Figure 4 The half-width of evoked action potentials from parvalbumin-positive interneurons in the somatosensory cortex of the mouse
  • NMR Nuclear Magnetic Resonance
  • MS_1 ESI
  • MS_2 ESI
  • HPLC-Mass spectra were taken on an Agilent 1 100 Series LC/MSD Mass Spectrometer coupled with HPLC instrument Agilent 1 100 Series, operating in positive or negative electrospray ionization mode and in both acidic and basic gradient conditions.
  • SPE-Si cartridges are silica solid phase extraction columns supplied by Varian. In a number of preparations, purification was performed on a Mass-Directed Autopurification (MDAP) system FractionlynxTM equipped with Waters 2996 PDA detector and coupled with ZQTM mass spectrometer (Waters) operating in positive and negative electrospray ionisation mode ES+, ES- (mass range 100-1000 or 100-900)
  • MDAP Mass-Directed Autopurification
  • Waters Waters 2996 PDA detector
  • ZQTM mass spectrometer Waters
  • Mobile phase A: (water + 10 mM aqueous solution of ammonium bicarbonate (adjusted to
  • Mobile phase A: water + 10 mM aqueous solution of ammonium bicarbonate (adjusted to pH 10 with ammonia), B: acetonitrile
  • Mobile phase A: water + 10 mM aqueous solution of ammonium bicarbonate (adjusted to pH 10 with ammonia), B: acetonitrile
  • Mobile phase A: (water + 10 mM aqueous solution of ammonium bicarbonate (adjusted to
  • Mobile phase A: water + 10 mM aqueous solution of ammonium bicarbonate (adjusted to pH 10 with ammonia), B: acetonitrile
  • Mobile phase A: water + 10 mM aqueous solution of ammonium bicarbonate (adjusted to pH 10 with ammonia), B: acetonitrile
  • SPE-SCX cartridges are ion exchange solid phase extraction columns supplied by Varian.
  • the eluent used with SPE-SCX cartridges is DCM and MeOH or MeCN or MeOH followed by ammonia solution in MeOH (typically 2 N).
  • the collected fractions are those eluted with the ammonia solution in MeOH unless otherwise stated.
  • reaction was quenched with brine (10 mL), diluted with water (5 mL) and extracted with diethyl ether (3 times 20 mL). The organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by silica gel chromatography (Biotage system, 25g, SNAP column) using as eluents a gradient cyclohexane/ethyl acetate from 100/0 to 70/30 to afford the title compound (440 mg) as a light yellow gum.
  • oxoethyljcarbamate (Intermediate 25, 56 mg) was dissolved in 3 mL of dry dichloromethane. To this solution at 0°C were added dropwise 30 equivalents of TFA (0.324 mL). The reaction was stirred at 0°C for 3 hours. The reaction mixture was evaporated. The crude obtained was purified by SCX on a 5g cartridge. 3 CV of methanol were used first, then the residue was adsorbed on the cartridge, washed with 5 CV of methanol and desorbed with 2 CV of methanolic ammonia (1 N). Evaporation of the volatiles, afforded the title compound (38 mg).
  • A/-ethyl-A/-(1-methylethyl)-2- propanamine (0.219 mL, 1.253 mmol) and A/-[(dimethylamino)(3/-/-[1 ,2,3]triazolo[4,5-i)]pyridin-3- yloxy)methylidene]-A/-methylmethanaminium hexafluorophosphate (381 mg, 1 .003 mmol) were added. The reaction mixture immediately became yellow and was stirred at room temperature for 15 minutes. 6-[(2,6-dimethylphenyl)oxy]-3-pyridinamine (Intermediate 42, 223.8 mg) was added and the reaction mixture was warmed to 60°C.
  • N- ⁇ [(1 , 1-dimethylethyl)oxy]carbonyl ⁇ -D-alanine (193 mg, 1.022 mmol) was dissolved in N,N-dimethylformamide (4 mL) to give a colorless solution.
  • A/-ethyl-A/-(1-methylethyl)-2- propanamine (0.223 mL, 1.277 mmol) and A/-[(1 H-1 ,2,3-benzotriazol-1- yloxy)(dimethylamino)methylidene]-A/-methylmethanaminium tetrafluoroborate (328 mg, 1.022 mmol) were added.
  • the cartridge was washed with 3 CV of methanol, then the compound was adsorbed on the cartridge, washed with 5 CV of methanol and desorbed with 2 CV of methanolic ammonia (1 N). After evaporation of the volatiles, the title compound was obtained (932 mg).
  • N- ⁇ [(1 , 1-dimethylethyl)oxy]carbonyl ⁇ -2-methylalanine (208 mg, 1.022 mmol) was dissolved in N,N-dimethylformamide (4 ml_) to give a colourless solution.
  • reaction mixture was stirred at room temperature for 15 min. 6-[(2- ethylphenyl)oxy]-3-pyridinamine (Intermediate 46, 228 mg) was added and the reaction mixture was warmed to 60°C. After 24 hours, additional 150 mg of A/-[(1 H-1 ,2,3-benzotriazol-1- yloxy)(dimethylamino)methylidene]-A/-methylmethanaminium tetrafluoroborate were added.
  • N- ⁇ [(1 , 1-dimethylethyl)oxy]carbonyl ⁇ -2-methylalanine (204 mg, 1.003 mmol) and N- ethyl-A/-(1-methylethyl)-2-propanamine (0.219 mL, 1.253 mmol) were dissolved in N,N- Dimethylformamide (4 mL) to give a pale yellow solution.
  • reaction mixture was evaporated and purified by silica gel chromatography (Companion system) with a gradient Cyclohexane/EtOAc from 100/0 to 40/60 in 20 minutes and then 40/60 during 15 min to afford the title compound (83 mg).
  • the aqueous phase was extracted twice with dichloromethane (twice 90 mL).
  • the organic phases were combined and washed with brine and dried over anhydrous sodium sulphate. Removal of the solvent afforded a residue which was purified by silica gel chromatography (Biotage system, 100g SNAP column) using as eluent a gradient and cyclohexane/ethyl acetate from 65/35 to 50/50 to afford the title compound as a white solid (1.27 g).
  • the two reactions mixtures A and B were added dropwise to a NaHC0 3 saturated aqueous solution and the pH was adjusted to 7 with the addition of solid NaHC0 3 .
  • the two phases were separated and the aqueous phase was extracted with DCM (1x) and with EtOAc (2x).
  • the combined organic phases were dried and evaporated to dryness to give the title compound in mixture with unreacted starting material (1.48 g) as a black oil. This mixture was used in the next step without further purification.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Addiction (AREA)
  • Anesthesiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
PCT/EP2010/068946 2009-12-11 2010-12-06 Imidazolidinedione derivatives WO2011069951A1 (en)

