WO2000034248A1 - New benzimidazolone-, benzoxazolone-, or benzothiazolone derivatives as ion channel modulating agents - Google Patents

New benzimidazolone-, benzoxazolone-, or benzothiazolone derivatives as ion channel modulating agents Download PDF

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WO2000034248A1
WO2000034248A1 PCT/DK1999/000681 DK9900681W WO0034248A1 WO 2000034248 A1 WO2000034248 A1 WO 2000034248A1 DK 9900681 W DK9900681 W DK 9900681W WO 0034248 A1 WO0034248 A1 WO 0034248A1
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group
disease
chemical compound
represents hydrogen
compound according
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English (en)
French (fr)
Inventor
Lene Teuber
Palle Christophersen
Dorte Strøbæk
Bo Skaaning Jensen
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NTG Nordic Transport Group AS
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Neurosearch AS
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Priority to NZ511334A priority Critical patent/NZ511334A/xx
Priority to AU15498/00A priority patent/AU760250B2/en
Priority to EP99957967A priority patent/EP1144387A1/en
Priority to CA002349616A priority patent/CA2349616A1/en
Priority to JP2000586696A priority patent/JP2002531552A/ja
Publication of WO2000034248A1 publication Critical patent/WO2000034248A1/en
Priority to US09/854,357 priority patent/US6624186B2/en
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Definitions

  • Ion channels are transmembrane proteins, which catalyse the transport of inorganic ions across cell membranes.
  • the ion channels participate in processes as diverse as the generation and timing of action potentials, synaptic transmissions, 0 secretion of hormones, contraction of muscles, etc.
  • anti-epileptic compounds like Phenytoin and Lamotrigine, which block voltage dependent Na + -channels in the brain
  • anti-hypertensive drugs like Nifedipine and Diltiazem
  • 5 stimulators of insulin release like Giibenclamide and Tolbutamide, which block an ATP-regulated K + -channel in the pancreas.
  • K + potassium channels
  • nerve and muscle cells they regulate the frequency and form of the action 0 potential, the release of neurotransmitters, and the degree of broncho- and vasodilation.
  • K + channels represent the largest and most diverse group of ion channels. For an overview they can be divided into five large subfamilies: Voltage-activated K + channels (K v ), long QT related K + channels
  • KvLQT inward rectifiers
  • KIR inward rectifiers
  • K T p two-pore K + channels
  • K ca calcium-activated K + channels
  • the latter group the Ca 2+ -activated K + channels, consists of three well- defined subtypes: SK channels, IK channels and BK channels.
  • SK, IK and BK refer to the single-channel conductance (Small, Intermediate and Big conductance K channel).
  • the SK, IK, and BK channels exhibit differences in e.g. voltage- and calcium-sensitivity, pharmacology, distribution and function.
  • Ca 2+ -activated SK channels are present in many central neurons and ganglia, where their primary function is to hyperpolarize nerve cells following one or several action potentials to prevent long trains of epileptogenic activity to occur.
  • SK channels are also present in several peripheral cells including skeletal muscle, gland cells, liver cells, and T-lymphocytes.
  • SK channels in the muscle of patients with myotonic muscle dystrophia suggest a role in the pathogenesis of the disease.
  • Ca 2+ -activated SK channel since it is highly K-selective, is activated by sub- micromolar concentrations of Ca 2+ , and has an inwardly rectifying conductance.
  • the unit conductance of the IK channel is 4-5 fold higher than that of the SK channel, and the distribution of the IK channel is restricted to the blood and vasculature.
  • the IK channel is not expressed in the nervous system and in muscle, but in endothelial cells, cells of epithelial origin and in red blood cells.
  • IK channels have also been implicated in the microvasculature of the kidney, where they may be responsible for the vasodilatory effects of bradykinin.
  • the decrease in blood pressure during septic shock is caused by an increased NO production by the endothelial cells, and the IK channels in these cells are responsible for maintaining the Ca 2+ influx activating the Ca 2+ -sensitive NO-synthase.
  • the Ca 2+ -activated BK channels present in many cells including most central and peripheral nerve cells, striated muscle cells, cardiac cells, smooth muscle cells of the airways, the vasculature, the gastrointestinal tract and bladder, in endo- and exocrine glands including pancreatic b-cells and in kidney tubules.
