Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • 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
  • A61K31/4965—Non-condensed pyrazines
  • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
• • 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
  • A61P27/00—Drugs for disorders of the senses
• • 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
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium ( 2 H or D), carbon-11 ( 11 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-15 ( 15 N), oxygen-15 ( 15 0), oxygen-17 ( 17 0), oxygen-18 ( 18 0), phosphorus-32 ( 32 P), sulphur-35 ( 35 S), chlorine-36 ( 36 CI), chlorine-37 ( 37 CI), fluorine-18 ( 18 F) iodine-123 ( 123 l), iodine-125 ( 125 l) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.
• an artificial or uncommon isotopes such as deuterium ( 2 H or D), carbon-11 ( 11 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-15 ( 15 N), oxygen-15 ( 15
• step (i): Compounds of formula (I) can be prepared by metal catalysed cross coupling reactions. In this reaction a halo-pyrazine derivative of formula (II) wherein typically X Br and a hydantoin of formula (III) are reacted in the presence of a metal catalyst such as copper(l) oxide in a suitable solvent, e.g. in N,N-dimethylacetamide, with conventional heating or microwave heating.
• a metal catalyst such as copper(l) oxide
• suitable solvent e.g. in N,N-dimethylacetamide
• a suitable base e.g. triethylamine or diisopropylethylamine at temperature ranging from 0
• a metal catalyst such as palladium (II) acetate
• a suitable ligand such as Xantphos
• a suitable base such as cesium carbonate
• step (i) Compounds of formula (XIII) can be prepared from N-protected (e.g.
• the compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates and/or derivatives thereof demonstrate comparable activity between modulation of Kv3.1 and Kv3.2 channels, for example the activity for one channel is less than 2 fold that for the other channel, such as less than 1.5 fold or less than 1.2 fold.
• the compounds of formula (I) or their pharmaceutically acceptable salts and/or solvates (e.g. salts) and/or derivatives thereof 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
• administration of the compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof may be initiated up to 2 months after an event which is anticipated to cause noise-induced acute hearing loss, such as up to 1 month, 2 weeks, 1 week, 6 days, 5 days, 4 days, 3 days, 2 days, 24 h, 12 h, 6 h, 5 h, 4 h, 3 h, 2 h, 1 h, 30 minutes or up to 15 minutes after an event which is anticipated to cause acute noise-induced hearing loss.
• the compound of formula (I) or a pharmaceutically acceptable salt, solvate and/or derivative thereof may be administered on multiple occasions after an event which is anticipated to cause noise-induced acute hearing loss.
• 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.
• compositions suitable for transdermal administration include ointments, gels and patches.
• the composition is in unit dose form such as a tablet, capsule or ampoule.
• a compound of formula (I) or a pharmaceutically acceptable, salt, solvate and/or derivative thereof is administered once or twice per day.
• a compound of formula (I) or a pharmaceutically acceptable, salt, solvate and/or derivative thereof is administered orally, once or twice per day, at 2 to 400 mg per day, such as 2 to 300 mg per day, especially 5 to 250 mg per day.
• methyl 2-amino-2-methyl-propanoate hydrochloride (1.4g, 9.1 mmol) was added at 0°C and the reaction mixture was stirred for 30 minutes at the same temperature. The reaction was quenched with a solution 0.2 N of HCI (100 ml) and the two phases were separated. The organic layer was washed with brine (100 ml), dried over Na 2 SC>4, filtered and evaporated affording the urea intermediate.
• reaction was performed in three different runs using about 20g of starting material each.
• General procedure to a mixture of methyl 1-(2,6-dibenzyloxyohenyl)cyclopropanecarboxylate (Intermediate 26, 20.4g, 52.52mmol) and palladium 5% wt. on carbon (1.02g) in ethanol (200ml), ammonium formate (16.56g, 262.6mmol) was added and the reaction mixture was stirred at 80°C for 1 hour. After cooling, the catalyst was filtered off on a cellulose pad and the filtrate was concentrated under vacuum up to ⁇ 20ml.