Priority Applications (45)

Application Number Priority Date Filing Date Title
EP10788314.2A EP2509961B1 (en) 2009-12-11 2010-12-06 Imidazolidinedione derivatives
US13/515,097 US8722695B2 (en) 2009-12-11 2010-12-06 Imidazolidinedione derivatives
DK10788314.2T DK2509961T3 (en) 2009-12-11 2010-12-06 Imidazolidinedione derivatives
CA2781685A CA2781685C (en) 2009-12-11 2010-12-06 Imidazolidinedione derivatives
JP2012542487A JP5788404B2 (ja) 2009-12-11 2010-12-06 イミダゾリジンジオン誘導体
KR1020127018080A KR101735675B1 (ko) 2009-12-11 2010-12-06 이미다졸리딘디온 유도체
AU2010330048A AU2010330048B9 (en) 2009-12-11 2010-12-06 Imidazolidinedione derivatives
ES10788314.2T ES2575215T3 (es) 2009-12-11 2010-12-06 Derivados de imidazolidindiona
BR112012015868A BR112012015868A2 (pt) 2009-12-11 2010-12-06 derivados de imidazolidinadiona
MX2012006615A MX2012006615A (es) 2009-12-11 2010-12-06 Derivados de imidazolidinodiona.
CN201080056084.0A CN102753533B (zh) 2009-12-11 2010-12-06 咪唑烷二酮衍生物
EA201290310A EA019970B8 (ru) 2009-12-11 2010-12-06 Производные имидазолидиндиона
PCT/GB2011/052414 WO2012076877A1 (en) 2010-12-06 2011-12-06 Hydantoin derivatives useful as kv3 inhibitors
PL11805571T PL2649066T3 (pl) 2010-12-06 2011-12-06 Pochodne hydantoiny przydatne jako inhibitory KV3
CA2817205A CA2817205C (en) 2010-12-06 2011-12-06 Hydantoin derivatives useful as kv3 inhibitors
MX2013006343A MX338489B (es) 2010-12-06 2011-12-06 Derivados de hidantoina utiles como inhibidores de kv3.
JP2013542606A JP5913357B2 (ja) 2010-12-06 2011-12-06 Ｋｖ３阻害剤として有用なヒダントイン誘導体
US13/991,486 US9346790B2 (en) 2010-12-06 2011-12-06 Hydantoin derivatives useful as Kv3 inhibitors
CN201180058712.3A CN103328467B (zh) 2010-12-06 2011-12-06 用作kv3抑制剂的乙内酰脲衍生物
EA201390609A EA023768B1 (ru) 2010-12-06 2011-12-06 ПРОИЗВОДНЫЕ ГИДАНТОИНА, ПОЛЕЗНЫЕ В КАЧЕСТВЕ ИНГИБИТОРОВ Kv3-КАНАЛОВ
BR112013013914-5A BR112013013914B1 (pt) 2010-12-06 2011-12-06 Compostos derivados de hidantoína úteis como inibidores de kv3, usos dos referidos compostos e composição farmacêutica compreendendo os mesmos
AU2011340258A AU2011340258C1 (en) 2010-12-06 2011-12-06 Hydantoin derivatives useful as Kv3 inhibitors
EP11805571.4A EP2649066B1 (en) 2010-12-06 2011-12-06 Hydantoin derivatives useful as kv3 inhibitors
DK11805571.4T DK2649066T3 (en) 2010-12-06 2011-12-06 Hydantoin derivatives using as KV3 inhibitors.
ES11805571.4T ES2560304T3 (es) 2010-12-06 2011-12-06 Derivados de hidantoína útiles como inhibidores de Kv3
KR1020137017537A KR101862375B1 (ko) 2010-12-06 2011-12-06 Kv3 억제제로서 유용한 하이단토인 유도체
SG2013035357A SG190203A1 (en) 2010-12-06 2011-12-06 Hydantoin derivatives useful as kv3 inhibitors
ZA2012/03233A ZA201203233B (en) 2009-12-11 2012-05-04 Imidazolidinedione derivatives
IL219628A IL219628A (en) 2009-12-11 2012-05-07 History of imidazolidinedione
HK13103330.8A HK1176353A1 (zh) 2009-12-11 2013-03-18 咪唑烷二酮衍生物
IL226256A IL226256A0 (en) 2010-12-06 2013-05-09 History of hydantoins used as @kv inhibitors
US14/226,988 US9216967B2 (en) 2009-12-11 2014-03-27 Imidazolidinedione derivatives
HK14103468.1A HK1190395A1 (en) 2010-12-06 2014-04-10 Hydantoin derivatives useful as kv3 inhibitors kv3
US14/935,939 US20160058737A1 (en) 2009-12-11 2015-11-09 Imidazolidinedione derivatives
JP2016023519A JP6118927B2 (ja) 2010-12-06 2016-02-10 Ｋｖ３阻害剤として有用なヒダントイン誘導体
US15/093,004 US20160251340A1 (en) 2010-12-06 2016-04-07 Hydantoin derivatives useful as kv3 inhibitors
US15/348,091 US9849131B2 (en) 2009-12-11 2016-11-10 Imidazolidinedione derivatives
US15/621,400 US10265316B2 (en) 2010-12-06 2017-06-13 Hydantoin derivatives useful as Kv3 inhibitors
IL253102A IL253102B (en) 2010-12-06 2017-06-22 History of hydantoins used as kv3 inhibitors
IL253104A IL253104A0 (en) 2010-12-06 2017-06-22 History of hydantoins used as kv3 inhibitors
US15/722,623 US10058551B2 (en) 2009-12-11 2017-10-02 Imidazolidinedione derivatives
US16/049,230 US10632118B2 (en) 2009-12-11 2018-07-30 Imidazolidinedione derivatives
US16/777,668 US20200163964A1 (en) 2009-12-11 2020-01-30 Imidazolidinedione derivatives
US16/985,160 US11197859B2 (en) 2010-12-06 2020-08-04 Hydantoin derivatives useful as Kv3 inhibitors
US17/517,620 US11583527B2 (en) 2010-12-06 2021-11-02 Hydantoin derivatives useful as Kv3 inhibitors