  • R 3 , R 4 and R 5 independently of each another represents hydrogen; halogen; -NO 2 ; -CN; -CF 3 ; an alkyl group; an alkoxy group; a phenyl or a benzyl group, which phenyl and benzyl groups may be substituted one or more times with substituents selected from halogen, -NO 2 , -CN, -CF 3 , alkyl, cycloalkyl, hydroxy, and alkoxy; or a group of the formula -SO 2 NR"R'", wherein R" and R'" independently of each another represents hydrogen or an alkyl group; or R 5 is as defined above and R 3 and R 4 together form an additional 4 to 7 membered fused ring, which fused ring may be aromatic or partially saturated, and which fused ring may optionally be substituted one or more times with substituents selected from the group consisting of halogen, -NO 2 , -CN, -CF 3 , or
  • the invention relates to the use of a chemical compound of the invention for the manufacture of a pharmaceutical composition for the treatment or alleviation of a disorder or a disease or a condition of a mammal, including a human, which disorder, disease or condition is responsive to modulation of SKc a , IKca and/or BKc a channels.
  • the invention provides a method for the treatment or alleviation of disorders or diseases or conditions of a living animal body, including a human, which disorder, disease or conditions are responsive to modulation of SK Ca , IKca and/or BKca channels, comprising the step of administering to such a living animal body, including a human, in need thereof a therapeutically effective amount of a compound of the invention.
  • R 3 and R 4 together form a 5- or 6- membered fused ring, which fused ring may be a heterocyclic ring, it may be an aromatic, saturated or partially saturated ring, and which fused ring may optionally be substituted one or more times with substituents selected from the group consisting of halogen, -NO 2 , -CN, -CF 3 , or a group of the formula -SO 2 NR"R'", wherein R" and R'" independently of each another represents hydrogen or an alkyl group.
  • R 1 , R 2 , R 5 and X are as defined above; and Y represents hydrogen, halogen, -NO 2 , -CN, -CF 3 , or a group of the formula -SO 2 NR"R'", wherein R" and R'" independently of each another represents hydrogen or an alkyl group.
  • the compound of the invention is a chemical compound of formula II, wherein R 1 represents hydrogen or an alkyl group.
  • the chemical compound of the invention is represented by formula I, in which R 3 and R 4 together form a 5-membered heterocyclic fused ring, which fused ring may optionally be substituted one or more times with substituents selected from the group consisting of halogen, -NO 2 , -CN, - CF 3 .
  • the heterocyclic ring is a 1 ,2 or 4-imidazolyl, 1 ,2,3,4- or 2,1 ,3,4-tetrazolyl, thiadiazol-3,4 or 5-yl, thiazol-2,4 or 5-yl, 2 or 3-thienyl.
  • an acyl group designates a carboxy group or an alkylcarbonyl group, wherein alkyl is as defined above.
  • alkyl is as defined above.
  • preferred acyl groups of the invention are carboxy, acetyl, and propionyl.
  • Examples of preferred aromatic heterocyclic monocyclic groups of the invention include 1 ,3,2,4- or 1 ,3,4,5-dioxadiazolyl, dioxatriazinyl, dioxazinyl, 1 ,2,3-, 1 ,2,4-, 1 ,3,2- or 1 ,3,4-dioxazolyl, 1 ,3,2,4- or 1 ,3,4,5-dithiadiazolyl, dithiatriazinyl, dithiazinyl, 1 ,2,3-dithiazolyl, 2- or 3-furanyl, furazanyl, 1 ,2 or 4-imidazolyl, isoindazolyl, isothiazoI-3,4 or 5-yl, isoxazol-3,4 or 5-yl, 1 ,2,3-, 1 ,2,4-, 1 ,2,5- or 1 ,3,4- oxadiazol-3,4 or 5-yl, oxatetrazinyl, oxatri
  • the chemical compounds of the present invention may also be resolved by the formation of diastereomeric amides by reaction of the chemical compounds of the present invention with an optically active activated carboxylic acid such as that derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) camphanic acid or by the formation of diastereomeric carbamates by reaction of the chemical compound of the present invention with an optically active chloroformate or the like.
  • an optically active activated carboxylic acid such as that derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) camphanic acid
  • the compounds of the invention is considered particularly useful for reducing or inhibiting undesired immunoregulatory actions.
  • the compounds of the may be used in the treatment or alleviation of a diseases, disorders or condition related to immune dysfunction, or in order to obtain immune suppression in an individual in need herefore.
  • the invention relates to the use of a compound of the invention in a combination therapy with known immune- suppressants for the treatment or alleviation of a diseases, disorders or condition related to immune dysfunction, or for obtaining immune suppression.
  • Preferred immune-suppressants to combine with the compounds of the invention include the calcineurin inhibitors (i.e. protein phosphatase 2B inhibitors), in particular Cyclosporin, and FK506.