• a stable cell line expressing human Kv3.2 channels (hKv3.2) is created by transfecting CHO-K1 cells with a pCIH5-hKv3.2 vector.
• Cells are cultured in DMEM/F12 medium supplemented by 10% Foetal Bovine Serum, 1X non-essential amino acids (Invitrogen) and 500ug/ml of Hygromycin-B (Invitrogen). Cells are grown and maintained at 37 °C in a humidified environment containing 5% CO2 in air.
• the recordings are analysed and filtered using both seal resistance (>20 MW) and peak current amplitude (>500 pA at the voltage step of 40 mV) in the absence of compound to eliminate unsuitable cells from further analysis.
• seal resistance >20 MW
• peak current amplitude >500 pA at the voltage step of 40 mV
• paired comparisons of evoked currents between pre- and post-drug additions measured for the -15 mV voltage step are used to determine the positive modulation effect of each compound.
• Kv3 channel-mediated outward currents are measured determined from the mean amplitude of the current over the final 10 ms of the -15 mV voltage pulse minus the mean baseline current at -70 mV over a 10 ms period just prior to the -15 mV step.
• Kv3.1 , Kv3.2 and Kv3.3 channels must activate and deactivate very rapidly in order to allow neurons to fire actions potentials at high frequency (Rudy et ai, 2001). Slowing of activation is likely to delay the onset of action potential repolarisation; slowing of deactivation could lead to hyperpolarising currents that reduce the excitability of the neuron and delay the time before the neuron can fire a further action potential. Together these two slowing effects on channel activation and deactivation are likely to lead to a reduction rather than a facilitation of the neurons ability to fire at high frequencies.
• S9 mix was prepared by the addition of S9 (10% v/v) to a NADPH generating system, which included NADP (3.15 mg/ml_), glucose 6 phosphate (1.5 mg/ml_), and 2% v/v of a saline solution containing MgCh (81.3 mg/ml_) and KCI (123 mg/ml_) in phosphate buffer pH 7.4.
• S9 mix was used at a final volume of 500 uL/plate.
• an equivalent volume of sterile phosphate buffer pH 7.4 was added in place of the S9 mix.
• test article precipitation At the end of the incubation period, plates were evaluated (by visual examination) for test article precipitation. Plates were scored electronically for bacterial colony formation using the colony counter ProtoCOL3 Synbiosis. Where test article precipitation occurred, the bacterial colony count for each strain was performed manually and halted at the lowest treatment concentration that did not interfere with the manual scoring.
• Clause 4 The compound according to any one of clauses 1 to 3, wherein R and R 3 are a spiro cyclopropyl ring.
• Clause 7 The compound according to any one of clauses 1 to 5, wherein R is ethyl.
• Clause 10 The compound according to any one of clauses 1 to 9 wherein when R 4 and R 5 are different and they have the following stereochemical arrangement:
• Clause 11 The compound according to any one of clauses 1 to 9 wherein when R 4 and R 5 are different and they have the following stereochemical arrangement:
• Clause 12 The compound according to any one of clauses 1 to 5, wherein R 4 and Rs, together with the carbon atom to which they are attached, form a spirocyclopropyl.
• Clause 13 The compound according to any one of clauses 1 to 5, wherein R and R 5 , together with the carbon atom to which they are attached, form a spirocyclobutyl.
• Clause 59 The compound, method, use, composition or derivative according to any one of clauses 1 to 48 or 52 to 58 for administration for a period of at least three months.
• Clause 63 The compound, method, use, composition or derivative according to clause 60 to a human subject of less than 18 years of age, such as 4 to 17 years old.
• Figueroa K et al. KCNC3 phenotype, mutations, channel biophysics - a study of 260 familial ataxia patients. Human Mutation. 2010;31;191-196.
• Roberts L et al. Ringing Ears The Neuroscience of Tinnitus. J. Neurosci. 2010:30(45);14972- 14979.

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