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB0921760.5 2009-12-11
GB0921760A GB0921760D0 (en) 2009-12-11 2009-12-11 Novel compounds
GB1012924.5 2010-07-30
GBGB1012924.5A GB201012924D0 (en) 2010-07-30 2010-07-30 Novel compounds

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US13/515,097 A-371-Of-International US8722695B2 (en) 2009-12-11 2010-12-06 Imidazolidinedione derivatives
US14/226,988 Continuation US9216967B2 (en) 2009-12-11 2014-03-27 Imidazolidinedione derivatives

Publications (1)

Publication Number Publication Date
WO2011069951A1 true WO2011069951A1 (en) 2011-06-16

Family

ID=43446689

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2010/068946 WO2011069951A1 (en) 2009-12-11 2010-12-06 Imidazolidinedione derivatives

Country Status (17)

Country Link
US (7) US8722695B2 (ko)
EP (1) EP2509961B1 (ko)
JP (1) JP5788404B2 (ko)
KR (1) KR101735675B1 (ko)
CN (1) CN102753533B (ko)
AU (1) AU2010330048B9 (ko)
BR (1) BR112012015868A2 (ko)
CA (1) CA2781685C (ko)
DK (1) DK2509961T3 (ko)
EA (1) EA019970B8 (ko)
ES (1) ES2575215T3 (ko)
HK (1) HK1176353A1 (ko)
IL (1) IL219628A (ko)
MX (1) MX2012006615A (ko)
PL (1) PL2509961T3 (ko)
WO (1) WO2011069951A1 (ko)
ZA (1) ZA201203233B (ko)

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012076877A1 (en) * 2010-12-06 2012-06-14 Autifony Therapeutics Limited Hydantoin derivatives useful as kv3 inhibitors
WO2012168710A1 (en) 2011-06-07 2012-12-13 Autifony Therapeutics Limited Hydantoin derivates as kv3 inhibitors
WO2013083994A1 (en) 2011-12-06 2013-06-13 Autifony Therapeutics Limited Hydantoin derivatives useful as kv3 inhibitors
WO2013175211A1 (en) * 2012-05-22 2013-11-28 Autifony Therapeutics Limited Hydantoin derivatives as kv3 inhibitors
WO2013175215A1 (en) * 2012-05-22 2013-11-28 Autifony Therapeutics Limited Triazoles as kv3 inhibitors
WO2013182850A1 (en) 2012-06-06 2013-12-12 Autifony Therapeutics Limited Isobenzofuran- 5 -yl-oxy- (hetero) aryl - imidazolidine - 2, 4 -dione derivatives modulators of kv3 potassium channels for the treatment of cns disorders.
WO2013182851A1 (en) * 2012-06-06 2013-12-12 Autifony Therapeutics Limited Prophylaxis or treatment of diseases where a modulator of kv3.3 channels is required
CN105837453A (zh) * 2016-03-31 2016-08-10 常州大学 一种3,5-二氯-4’-硝基二苯醚的合成方法
WO2016100652A3 (en) * 2014-12-19 2016-08-25 Aragon Pharmaceuticals, Inc. Process for the preparation of a diarylthiohydantoin compound
WO2018109484A1 (en) 2016-12-16 2018-06-21 Autifony Therapeutics Limited Hydantoin modulators of kv3 channels
AU2014312756B2 (en) * 2013-08-29 2018-11-22 Kyoto Pharmaceutical Industries, Ltd. Novel aromatic compound and use thereof
WO2018221667A1 (en) 2017-05-31 2018-12-06 Otsuka Pharmaceutical Co., Ltd. Pyrimidine compound
JP2019506367A (ja) * 2015-12-10 2019-03-07 アウトイフオンイ トヘラペウトイクス リミテッド 疼痛を治療するためのｋｖ３チャネルのモジュレーター
WO2019222816A1 (en) 2018-09-21 2019-11-28 Bionomics Limited Substituted-pyridinyl compounds and uses thereof
WO2020000065A3 (en) * 2019-03-25 2020-02-13 Bionomics Limited Substituted-n-heteroaryl compounds and uses thereof
EP3510016A4 (en) * 2016-11-25 2020-02-26 Siegfried (Nantong) Pharmaceuticals Co. Ltd. METHOD FOR PRODUCING N-BOC-2-AMINO-3,3-DIMETHYLBUTTERIC ACID
WO2020079422A1 (en) 2018-10-16 2020-04-23 Autifony Therapeutics Limited Novel compounds
US10632118B2 (en) 2009-12-11 2020-04-28 Autifony Therapeutics Limited Imidazolidinedione derivatives
WO2020111263A1 (en) 2018-11-30 2020-06-04 Otsuka Pharmaceutical Co., Ltd. Heterocyclic compounds for the treatment of epilepsy
US10934278B2 (en) 2016-07-29 2021-03-02 Autifony Therapeutics Limited Compounds
WO2021156584A1 (en) 2020-02-06 2021-08-12 Autifony Therapeutics Limited Kv3 modulators
GB2594931A (en) * 2020-05-06 2021-11-17 Syngenta Crop Protection Ag Improvements in or relating to organic compounds
US11427549B2 (en) 2017-05-02 2022-08-30 Fmc Corporation Pyrimidinyloxy benzo-fused compounds as herbicides
WO2023017263A1 (en) 2021-08-10 2023-02-16 Autifony Therapeutics Limited Potassium channel modulators

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8519176B1 (en) * 2009-10-05 2013-08-27 Boehringer Ingelheim International Gmbh Process for preparation of substituted P-aminophenol
BR112013007907A2 (pt) 2010-10-08 2016-06-14 N30 Pharmaceuticals Inc novos compostos de quinolina substituída como inibidores de s-nitrosoglutationa reductase
JP6870064B2 (ja) * 2018-11-30 2021-05-12 大塚製薬株式会社 ピリミジン化合物の医薬用途
CN114605331A (zh) * 2022-03-17 2022-06-10 上海健康医学院 一种尼鲁米特及其中间体的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4675403A (en) * 1985-10-16 1987-06-23 American Home Products Corporation 3-Aminoalkyl derivatives of 5,5-disubstituted hydantoins with psychotropic activity
EP0726898B1 (en) * 1993-11-01 2000-12-20 H. Lundbeck A/S Phenylindole compounds