  • compositions of the invention may be those suitable for oral, rectal, bronchial, nasal, topical (including buccal and sub-lingual), transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, and intravenous injection) administration, or those in a form suitable for administration by inhalation or insufflation.
  • the chemical compound of the invention, together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof.
  • Such forms include solids, and in particular tablets, filled capsules, powder and pellet forms, and liquids, in particular aqueous or non-aqueous solutions, suspensions, emulsions, elixirs, and capsules filled with the same, all for oral use, suppositories for rectal administration, and sterile injectable solutions for parenteral use.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • the chemical compound of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a chemical compound of the invention or a pharmaceutically acceptable salt of a chemical compound of the invention.
  • the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glyceride or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.
  • Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Liquid preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions.
  • parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
  • compositions suitable for topical administration in the mouth include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
  • the compositions may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomising spray pump.
  • Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • CFC chlorofluorocarbon
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by provision of a metered valve.
  • the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • a powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
  • the compound In compositions intended for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
  • ED50 and LD 5 may be determined by standard pharmacological procedures in cell cultures or experimental animals.
  • the dose ratio between therapeutic and toxic effects is the therapeutic index and may be expressed by the ratio LD 50 /ED 50 .
  • compositions which exhibit large therapeutic indexes are preferred.
  • compositions containing of from about 0.1 to about 500 mg of active ingredient per individual dose, preferably of from about 1 to about 100 mg, most preferred of from about 1 to about 10 mg, are suitable for therapeutic treatments.
  • the active ingredient may be administered in one or several doses per day.
  • a satisfactory result can, in certain instances, be obtained at a dosage as low as 0.1 ⁇ g/kg i.v. and 1 ⁇ g/kg p.o.
  • the upper limit of the dosage range is presently considered to be about 10 mg/kg i.v. and 100 mg/kg p.o.
  • Preferred ranges are from about 0.1 ⁇ g/kg to about 10 mg/kg/day i.v., and from about 1 ⁇ g/kg to about 100 mg/kg/day p.o.
  • the disease, disorder or condition is asthma, cystic fibrosis, chronic obstructive pulmonary disease and rhinorrhea, convulsions, vascular spasms, coronary artery spasms, renal disorders, polycystic kidney disease, bladder spasms, urinary incontinence, bladder outflow obstruction, irritable bowel syndrome, gastrointestinal dysfunction, secretory diarrhoea, ischaemia, cerebral ischaemia, ischaemic hearth disease, angina pectoris, coronary hearth disease, traumatic brain injury, psychosis, anxiety, depression, dementia, memory and attention deficits, Alzheimer's disease, dysmenorrhea, narcolepsy, Reynaud's disease, intermittent claudication, Sjorgren's syndrome, migraine, arrhythmia, hypertension, absence seizures, myotonic muscle dystrophia, xerostomi, diabetes type II, hyperinsulinemia, premature labour, baldness, cancer, and immune suppression.
  • 1-(Acetylamino)-2-nitro-5, 6,7,8- tetrahydronaphtalene (2.5 g; 10.7 mmol) was suspended in a mixture of dimethoxyethane (30 ml) and aqueous sodium hydroxide (32 ml, 1 M). The mixture was heated to reflux for 2 hours. After cooling two volumes of ice-water was added, and the mixture was neutralised by addition of hydrochloric acid (32 ml, 1 M).
  • Naphto[1,2-d]oxazolinone (2e) When 1-(acetylamino)-4-bromo-2-nitronaphtalene was treated with aqueous sodium hydroxide as described above the product was 4- bromo-2-nitro-1-naphtol - i.e. substitution occurred instead of hydrolysis. Subsequent hydrogenation and treatment with urea yielded naphto[1 ,2-d]oxazoline in 44% overall yield.
  • the biological activity of the compounds of the invention is demonstrated using electrophysiologic patch-clamp techniques.
  • IK channels Intermediate-conductance Ca 2+ -activated K + channels
  • HEK293 tissue culture cells were grown in DMEM (Dulbecco's Modified
  • FCS calcium calf serum
  • the lipofection mixture was overlaid on the cells and incubated at 37°C for 5 hours. The cells were then rinsed with regular media and grown for 72 hours in DMEM, 10% FCS at 37°C in 5% CO 2 .
  • cells transfected with pNS1Z_hlK were selected in media supplemented with 0.25mg/ml Zeocin. Single clones were picked and propagated in selection media until sufficient cells for freezing were available. Hereafter the cells were cultured in regular medium without selection agent.
  • the whole-cell configuration of the patch clamp technique is applied.