Family Cites Families (62)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1147725A (en) * 1966-03-30 1969-04-02 Mitsui Kagaku Kogyo Kabushiki Novel halodiphenylethers for use as herbicides
US4099007A (en) * 1969-04-02 1978-07-04 Hoechst Aktiengesellschaft N,n-substituted 2,4,5-triketoimidazolidines and a process for their preparation
DE2916647A1 (de) * 1979-04-25 1980-11-06 Basf Ag Parabansaeurederivate
DE3015090A1 (de) 1980-04-19 1981-10-22 Basf Ag, 6700 Ludwigshafen ]-(trihalogenmethyl-sulfenyl)-4-aryl-1,2,4-triazolidin-5-one, verfahren zu ihrer herstellung, diese enthaltende fungizide und verfahren zur bekaempfung von pilzen mit diesen verbindungen
DE3133405A1 (de) 1981-08-24 1983-03-10 Basf Ag, 6700 Ludwigshafen 1-(trihalogenmethyl-sulfenyl)-4-aryl-1,2,4-triazolidin-5-one und diese enthaltende fungizide
JP2514945B2 (ja) 1987-02-05 1996-07-10 三井石油化学工業株式会社 芳香族アミン誘導体
DE3810848A1 (de) 1988-03-30 1989-10-19 Boehringer Ingelheim Kg Neue 2,3,4-substituierte imidazole und 3,4,5-substituierte 1,2,4-triazole, ihre herstellung und verwendung
DE3836175A1 (de) 1988-10-24 1990-05-03 Bayer Ag Fluor enthaltende phenole
MX22406A (es) 1989-09-15 1994-01-31 Pfizer Nuevos derivados de n-aril y n-heteroarilamidas y urea como inhibidores de acil coenzima a: acil transferasa del colesterol (acat).
US5362878A (en) 1991-03-21 1994-11-08 Pfizer Inc. Intermediates for making N-aryl and N-heteroarylamide and urea derivatives as inhibitors of acyl coenzyme A: cholesterol acyl transferase (ACAT)
FR2706456B1 (fr) * 1993-06-18 1996-06-28 Rhone Poulenc Agrochimie Dérivés optiquement actifs de 2-imidazoline-5-ones et 2-imidazoline-5-thiones fongicides.
US6002016A (en) * 1991-12-20 1999-12-14 Rhone-Poulenc Agrochimie Fungicidal 2-imidazolin-5-ones and 2-imidazoline-5-thiones
KR19990014855A (ko) 1995-05-17 1999-02-25 미암리 디, 메코너헤이 살진균성 시클릭 아미드
WO1996036229A1 (en) 1995-05-17 1996-11-21 E.I. Du Pont De Nemours And Company Fungicidal cyclic amides
WO1997000612A1 (en) 1995-06-20 1997-01-09 E.I. Du Pont De Nemours And Company Arthropodicidal and fungicidal cyclic amides
EP0934283A2 (en) 1996-08-01 1999-08-11 E.I. Du Pont De Nemours And Company Arthropodicidal and fungicidal cyclic amides
BR9713415A (pt) 1996-11-26 2000-04-18 Du Pont Método para controlar artrópodes, composto, composição fungicida, composição artropodicida e método para controlar doenças de plantas
WO1998023155A1 (en) 1996-11-26 1998-06-04 E.I. Du Pont De Nemours And Company Arthropodicidal and fungicidal cyclic amides
WO1998033382A1 (en) 1997-01-30 1998-08-06 E.I. Du Pont De Nemours And Company Fungicidal compositions
CA2470183C (en) * 1997-02-21 2008-01-29 Bayer Aktiengesellschaft Intermediates for preparing arylsulphonamides and analogues
JP4171549B2 (ja) 1998-01-28 2008-10-22 大正製薬株式会社 含フッ素アミノ酸誘導体
AR015733A1 (es) * 1998-03-25 2001-05-16 Otsuka Pharma Co Ltd DERIVADO DE PIRIDINA, EL PRODUCTO Y LA COMPOSICIoN FARMACEUTICA QUE CONTIENE DICHO DERIVADO.
JP4194715B2 (ja) 1998-08-31 2008-12-10 大正製薬株式会社 ６−フルオロビシクロ［３．１．０］ヘキサン誘導体
JP2000072731A (ja) 1998-08-31 2000-03-07 Taisho Pharmaceut Co Ltd ４−置換−２−アミノビシクロ［３．１．０］ヘキサン−２，６−ジカルボン酸誘導体及び製薬用組成物
GB9910577D0 (en) * 1999-05-08 1999-07-07 Zeneca Ltd Chemical compounds
AU763976B2 (en) 1999-07-23 2003-08-07 Shionogi & Co., Ltd. Th2 differentiation inhibitors
KR20030009416A (ko) 2000-04-04 2003-01-29 시오노기세이야쿠가부시키가이샤 고지용성 약물을 함유하는 유성 조성물
WO2001076582A1 (fr) 2000-04-05 2001-10-18 Shionogi & Co., Ltd. Micro-emulsions huile dans eau contenant des composes tricycliques ou des preconcentres de ceux-ci
FR2812633A1 (fr) 2000-08-04 2002-02-08 Aventis Cropscience Sa Derives de phenyl(thio)urees et phenyl(thio)carbamates fongicides
GB0026838D0 (en) 2000-11-02 2000-12-20 Glaxo Group Ltd Treatment method
JPWO2003048134A1 (ja) 2001-12-05 2005-04-14 日本たばこ産業株式会社 トリアゾール化合物及びその医薬用途
TW200307539A (en) * 2002-02-01 2003-12-16 Bristol Myers Squibb Co Cycloalkyl inhibitors of potassium channel function
ES2311711T3 (es) 2002-02-07 2009-02-16 The Curators Of The University Of Missouri Compuestos de 4-(3-hidroxifenil) o 4-(3-alcoxifenil)-1,2,4-triazol activos como receptores de opioides.
AU2003242249A1 (en) * 2002-05-16 2003-12-02 Bayer Cropscience Gmbh Pyridine carboxamide derivatives and their use as pesticides
ATE372324T1 (de) 2003-04-30 2007-09-15 Inst For Pharm Discovery Inc Substituierte heteroarylverbindungen als inhibitoren von proteintyrosinphosphatasen
WO2005000309A2 (en) 2003-06-27 2005-01-06 Ionix Pharmaceuticals Limited Chemical compounds
GB0325175D0 (en) 2003-10-28 2003-12-03 Novartis Ag Organic compounds
US7256208B2 (en) 2003-11-13 2007-08-14 Bristol-Myers Squibb Company Monocyclic N-Aryl hydantoin modulators of androgen receptor function
GB0413879D0 (en) 2004-06-21 2004-07-21 Glaxo Group Ltd Compounds
US20060211697A1 (en) 2004-12-08 2006-09-21 Liren Huang 2-(2 Or 4-substituted aryloxy)-phenol derivatives as antibacterial agents
DE102005001411A1 (de) * 2005-01-12 2006-07-27 Sanofi-Aventis Deutschland Gmbh Substituierte 4-Phenyltetrahydroisochinoline, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament, sowie sie enthaltendes Medikament
SG160329A1 (en) 2005-02-18 2010-04-29 Novartis Vaccines & Diagnostic Proteins and nucleic acids from meningitis/sepsis-associated escherichia coli
US7709517B2 (en) 2005-05-13 2010-05-04 The Regents Of The University Of California Diarylhydantoin compounds
KR101169832B1 (ko) 2005-05-13 2012-07-30 더 리전트 오브 더 유니버시티 오브 캘리포니아 디아릴히단토인 화합물
US20100113959A1 (en) 2006-03-07 2010-05-06 Beth Israel Deaconess Medical Center, Inc. Transcranial magnetic stimulation (tms) methods and apparatus
EP3412290B1 (en) 2006-03-27 2021-03-03 The Regents of The University of California Androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases
CN101460467B (zh) 2006-03-29 2012-09-19 加利福尼亚大学董事会 二芳基硫代乙内酰脲化合物
AU2007283113A1 (en) 2006-08-08 2008-02-14 Sanofi-Aventis Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, processes for preparing them, medicaments comprising these compounds, and their use
AU2008242767A1 (en) 2007-04-20 2008-10-30 Deciphera Pharmaceuticals, Llc Kinase inhibitors useful for the treatment of myleoproliferative diseases and other proliferative diseases
EP2242747A1 (de) * 2008-02-07 2010-10-27 Sanofi-Aventis Substituierte imidazolidin-2,4-dione, verfahren zu ihrer herstellung, diese verbindungen enthaltende arzneimittel und ihre verwendung
WO2009097998A1 (de) 2008-02-07 2009-08-13 Sanofi-Aventis Arylchalcogeno-arylalkyl-substituierte imidazolidin-2,4-dione, verfahren zu ihrer herstellung, diese verbindungen enthaltende arzneimittel und ihre verwendung
EP2328928A2 (en) 2008-08-25 2011-06-08 Dana-Farber Cancer Institute, Inc. Conserved influenza hemagglutinin epitope and antibodies thereto
BRPI0924121A2 (pt) 2008-12-22 2019-09-24 Hoffmann La Roche compostos antivirais heterocíclicos
US20120142609A1 (en) 2009-06-26 2012-06-07 Abdoulaye Sene Non human animal models for increased retinal vascular permeability
EA019970B8 (ru) 2009-12-11 2014-11-28 Отифони Терапеутикс Лимитед Производные имидазолидиндиона
AR079440A1 (es) 2009-12-14 2012-01-25 Hoffmann La Roche Compuestos heterociclicos antivirales
BR112013013914B1 (pt) * 2010-12-06 2021-10-26 Autifony Therapeutics Limited Compostos derivados de hidantoína úteis como inibidores de kv3, usos dos referidos compostos e composição farmacêutica compreendendo os mesmos
US8648118B2 (en) 2010-12-17 2014-02-11 Boehringer Ingelheim International Gmbh Bicyclic ring system substituted amide functionalised phenols as medicaments
US8648070B2 (en) 2010-12-17 2014-02-11 Boehringer Ingelheim International Gmbh Bicyclic ring system substituted sulfonamide functionalised phenols as medicaments
WO2012168710A1 (en) * 2011-06-07 2012-12-13 Autifony Therapeutics Limited Hydantoin derivates as kv3 inhibitors
BR112014028718A2 (pt) * 2012-05-22 2017-06-27 Autifony Therapeutics Ltd derivados de hidantoína como inibidores de kv3
EP2852589B1 (en) * 2012-05-22 2021-04-28 Autifony Therapeutics Limited Triazoles as kv3 inhibitors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4675403A (en) * 1985-10-16 1987-06-23 American Home Products Corporation 3-Aminoalkyl derivatives of 5,5-disubstituted hydantoins with psychotropic activity
EP0726898B1 (en) * 1993-11-01 2000-12-20 H. Lundbeck A/S Phenylindole compounds

Non-Patent Citations (41)

* Cited by examiner, † Cited by third party
Title
"Diagnostic and Statistical Manual of Mental Disorders", AMERICAN PSYCHIATRIC ASSOCIATION
"International Classification of Diseases"
ARONIADOU-ANDERJASKA ET AL., AMINO ACIDS, vol. 32, 2007, pages 305 - 315
ATZORI ET AL., NAT. NEUROSCI., vol. 3, 2000, pages 791 - 798
BEN-ARI, CRIT. REV. NEUROBIOL., vol. 18, 2006, pages 135 - 144
BENES ET AL., PNAS, vol. 105, 2008, pages 20935 - 20940
BERGE; BIGHLEY; MONKHOUSE, J.PHARM.SCI, vol. 66, 1977, pages 1 - 19
BRAMBILLA ET AL., MOL. PSYCHIATRY., vol. 8, 2003, pages 721 - 37,715
CHANG ET AL., J. COMP. NEUROL., vol. 502, 2007, pages 953 - 972
CHOW ET AL., J.NEUROSCI., vol. 19, 1999, pages 9332 - 9345
DIOCHOT ET AL., J. BIOL. CHEM., vol. 273, 1998, pages 6744 - 6749
ENGEL ET AL., NAT.REV.NEUROSCI., vol. 2, 2001, pages 704 - 716
ESPINOSA ET AL., J.NEUROSCI., vol. 21, 2001, pages 6657 - 6665
ESPINOSA ET AL., J.NEUROSCI., vol. 28, 2008, pages 5570 - 5581
FISAHN ET AL., J.PHYSIOL, vol. 562, 2005, pages 65 - 72
GOLDMAN; HOLME, DRUG DISCOVERY TODAY, vol. 15, 2010, pages 253 - 255
JOHO ET AL., J.NEUROPHYSIOL., vol. 82, 1999, pages 1855 - 1864
JUNG ET AL., NEUROL. RES., vol. 27, 2005, pages 436 - 440
KACZMAREK ET AL., HEARING RES., vol. 206, 2005, pages 133 - 145
KASTEN ET AL., J.PHYSIOL., vol. 584, 2007, pages 565 - 582
KIMBALL AW; BURNETT WT JR; DOHERTY DG., RADIAT RES., vol. 7, no. 1, 1957, pages 1 - 12
LAU ET AL., J.NEUROSCI., vol. 20, 2000, pages 9071 - 9085
LI ET AL., J. COMP. NEUROL., vol. 437, 2001, pages 196 - 218
MARKRAM ET AL., NAT.REV.NEUROSCI., vol. 5, 2004, pages 793 - 807
MARTINA ET AL., J.NEUROSCI., vol. 18, 1998, pages 8111 - 8125
MCDONALD; MASCAGNI, NEUROSCI., vol. 138, 2006, pages 537 - 547
MCMAHON ET AL., EUR. J.NEUROSCI., vol. 19, 2004, pages 3317 - 3327
REYNOLDS ET AL., NEUROTOX. RES., vol. 6, 2004, pages 57 - 61
RUDY; MCBAIN, TRENDS IN NEUROSCI., vol. 24, 2001, pages 517 - 526
RUDY; MCBAIN, TRENDS IN NEUROSCIENCES, vol. 24, 2001, pages 517 - 526
SACCO ET AL., MOL. CELL. NEUROSCI., vol. 33, 2006, pages 170 - 179
SCHULZ; STEIMER, CNS DRUGS, vol. 23, no. 2, 2009, pages 3 - 13
SONG ET AL., NAT NEUROSCI., vol. 8, 2005, pages 1335 - 1342
SPENCER ET AL., PNAS, vol. 101, 2004, pages 17288 - 17293
STEAN TO; ATKINS AR; HEIDBREDER CA; QUINN LP; TRAIL BK; UPTON N., BR J PHARMACOL., vol. 144, no. 5, 2005, pages 628 - 35
STRUMBOS ET AL., J.NEUROSCIENCE, 2010
TETRAHEDRON, vol. 44, no. 15, 1988, pages 4793 - 6
TETRAHEDRON, vol. 62, no. 42, 2006, pages 9966 - 9972
VON HEHN ET AL., J. NEUROSCI., vol. 24, 2004, pages 1936 - 1940
WEISER ET AL., J.NEUROSCI., vol. 14, 1994, pages 949 - 972
YEUNG ET AL., J.NEUROSCI., vol. 25, 2005, pages 8735 - 8745