  • the tip of a borosilicate pipette (resistance 2-4 M ⁇ ) is gently (remote control system) placed on the cell membrane.
  • Light suction results in a giga seal (pipette resistance increases to more than 1 G ⁇ ) and the cell membrane is then ruptured by more powerful suction.
  • Cell capacitance is electronically compensated and the resistance between the pipette and the cell interior (the series resistance, Rs) is measured and compensated for.
  • the cell capacitance ranges from 5 to 20 pF (depending on cell size) and the series resistance is in the range 3 to 6 M ⁇ .
  • Rs- as well as capacitance compensation are updated during the experiments (before each stimulus).

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PCT/DK1999/000681 1998-12-04 1999-12-03 New benzimidazolone-, benzoxazolone-, or benzothiazolone derivatives as ion channel modulating agents Ceased WO2000034248A1 (en)

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NZ511334A NZ511334A (en) 1998-12-04 1999-12-03 Benzimidazolone derivatives useful as ion channel modulating agents
AU15498/00A AU760250B2 (en) 1998-12-04 1999-12-03 New benzimidazolone-, benzoxazolone-, or benzothiazolone derivatives as ion channel modulating agents
EP99957967A EP1144387A1 (en) 1998-12-04 1999-12-03 New benzimidazolone-, benzoxazolone-, or benzothiazolone derivatives as ion channel modulating agents
CA002349616A CA2349616A1 (en) 1998-12-04 1999-12-03 New benzimidazolone-, benzoxazolone-, or benzothiazolone derivatives as ion channel modulating agents
JP2000586696A JP2002531552A (ja) 1998-12-04 1999-12-03 イオンチャネル調節剤としての新規ベンズイミダゾロン−、ベンズオキサゾロン−又はベンゾチアゾロン−誘導体
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WO2002066426A3 (en) * 2001-02-20 2002-11-21 Bristol Myers Squibb Co Fluoro oxindole derivatives as modulators of kcnq potassium channels
WO2002053171A3 (de) * 2000-12-28 2003-03-20 Switch Biotech Ag Verwendung von 'intermediate-conductance kaliumkanälen und modulatoren zur diagnose und behandlung von krankheiten mit gestörter keratinozytenaktivität
WO2004035037A3 (en) * 2002-10-21 2004-06-03 Univ Ramot Derivatives of n-phenylanthranilic acid and 2-benzimidazolon as potassium channel and/or cortical neuron activity modulators
WO2004064835A1 (en) * 2003-01-17 2004-08-05 Neurosearch A/S Use of ion channel modulating agents for treating pain
WO2004039409A3 (de) * 2002-10-31 2004-09-10 Switch Biotech Ag Zusammensetzung enthaltend aktivatoren von ik-kaliumkanälen und calcineurin-antagonisten und deren verwendung
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US7632866B2 (en) 2002-10-21 2009-12-15 Ramot At Tel Aviv University Derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel and/or neuron activity modulators
EP2583678A2 (en) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Small molecule immunopotentiators and assays for their detection
WO2013063459A1 (en) * 2011-10-28 2013-05-02 Merck Sharp & Dohme Corp. Benzoxazolinone compounds with selective activity in voltage-gated sodium channels
WO2014067861A1 (en) * 2012-10-29 2014-05-08 F. Hoffmann-La Roche Ag 3,4-disubstituted oxazolidinone derivatives and their use as inhibitors of the calcium activated potassium channel
US8765815B2 (en) 2007-09-20 2014-07-01 Ramot At Tel-Aviv University Ltd. N-phenyl anthranilic acid derivatives and uses thereof
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US9271978B2 (en) 2012-12-21 2016-03-01 Zenith Epigenetics Corp. Heterocyclic compounds as bromodomain inhibitors
US9278940B2 (en) 2012-11-21 2016-03-08 Zenith Epigenetics Corp. Cyclic amines as bromodomain inhibitors
US9663520B2 (en) 2013-06-21 2017-05-30 Zenith Epigenetics Ltd. Bicyclic bromodomain inhibitors
US9765039B2 (en) 2012-11-21 2017-09-19 Zenith Epigenetics Ltd. Biaryl derivatives as bromodomain inhibitors
US9855271B2 (en) 2013-07-31 2018-01-02 Zenith Epigenetics Ltd. Quinazolinones as bromodomain inhibitors
US10179125B2 (en) 2014-12-01 2019-01-15 Zenith Epigenetics Ltd. Substituted pyridines as bromodomain inhibitors