Cited By (80)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10632118B2 (en) 2009-12-11 2020-04-28 Autifony Therapeutics Limited Imidazolidinedione derivatives
US10098881B2 (en) 2010-12-06 2018-10-16 Autifony Therapeutics Limited Compounds
EA023768B1 (ru) * 2010-12-06 2016-07-29 Отифони Терапеутикс Лимитед ПРОИЗВОДНЫЕ ГИДАНТОИНА, ПОЛЕЗНЫЕ В КАЧЕСТВЕ ИНГИБИТОРОВ Kv3-КАНАЛОВ
CN103328467A (zh) * 2010-12-06 2013-09-25 奥蒂福尼疗法有限公司 用作kv3抑制剂的乙内酰脲衍生物
US11583527B2 (en) 2010-12-06 2023-02-21 Autifony Therapeutics Limited Hydantoin derivatives useful as Kv3 inhibitors
US11541052B2 (en) 2010-12-06 2023-01-03 Autifony Therapeutics Limited Compounds
US11197859B2 (en) 2010-12-06 2021-12-14 Autifony Therapeutics Limited Hydantoin derivatives useful as Kv3 inhibitors
US10835534B2 (en) 2010-12-06 2020-11-17 Autifony Therapeutics Limited Compounds
JP2013544873A (ja) * 2010-12-06 2013-12-19 アウトイフオンイ トヘラペウトイクス リミテッド Ｋｖ３阻害剤として有用なヒダントイン誘導体
AU2011340258C1 (en) * 2010-12-06 2016-10-20 Autifony Therapeutics Limited Hydantoin derivatives useful as Kv3 inhibitors
EA027532B1 (ru) * 2010-12-06 2017-08-31 Отифони Терапеутикс Лимитед Производные гидантоина, полезные в качестве ингибиторов kv3-каналов
US9833452B2 (en) 2010-12-06 2017-12-05 Autifony Therapeutics Limited Compounds
KR101862375B1 (ko) 2010-12-06 2018-05-29 오티포니 세라피틱스 리미티드 Kv3 억제제로서 유용한 하이단토인 유도체
US9422272B2 (en) 2010-12-06 2016-08-23 Autifony Therapeutics Limited Compounds
JP2016145215A (ja) * 2010-12-06 2016-08-12 アウトイフオンイ トヘラペウトイクス リミテッド Ｋｖ３阻害剤として有用なヒダントイン誘導体
US10555945B2 (en) 2010-12-06 2020-02-11 Autifony Therapeutics Limited Compounds
US10265316B2 (en) 2010-12-06 2019-04-23 Autifony Therapeuctics Limited Hydantoin derivatives useful as Kv3 inhibitors
US20190000849A1 (en) * 2010-12-06 2019-01-03 Autifony Therapeutics Limited Novel compounds
CN103328467B (zh) * 2010-12-06 2016-08-10 奥蒂福尼疗法有限公司 用作kv3抑制剂的乙内酰脲衍生物
US9133175B2 (en) 2010-12-06 2015-09-15 Autifony Therapeutics Limited Compounds
WO2012076877A1 (en) * 2010-12-06 2012-06-14 Autifony Therapeutics Limited Hydantoin derivatives useful as kv3 inhibitors
AU2011340258B2 (en) * 2010-12-06 2016-05-19 Autifony Therapeutics Limited Hydantoin derivatives useful as Kv3 inhibitors
US9346790B2 (en) 2010-12-06 2016-05-24 Autifony Therapeutics Limited Hydantoin derivatives useful as Kv3 inhibitors
US9193704B2 (en) 2011-06-07 2015-11-24 Autifony Therapeutics Limited Hydantoin derivatives as KV3 inhibitors
WO2012168710A1 (en) 2011-06-07 2012-12-13 Autifony Therapeutics Limited Hydantoin derivates as kv3 inhibitors
JP2014516073A (ja) * 2011-06-07 2014-07-07 アウトイフオンイ トヘラペウトイクス リミテッド Ｋｖ３阻害剤としてのヒダントイン誘導体
US20140107139A1 (en) * 2011-06-07 2014-04-17 Autifony Therapeutics Limited Hydantoin derivatives as kv3 inhibitors
CN103596943B (zh) * 2011-06-07 2016-10-12 奥蒂福尼疗法有限公司 用作kv3抑制剂的乙内酰脲衍生物
CN103596943A (zh) * 2011-06-07 2014-02-19 奥蒂福尼疗法有限公司 用作kv3抑制剂的乙内酰脲衍生物
CN103974944A (zh) * 2011-12-06 2014-08-06 奥蒂福尼疗法有限公司 用作kv3抑制剂的乙内酰脲衍生物
WO2013083994A1 (en) 2011-12-06 2013-06-13 Autifony Therapeutics Limited Hydantoin derivatives useful as kv3 inhibitors
JP2015502951A (ja) * 2011-12-06 2015-01-29 アウトイフオンイ トヘラペウトイクス リミテッド Ｋｖ３阻害剤として有用なヒダントイン誘導体
AU2012349847B2 (en) * 2011-12-06 2017-02-16 Autifony Therapeutics Limited Hydantoin derivatives useful as Kv3 inhibitors
US11180461B2 (en) 2012-05-22 2021-11-23 Autifony Therapeutics Limited Triazoles as Kv3 inhibitors
US20150157631A1 (en) * 2012-05-22 2015-06-11 Autifony Therapeutics Limited Hydantoin derivatives as kv3 inhibitors
WO2013175215A1 (en) * 2012-05-22 2013-11-28 Autifony Therapeutics Limited Triazoles as kv3 inhibitors
WO2013175211A1 (en) * 2012-05-22 2013-11-28 Autifony Therapeutics Limited Hydantoin derivatives as kv3 inhibitors
CN104334548A (zh) * 2012-05-22 2015-02-04 奥蒂福尼疗法有限公司 作为kv3抑制剂的乙内酰脲衍生物
US9422252B2 (en) 2012-05-22 2016-08-23 Autifony Therapeutics Limited Triazoles as Kv3 inhibitors
US9669030B2 (en) 2012-05-22 2017-06-06 Autifony Therapeutics Limited Hydantoin derivatives as Kv3 inhibitors
JP2015520764A (ja) * 2012-05-22 2015-07-23 アウトイフオンイ トヘラペウトイクス リミテッド Ｋｖ３阻害剤としてのトリアゾール
CN104334547B (zh) * 2012-05-22 2017-06-06 奥蒂福尼疗法有限公司 作为kv3抑制剂的三唑类
US10611735B2 (en) 2012-05-22 2020-04-07 Autifony Therapeutics Limited Triazoles as Kv3 inhibitors
CN104334547A (zh) * 2012-05-22 2015-02-04 奥蒂福尼疗法有限公司 作为kv3抑制剂的三唑类
US10160730B2 (en) 2012-05-22 2018-12-25 Autifony Therapeutics Limited Triazoles as KV3 inhibitors
JP2015517563A (ja) * 2012-05-22 2015-06-22 アウトイフオンイ トヘラペウトイクス リミテッド Ｋｖ３阻害剤としてのヒダントイン誘導体
WO2013182851A1 (en) * 2012-06-06 2013-12-12 Autifony Therapeutics Limited Prophylaxis or treatment of diseases where a modulator of kv3.3 channels is required
WO2013182850A1 (en) 2012-06-06 2013-12-12 Autifony Therapeutics Limited Isobenzofuran- 5 -yl-oxy- (hetero) aryl - imidazolidine - 2, 4 -dione derivatives modulators of kv3 potassium channels for the treatment of cns disorders.
AU2014312756B2 (en) * 2013-08-29 2018-11-22 Kyoto Pharmaceutical Industries, Ltd. Novel aromatic compound and use thereof
US9688655B2 (en) 2014-12-19 2017-06-27 Janssen Pharmaceutica Nv Process for the preparation of a diarylthiohydantoin compound
CN107108507A (zh) * 2014-12-19 2017-08-29 阿拉贡药品公司 制备二芳基硫代乙内酰脲化合物的方法
WO2016100652A3 (en) * 2014-12-19 2016-08-25 Aragon Pharmaceuticals, Inc. Process for the preparation of a diarylthiohydantoin compound
US11147813B2 (en) 2015-12-10 2021-10-19 Autifony Therapeutics Limited Modulators of KV3 channels to treat pain
JP2019506367A (ja) * 2015-12-10 2019-03-07 アウトイフオンイ トヘラペウトイクス リミテッド 疼痛を治療するためのｋｖ３チャネルのモジュレーター
JP7149847B2 (ja) 2015-12-10 2022-10-07 アウトイフオンイ トヘラペウトイクス リミテッド 疼痛を治療するためのｋｖ３チャネルのモジュレーター
US11944623B2 (en) 2015-12-10 2024-04-02 Autifony Therapeutics Limited Modulators of Kv3 channels to treat pain
JP2022141699A (ja) * 2015-12-10 2022-09-29 アウトイフオンイ トヘラペウトイクス リミテッド 疼痛を治療するためのｋｖ３チャネルのモジュレーター
CN105837453A (zh) * 2016-03-31 2016-08-10 常州大学 一种3,5-二氯-4’-硝基二苯醚的合成方法
US10934278B2 (en) 2016-07-29 2021-03-02 Autifony Therapeutics Limited Compounds
EP3510016A4 (en) * 2016-11-25 2020-02-26 Siegfried (Nantong) Pharmaceuticals Co. Ltd. METHOD FOR PRODUCING N-BOC-2-AMINO-3,3-DIMETHYLBUTTERIC ACID
US10822304B2 (en) 2016-11-25 2020-11-03 Siegfried (Nantong) Pharmaceuticals Co. Ltd. Process for the production of N-Boc-2-amino-3,3-dimethylbutyric acid
WO2018109484A1 (en) 2016-12-16 2018-06-21 Autifony Therapeutics Limited Hydantoin modulators of kv3 channels
US11427549B2 (en) 2017-05-02 2022-08-30 Fmc Corporation Pyrimidinyloxy benzo-fused compounds as herbicides
IL270579B1 (en) * 2017-05-31 2023-04-01 Otsuka Pharma Co Ltd A pyrimidine compound
JP2020503334A (ja) * 2017-05-31 2020-01-30 大塚製薬株式会社 ピリミジン化合物
WO2018221667A1 (en) 2017-05-31 2018-12-06 Otsuka Pharmaceutical Co., Ltd. Pyrimidine compound
EA038907B1 (ru) * 2017-05-31 2021-11-08 Оцука Фармасьютикал Ко., Лтд. Пиримидиновое соединение
CN110603248A (zh) * 2017-05-31 2019-12-20 大塚制药株式会社 嘧啶化合物
KR20200011962A (ko) 2017-05-31 2020-02-04 오츠카 세이야쿠 가부시키가이샤 피리미딘 화합물
US10800758B2 (en) 2017-05-31 2020-10-13 Otsuka Pharmaceutical Co., Ltd. Pyrimidine compound
CN110603248B (zh) * 2017-05-31 2023-07-04 大塚制药株式会社 嘧啶化合物
WO2019222816A1 (en) 2018-09-21 2019-11-28 Bionomics Limited Substituted-pyridinyl compounds and uses thereof
WO2020079422A1 (en) 2018-10-16 2020-04-23 Autifony Therapeutics Limited Novel compounds
KR20210097148A (ko) 2018-11-30 2021-08-06 오츠카 세이야쿠 가부시키가이샤 간질의 치료를 위한 헤테로시클릭 화합물
WO2020111263A1 (en) 2018-11-30 2020-06-04 Otsuka Pharmaceutical Co., Ltd. Heterocyclic compounds for the treatment of epilepsy
JP2022528631A (ja) * 2019-03-25 2022-06-15 バイオノミクス リミテッド 置換ｎ－ヘテロアリール化合物及びその使用
WO2020000065A3 (en) * 2019-03-25 2020-02-13 Bionomics Limited Substituted-n-heteroaryl compounds and uses thereof
WO2021156584A1 (en) 2020-02-06 2021-08-12 Autifony Therapeutics Limited Kv3 modulators
GB2594931A (en) * 2020-05-06 2021-11-17 Syngenta Crop Protection Ag Improvements in or relating to organic compounds
WO2023017263A1 (en) 2021-08-10 2023-02-16 Autifony Therapeutics Limited Potassium channel modulators