US10231953B2 (en) 2014-12-17 2019-03-19 Zenith Epigenetics Ltd. Inhibitors of bromodomains
US10292968B2 (en) 2014-12-11 2019-05-21 Zenith Epigenetics Ltd. Substituted heterocycles as bromodomain inhibitors
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WO2002017963A3 (en) * 2000-09-01 2002-08-01 Pfizer Ltd Modulators of intermediate conductance calcium-activated potassium (ikca) channel activity for treating sexual dysfunction
WO2002053171A3 (de) * 2000-12-28 2003-03-20 Switch Biotech Ag Verwendung von 'intermediate-conductance kaliumkanälen und modulatoren zur diagnose und behandlung von krankheiten mit gestörter keratinozytenaktivität
WO2002066426A3 (en) * 2001-02-20 2002-11-21 Bristol Myers Squibb Co Fluoro oxindole derivatives as modulators of kcnq potassium channels
US7022480B1 (en) 2001-10-11 2006-04-04 The Regents Of The University Of California Exons of the hSKCa3/KCNN3 gene
US7002021B2 (en) 2002-07-10 2006-02-21 Clariant Gmbh Diketopyrrolopyrrole pigments
US8278357B2 (en) 2002-10-21 2012-10-02 Ramot At Tel-Aviv University Ltd. Derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel and/or neuron activity modulators
US8618169B2 (en) 2002-10-21 2013-12-31 Ramot At Tel-Aviv University Ltd. Derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel and/or neuron activity modulators
WO2004035037A3 (en) * 2002-10-21 2004-06-03 Univ Ramot Derivatives of n-phenylanthranilic acid and 2-benzimidazolon as potassium channel and/or cortical neuron activity modulators
US7632866B2 (en) 2002-10-21 2009-12-15 Ramot At Tel Aviv University Derivatives of N-phenylanthranilic acid and 2-benzimidazolone as potassium channel and/or neuron activity modulators
AU2005201685B2 (en) * 2002-10-21 2008-10-09 Ramot At Tel Aviv University Ltd. Derivatives of N-Phenylanthranilic Acid and 2-Benzimidazolon as Potassium Channel and/or Cortical Neuron Activity Modulators
WO2004039409A3 (de) * 2002-10-31 2004-09-10 Switch Biotech Ag Zusammensetzung enthaltend aktivatoren von ik-kaliumkanälen und calcineurin-antagonisten und deren verwendung
WO2004064835A1 (en) * 2003-01-17 2004-08-05 Neurosearch A/S Use of ion channel modulating agents for treating pain
US7176214B2 (en) 2003-05-21 2007-02-13 Bristol-Myers Squibb Company Imidazo-fused oxazolo[4,5-β]pyridine and imidazo-fused thiazolo[4,5-β]pyridine based tricyclic compounds and pharmaceutical compositions comprising same
EP2583678A2 (en) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Small molecule immunopotentiators and assays for their detection
EP1958947A1 (en) 2007-02-15 2008-08-20 Ranbaxy Laboratories Limited Inhibitors of phosphodiesterase type 4
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US8765815B2 (en) 2007-09-20 2014-07-01 Ramot At Tel-Aviv University Ltd. N-phenyl anthranilic acid derivatives and uses thereof
US9913828B2 (en) 2011-09-06 2018-03-13 Novartis Ag Benzothiazolone compound
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EA026161B1 (ru) * 2012-10-29 2017-03-31 Ф. Хоффманн-Ля Рош Аг Производные 3,4-дизамещенного оксазолидинона и их применение в качестве ингибиторов кальций-активируемых калиевых каналов
US9611232B2 (en) 2012-10-29 2017-04-04 Hoffmann-La Roche Inc. Oxazolidinone and imidazolidinone compounds
US9278940B2 (en) 2012-11-21 2016-03-08 Zenith Epigenetics Corp. Cyclic amines as bromodomain inhibitors
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US11446306B2 (en) 2013-06-21 2022-09-20 Zenith Epigenetics Ltd. Bicyclic bromodomain inhibitors
US9662311B2 (en) 2013-06-21 2017-05-30 Zenith Epigenetics Ltd. Substituted bicyclic compounds as bromodomain inhibitors
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US20020055526A1 (en) 2002-05-09
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JP2002531552A (ja) 2002-09-24
CN1329601A (zh) 2002-01-02
AU1549800A (en) 2000-06-26
AU760250B2 (en) 2003-05-08
US20040029937A1 (en) 2004-02-12
EP1144387A1 (en) 2001-10-17
CA2349616A1 (en) 2000-06-15
NZ511334A (en) 2003-06-30

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