Also Published As

Publication number Publication date
KR20120107490A (ko) 2012-10-02
US9849131B2 (en) 2017-12-26
HK1176353A1 (zh) 2013-07-26
US9216967B2 (en) 2015-12-22
EA201290310A1 (ru) 2013-01-30
ZA201203233B (en) 2013-01-30
ES2575215T3 (es) 2016-06-27
AU2010330048A1 (en) 2012-05-31
US8722695B2 (en) 2014-05-13
JP5788404B2 (ja) 2015-09-30
EP2509961B1 (en) 2016-03-09
IL219628A (en) 2014-09-30
AU2010330048B9 (en) 2015-02-19
US20160058737A1 (en) 2016-03-03
CN102753533B (zh) 2014-07-30
AU2010330048B2 (en) 2015-01-22
EA019970B1 (ru) 2014-07-30
EP2509961A1 (en) 2012-10-17
US20120289526A1 (en) 2012-11-15
CA2781685C (en) 2018-09-04
US20180338974A1 (en) 2018-11-29
CA2781685A1 (en) 2011-06-16
DK2509961T3 (en) 2016-05-17
PL2509961T3 (pl) 2016-09-30
US20200163964A1 (en) 2020-05-28
US20150018377A1 (en) 2015-01-15
MX2012006615A (es) 2012-10-05
KR101735675B1 (ko) 2017-05-15
EA019970B8 (ru) 2014-11-28
JP2013513564A (ja) 2013-04-22
CN102753533A (zh) 2012-10-24
IL219628A0 (en) 2012-07-31
US20170065585A1 (en) 2017-03-09
US20180021336A1 (en) 2018-01-25
US10632118B2 (en) 2020-04-28
BR112012015868A2 (pt) 2017-06-20
US10058551B2 (en) 2018-08-28

Similar Documents

Publication Publication Date Title
US10632118B2 (en) Imidazolidinedione derivatives
US11583527B2 (en) Hydantoin derivatives useful as Kv3 inhibitors
CA2856654C (en) Hydantoin derivatives useful as kv3 inhibitors

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 201080056084.0

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10788314

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2010330048

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 219628

Country of ref document: IL

ENP Entry into the national phase

Ref document number: 2781685

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2010330048

Country of ref document: AU

Date of ref document: 20101206

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2010788314

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 201290310

Country of ref document: EA

WWE Wipo information: entry into national phase

Ref document number: 2012542487

Country of ref document: JP

Ref document number: MX/A/2012/006615

Country of ref document: MX

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 13515097

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 1494/KOLNP/2012

Country of ref document: IN

ENP Entry into the national phase

Ref document number: 20127018080

Country of ref document: KR

Kind code of ref document: A

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112012015868

Country of ref document: BR

ENPW Started to enter national phase and was withdrawn or failed for other reasons

Ref document number: 112012015868

Country of ref document: BR

ENPZ Former announcement of the withdrawal of the entry into the national phase was wrong

Ref document number: 112012015868

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 112012015868

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20120612